Monday, February 22, 2016

The new CHEST guidelines for antithrombotic therapy

This go round the update is being handled a bit differently it would seem, by releasing one section at a time.  As of now only the section on VTE treatment has been posted, and the full text can be accessed here.  The rest of the guidelines, e.g. those for antiplatelet therapy and VTE prevention, will, I'm guessing, be posted later, a section at a time.

Retired Doc has already written a nice summary post which you can access here.

For my own take, I'll highlight the major changes and comment on some other points of particular interest.  In this edition as in previous ones the authors are true to the first principle of evidence based medicine (EBM) which is that the ultimate decision maker for treatment is the patient, providing he or she wants to be, as opposed to some pathway, core measure or central controlling authority.  This is illustrated by phrases throughout the paper, often used after their recommendation statements, to the effect that the patient may choose this over that treatment.  The document is well referenced and the recommendations seem based on careful consideration of the evidence.  Those good things being said, the paper is also a masterpiece of obfuscation, examples of which I will point out along the way.  Although there is some sense to be made of it (as I try to provide in plain language below) the process of doing so was very difficult.  The guideline is worth reading in the original text but do so when you are rested, fed and have plenty of time.

The 2012 definitions for duration of therapy are maintained.

Somewhere along the line, in 2012 I believe, the guideline authors changed the category definitions for VTE treatment duration.  They have now been around for a while but, I believe, still confuse clinicians.  The old classification seemed pretty straightforward:  short term (3 months, mainly for patients with transient risk factors), usual (6 months, appropriate for most patients with spontaneous events) and indefinite (potentially for the rest of the patient's life, for those with especially high risk of recurrence).   But the current classification turns that all around.  “Long term” is now defined as 3 months of treatment.  The middle category, “longer, time limited” is defined as 6-12 months.  The third category, termed “extended,” could be any time of longer than 3 months but without a scheduled stop date.  At the risk of pushing this to absurdity extended treatment could be as little as 3 months and one day, meaning that the order of this listing is not necessarily in order of treatment duration though it is implicit in the discussions in the paper that “extended” usually means longer than a year.

So what are the recommended durations of treatment for various clinical circumstances?

For VTE (for purposes of this post that means DVT and/or PE) not associated with active cancer and associated with a transient risk factor, surgical or otherwise, the guideline calls for 3 months treatment.  The strength of the statement (we recommend versus we suggest) varies with bleeding risk but the guideline always prefers 3 months over longer time limited or extended. 

For VTE not associated with active cancer and not associated with a transient risk factor, the order of preference for duration is extended preferred over 3 months which in turn is preferred over longer time limited (see the one exception below).  It is really difficult to make sense of this when, in plain language, it says “potentially for the rest of your life” is choice number 1, 3 months is choice number 2 and 6-12 months is choice number 3.  That is, the descending order of preference does not equal the descending order of duration!  The exception is that if the bleeding risk is high (I'll explain how the guideline defines that later) 3 months of treatment is the preference over the other two options.

To add to the confusion (and perhaps the entertainment value) of the guideline check out this statement from section 9 regarding the decision making process for patients who are potential candidates for extended (as opposed to 3 month) treatment:

Patient sex and D-dimer level measured a month after stopping anticoagulant therapy may influence the decision to stop or extend anticoagulant therapy..

But a month after stopping, well, you've already stopped!  It's almost comical when you think about it.  The plain language version would be stop treatment, wait a while, then run a test to see if you should stop.  What they really must have meant was stop treatment, wait a while, then run a test to see if you should have stopped.  It seems the authors didn't say what they really meant, perhaps because that would have sounded as though they were recommending you put the patient at undue risk.  But I do think there is a basis for this.  The body of the paper cites evidence.  I will appeal to pathophysiology and attempt to explain it this way.  While the patient is systemically anticoagulated the coagulation system is held at bay.  Once you stop, there are certain higher risk patients who will reactivate their coagulation systems in a subclinical manner, with the process simmering beneath the surface.  Such patients, identified by an elevated D dimer, would be considered poised to clot again soon.  So, in certain circumstances, the D dimer may be a useful decision tool.  But what is gender specific about it, as implied in the indented text above?  More from the guideline on that:

..patient sex and D-dimer level measured about 1 month after stopping anticoagulant therapy can help to further stratify the risk of recurrent VTE. 66-69  Men have about a 75% higher (1.75-fold) risk of recurrence compared with women, whereas patients with a positive D-dimer result have about double the risk of recurrence compared with those with a negative D-dimer, and the predictive value of these two factors appears to be additive. The risk of recurrence in women with a negative posttreatment D dimer appears to be similar to the risk that we have estimated for patients with a proximal DVT or PE that was provoked by a minor transient risk factor (approximately 15% recurrence at 5 years); consequently, the argument for extended anticoagulation in these women is not strong, suggesting that D-dimer testing will often influence a woman’s decision. The risk of recurrence in men with a negative D-dimer is not much less than the overall risk of recurrence that we have estimated for patients with an unprovoked proximal DVT or PE (approximately 25% compared with approximately 30% recurrence at 5 years); consequently, the argument for extended anticoagulation in these men is still substantial, suggesting that D-dimer testing will often not influence a male’s decision.

For patients without active cancer who have had two or more spontaneous events the recommendations are the same as for patients with a single spontaneous (ie no transient risk factor) event.

For patients with active cancer extended therapy is favored for all, although the strength of the recommendation varies with bleeding risk. 

No special consideration is given for other high risk situations (eg thrombophilia, clots in unusual places).

Finally, the guideline says that if systemic anticoagulation is stopped for any reason aspirin, absent a contraindication, is considered better than nothing, making the special point that aspirin is not an acceptable alternative for extended systemic anticoagulation.

Choice of anticoagulant:  it's complicated.

The recommendation summary is simple enough but there are many nuances.  In general, for VTE in non-cancer patients the order of preference of agents is a NOAC over warfarin.  The authors give no order of preference among the NOACs.  Concerning initiation of treatment:

Initial parenteral anticoagulation is given before dabigatran and edoxaban, is not given before rivaroxaban and apixaban, and is overlapped with VKA therapy.

There are exceptions to be noted, mainly in unstable patients, for the recommendation not to start with parenteral anticoagulants before administration of some of the NOACs listed above.

For VTE patients with active cancer LMWH is recommend over all the others for initial and long term treatment and, by implication, extended treatment.  There is no order of preference for any of the ones after LMWH (orals). 

Now for the nuances that apply to certain special situations, from table 6:

If the patient has liver disease sufficiently severe to alter the coag tests LMWH is indicated for all phases of treatment.  Two reasons are stated for this, one being that NOACs are contraindicated if the INR is raised by liver disease, and the other being that warfarin is difficult to control in such circumstances and its monitoring is confounded since when the INR is altered by liver disease it is not a reliable indicator of antithrombotic effect.

Renal impairment with clearance below 30 is considered a contraindication to all NOACs for treatment of VTE in the guideline even though the product labeling of some of them allows usage with such reduction in renal function.

Dabigatran is not recommend if the patient has CAD, dyspepsia or prior history or GI bleeding (even if remote).

Similarly rivaroxaban and edoxaban are not recommend if there has been GI bleeding.

If there is concern for poor compliance, warfarin is favored over the NOACs, since it can be detected in the lab and its consequences are not immediate.

Unfractionated heparin is favored for initial treatment if thrombolytics are used or are being considered.

I checked Up to Date regarding the choice of anticoagulant and found that it is more conservative, favoring the traditional approach over starting with a NOAC.

Distal leg DVT.

The recommendations for distal leg DVT are essentially the same as those for proximal DVT except for the acknowledgment that clinical judgment will dictate withholding treatment in some patients.  The guideline “suggests” such a strategy of withholding treatment if there are not severe symptoms or risk factors for recurrence.  In such patients serial imaging is recommended. 

Catheter directed (regional) thrombolysis is not recommended.

The authors imply that it is worthy of consideration in certain circumstances but come short of making even a soft recommendation:

Patients who are most likely to benefit from CDT (see text), who attach a high value to prevention of PTS, and a lower value to the initial complexity, cost, and risk of bleeding with CDT, are likely to choose CDT over anticoagulation alone.

An exception to this non-recommendation is “impending venous gangrene.”  Another exceptional situation, May Thurner syndrome, is not addressed.

(Note: this applies to both upper and lower extremity DVT).

The guideline finds no indication for IVC filter insertion in any patient who can be anticoagulated.

---which is another way of saying that they would recommend an IVC filter only for patients with acute VTE and an absolute contraindication to anticoagulation.  Acknowledging low level data in favor of combined anticoagulation and IVC filter insertion in patients whose PE is severe or unstable (variously defined) the guideline makes this statement:

However, because it is uncertain if there is benefit to placement of an IVC filter in anticoagulated patients with severe PE (eg, with hypotension), and this is done by some experts, our recommendation against insertion of an IVC filter in patients with acute PE who are anticoagulated may not apply to this select subgroup of patients.

Thus the guideline gives little support for IVC filter insertion in any but the strictest indications, which may be important in light of the current FDA Safety Communication on filters and the resulting flurry of legal actions.

What about compression stockings?

Although the guideline authors acknowledge that they may be useful to control leg swelling they are no longer recommended for the singular purpose of prevention of post thrombotic syndrome.

Some small pulmonary artery filling defects may not need to be treated at all.

How is this determined?  Here's the recommendation:

In patients with subsegmental PE (no involvement of more proximal pulmonary arteries) and no proximal DVT in the legs who have a (i) low risk for recurrent VTE (see text), we suggest clinical surveillance over anticoagulation (Grade 2C), and (ii) high risk for recurrent VTE (see text), we suggest anticoagulation over clinical surveillance..

As simple as this sounds it requires some elaboration.  Unanswered questions include: 1)  are they talking about a single subsegmental defect or can treatment be withheld in some cases of more than one?  2)  Is the recommendation based on the idea of a false positive (non VTE filling defect), or that such low clot burdens, even if real, don't require treatment, or both?  The discussion in the body of the paper talks around these issues but is not definitive on either one.  Suffice it to say the recommendations leave much to clinical judgment and patient preference.  Despite such ambiguity in the text here is my take:

The text contradicts itself on whether treatment can ever be withheld in real subsegmental PEs however tiny the clot burden.  However, from the explanatory text it can be inferred that all filling defects judged to be “real” should be treated since such a determination is a risk factor for progression.

Subject to variations based on bleeding risk, patient preference and other clinical judgment factors, for treatment to be withheld ALL the following conditions must be met:

The defect is single.

The CT angio leaves doubt about whether the filling defects really represent PE (ie false positive is likely).

The filling defect is distally situated in a subsegmental branch.

The patient is asymptomatic (usually meaning that the discovery of the filling defect was incidental).

Clinical pretest probability is low or intermediate.

The D dimer is normal or minimally elevated and the elevation is otherwise explained.

The patient is not hospitalized already.

The patient has no recent history of immobility.

The patient does not have active cancer.

The patient has good cardiopulmonary reserve.

DVT is ruled out by lower extremity ultrasound (the upper extremity should also be evaluated if there are risk factors such as lines).

Again this is just my attempt to make sense of the text of this portion of the guideline, which is in places ambiguous and self contradictory.  However one interprets this portion it is suggested between the lines that the authors are concerned about an emerging problem of over treatment of small filling defects, a problem that would nearly cease to exist if clinicians relied on the best evidence and chose VQ over CT scanning as the initial imaging modality to assess for PE.

A prospective observational cohort study is underway to help answer the question.

Some patients with acute PE can be treated at home.

---meaning that they can be sent straight home from the ER or sent home after only very brief (a day or so) hospitalization.  The last edition of the guidelines said that some PE patients can be sent home after a very short stay.  The current ones take it a step further to say some patients can have their entire treatment outside the hospital.  In order to be eligible the following conditions are specified in the text, all of which must be met:

1) clinically stable with good cardiopulmonary reserve; (2) no contraindications such as recent bleeding, severe renal or liver disease, or severe thrombocytopenia (ie,less than 70,000/mm 3);  (3) expected to be compliant with treatment; and (4) the patient feels well enough to be treated at home.

Note that risk scores (eg PESI), biomarkers and other clinical indicators for RV dysfunction are not included explicitly in these criteria although criterion #1 would imply that there has been some assessment of RV function and in the text the authors say that elevated biomarkers or other indicators of RV dysfunction should discourage outpatient treatment.

As in the previous edition of the guidelines, it is suggested that hypotensive PE be treated with systemic thrombolytic therapy.

---but not generally normotensive PE even when the latter is associated with RV dysfunction (aka submassive PE).  The guideline suggests that if patients with submassive PE not initially treated with thrombolysis subsequently deteriorate, even short of developing hypotension, that lysis may then be indicated.

Catheter delivered regional thrombolysis for hypotensive PE is only suggested in certain circumstances.

These are stated in the guideline thusly:

..acute PE associated with hypotension and who have (i) a high bleeding risk, (ii) failed systemic thrombolysis, or (iii) shock that is likely to cause death before systemic thrombolysis can take effect (eg, within hours)..

What about anticoagulant failure?

From the guideline text:

In patients who have recurrent VTE on VKA therapy (in the therapeutic range) or on dabigatran, rivaroxaban, apixaban, or edoxaban (and are believed to be compliant), we suggest switching to treatment with LMWH at least temporarily (Grade 2C)…

In patients who have recurrent VTE on long-term LMWH (and are believed to be compliant), we suggest increasing the dose of LMWH by about one-quarter to one-third (Grade 2C).

How is bleeding risk assessed?

Many of the recommendations and suggestions above vary with bleeding risk.  Low risk is defined as no risk factors, moderate risk is defined as 1, and 2 or more mean high.  The factors are age over 65, prior bleeding, cancer, renal failure, liver failure, thrombocytopenia, prior stroke, DM, anemia, antiplatelet therapy, poor anticoagulant control, comorbidities causing reduced functional capacity, recent surgery, frequent falls, alcohol abuse and use of nsaids. 

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