antithrombotic therapy guidelines

The American College of Chest Physicians just came out with updated guidelines on antithrombotic therapy (see antithrombotic therapy guidelines 2016 in dropbox, or 10.1016/j.chest.2015.11.026). details of those recommendations that are important for primary care providers (ie, not including those critically ill, use of thrombolytic therapy, catheter-based thrombus removal):

--they suggest using dabigatran, rivaroxaban, apixaban, or edoxaban over vitamin K antagonists (VKA, such as warfarin) for those with venous thromboembolic disease (VTE) and no cancer (all grade 2B recommendations, where Grade 2 recommendations are "weak recommendations", based on "moderate" evidence = Grade B)

--for those with VTE and cancer: low molecular weight heparin (LMWH) preferred over dabigatran/rivaroxaban/apixaban/edoxaban -- ie NOACs  (non-vitamin K oral anticoagulants)  (grade 2C, where C="low quality evidence")

--for those with VTE and on anticoagulants, do NOT use IVC filter -- Grade 1B (strong recommendation)

--recommends against using compression stockings routinely to prevent post-thrombotic syndrome (PTS) -- grade 2B [a large study did not find stockings decreased PTS or reduce leg pain, though they may be useful for chronic symptoms of PTS]

--for those with subsegmental PE and no proximal DVT, they suggest clinical surveillance over anticoagulation if a low risk of recurrent DVT (grade 2C), but anticoagulation if high risk (also grade 2C) [2 issues here: these are often picked up by CT scan and can be false positives; and if real, are likely from small DVT and risk of recurrence or progression is small, but there are NO RCTs on this. reasonable to do bilateral leg ultrasounds, and upper extremity one if there is a central venous catheter]

--for those with recurrent DVT while on non-LMWH therapy, then give LMWH (grade 2C); and if already on LMWH, then increase the dose (grade 2C)

in the body of the article, they note:

--for those with proximal DVT or PE and nonsurgical transient risk factor, anticoagulate for 3 months

--for patients with distal DVT provoked by surgery or nonsurgical transient risk factor, anticoagulate for 3 months [they note that there is a 15% risk of extension to the popliteal vein, and note that the decision to anticoagulate is not clear, with some providers suggesting anticoagulation, others only if there is proximal propagation in 1-2 week followup ultrasound. they also comment  that a risk factor for extension is a positive D-dimer, especially if very high (not specified further), if thrombosis is multiple or >5cm long, if close to proximal vein, if active cancer, if history VTE, also if DVT not in the muscular veins of the soleus or gastrocs). 

--in those with unprovoked DVT (isolated distal or proximal DVT/PE), they recommend 3 months of anticoagulation. re-evaluate the patient after 3 months for risk-benefit of continued therapy. Later in the text of the article, they comment: in those with isolated acute distal DVT and without severe symptoms or risk factors for extension (see above), do serial imaging of deep veins. if the thrombus extends, even within the distal veins, then anticoagulate

--but, in those with a first VTE which is an unprovoked proximal DVT/PE and low to mod bleeding risk, give extended anticoagulation without stop date. if high risk of bleeding, then 3 months of anticoagulants [they do comment that d-dimer levels 1 months after stopping therapy might influence the decision to continue therapy)

--those with a second unprovoked VTE and low bleeding risk, extended therapy without stop date; high risk = 3 months. re-evaluate periodically, such as annually

--those with DVT/PE and active cancer really should get anticoagulant therapy without stop date, but re-evaluate annually

--in those with unprovoked proximal DVT/PE and the decision is to stop anticoagulants, you should give aspirin if no contraindication

--in those with upper extremity DVT involving axillary or more proximal veins, anticoagulate

--in terms of the choice of NOACs vs VKAs, they comment that the efficacy is similar though the risk of bleeding is less with NOACs (esp intracranial), though in patients with atrial fibrillation, there is more GI bleeding with NOACs

of note, of the 54 recommendations in the 30 statements in the article, "20 were strong and none were based on high quality evidence highlighting the need for further research" [my highlight]

--their estimates of risks of recurrent VTEs are:

    --VTE provoked by surgery: 3%  at 5 years

    --VTE provoked by non-surgical transient risk factor (eg estrogen therapy, pregnancy, leg injury, flight>8hrs,: 15% at 5 years

    --unprovoked VTE: 30% at 5 years

    --cancer-associated thrombosis: 15%/year

--in terms of determining length of therapy (and leading to above recommendations):

    --an isolated distal DVT has 1/2 the risk of a proximal one for PE

    --a second unprovoked proximal DVT/PE increases the risk by an additional 50%

    --categories for bleeding risk: [bleeding risk, per them, is similar to the HAS-BLED algorithm, including age (esp>75, though some increase >65), cancer, liver/kidney dz, diabetes, antiplatelet drugs, NSAIDs, alcohol, frequent falls]

        --low (no bleeding factors): 0.8%/yr

        --moderated (one bleeding factor): 1.6%/yr

        --high (2 or more bleeding factors): >6.5%/yr

    ​--a common issue is the patient with an unprovoked proximal DVT/PE without high risk of bleeding. they suggest that men have 75% increased risk of recurrence (the risk of recurrence in women is about 15% at 5 years) and those with positive D-dimer measured 1 month after stopping anticoagulation doubles the risk [i would add that there also was a study looking at D-dimer prior to stopping, finding that a raised level also predicted further VTEs. so i have been using both: D-dimer prior to stopping, and if normal, then 1 month after stopping. and i have been prescribing aspirin therapy in those who stop the anticoagulation, which has been further validated by 2 trials, with 35% reduced risk].

--outpatient treatment of acute PE: there are studies (not involving patients treated outside the hospital) finding that NOACs seem okay without initial heparin therapy

so, because of newer studies finding that NOACs seem to work well in patients with VTE, including in the setting of active cancer or recurrent VTE, and with the reported decrease in bleeding, the main change in the new guidelines over the previous ones is the elevation of NOACs over VKA's. however, i would add that they do hedge on the quality of this data (none of these recommendations are Grade A)  as noted above, and i am very concerned that many of those involved in the guidelines were involved in the NOAC studies with drug company support, and that there have been very real concerns about serious adverse events with NOACs and with drug company malfeasance/withholding damning data in their reporting (i am appending old blogs, some predating their posting on  BMJ, with drug company data itself suggesting that drug levels for dabagratan for example be monitored (one of the major selling points of NOACs is the lack of necessity to monitor levels, as INRs with VKAs).

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1/12/12: Recent article which found an increase in MI/ACS (acute coronary syndromes) in meta-analysis of dabagatran use (see dabigatran and inc ACS ArchMed2012 in dropbox,or doi:10.1001/archinternmed.2011.1666).  This was large meta-analysis (30,514 pts) on dabagatran in a variety of trials ( 2 on afib, 1 acute dvt prophylaxis, 1 ACS, 3 on short-term prophylaxis of DVT) comparing dabigatran to warfarin/enoxaparin or placebo, which found a small but significant increase in MI/ACS (30% relative risk increase, though only about 0.17% absolute increase from 0.79% to 1.19%, OR=1.33 (1.03-1.71, p=0.03).  Not sure how to explain this since it works in preventing emboli in afib, though there was a paper reporting increased inflammatory markers with the use of dabagatran.

Brings up the all-to-frequent medical scenario.  New drug comes to market. Works in preliminary studies (pretty much all funded by drug company). Drug makes sense to us (using a direct thrombin inhibitor should decrease thrombotic events, much easier to use than warfarin -- no need for INR monitoring). BUT…. Subsequent studies start to find problems, especially when looking at other than the marker initially studied (thromboemboli in afib, preventing thrombosis in pts with joint replacement, acute DVT) 

8/9/12: Recent editorial in annals on large number of adverse effects of dabigatran (see dabigatran adverse effects annals 2012 in dropbox). In its first 6 months, 505 adverse events from hemorrhage with 65 deaths, vs 176 for warfarin. In initial 6 weeks of marketing, "the Institute for Safe Medication Practices reported that dabigatran was responsible for more serious adverse events than 98.7% of all medications".  Reinforces importance not to jump on bandwagon and use new meds (esp given that vast majority of studies done by the pharmaceutical companies who stand to benefit….).  A recurrent theme.​

9/25/12: meta-analysis of 7 prospective randomized controlled trials see dabigatran and inc ACS ArchMed2012​ in dropbox, or doi:10.1001/archinternmed.2011.1666

“For the period January 1, 2000, through December 31, 2011, the researchers identified 7 prospective randomized placebo-controlled clinical trials that met the study criteria, involving 31 286 patients. Based on the pooled results, the use of new-generation oral anticoagulant agents in patients receiving antiplatelet therapy after an ACS was associated with a dramatic increase in major bleeding events (odds ratio, 3.03; 95% CI, 2.20-4.16; P < .001). Significant but moderate reductions in the risk for stent thrombosis or composite ischemic events were observed, without a significant effect on overall mortality. For the net clinical benefit, treatment with new-generation oral anticoagulant agents provided no advantage over placebo (odds ratio, 0.98; 95% CI, 0.90-1.06; P = .57).”

7/28/14 blog (for some reason not in my BMJ blogs): the BMJ's last issue had 6 articles on dabigatran (Pradaxa), showing the malfeasance of the drug company in promoting this agent [dabigatran is a direct thrombin inhibitor, specifically marketed as a competitor of warfarin for nonvalvular atrial fibrillation, though promoted for other indications as well, with the specific selling points based on a single key trial (RE-LY, see critique below) finding slightly lower incidence of major bleeding (16.4% vs 18.15%) without the costly and inconvenient monitoring of INRs required for warfarin -- ie, the high cost of the drug was more than justified by the savings from office visits and laboratory monitoring for warfarin. the following issues were discovered from the drug maker (Boehringer Ingelheim), largely through internal previously confidential documents:

    --the RE-LY trial was felt to have poor design and oversight, with a Canadian agency calling for "an independent audit of RE-LY to check for irregularities in conduct, sources of bias (this was an open-labeled, not blinded trial) and the cause of the unusually high incidence of intracranial hemorrhage in the warfarin arm" (thereby exaggerating the benefit of dabigatran), requesting patient level data to be made public. the FDA specifically was concerned about the likely high frequency of errors in the data set (misreporting of events), with subsequent FDA-mandated review by the company finding a further 3848 events. of note, the increase in new MIs (n=270) found in the dabigatran​ group was dismissed as due to chance because of small numbers, but the increase in warfarin-associated intracranial hemorrhages was highlighted, even though there were many fewer of such events (n=155). the FDA found that the "blinded adjudicator of events" in fact was unblinded in 20% of the cases (eg, by seeing identifying patient information)

    ​--the drug company has settled for $650M in litigation because the evidence provided by the company was incomplete.  The lawsuit was from fatal hemorrhage cases in the RE-LY trial, cases which it turns out were not included in the RE-LY trial’s initial compilation of adverse events, nor in the FDA-mandated recalculation, which it turns out was conducted by company scientists!!  previously unreleased documents came to light through this litigation and freedom of information act

    --the drug company noted in internal documents that the risk of bleeding could have been reduced by 30-40% if plasma levels of dabigatran were in fact monitored(company's own unreleased data), and with appropriate dosage adjustment (ie undercutting their main selling point for the drug that there didn’t need to be drug level monitoring).  internal emails in the company released in the litigation showed that the company did not want this information released. both the FDA and EMA (european medicines agency, the european FDA equivalent) specifically inquired about monitoring drug levels to improve safety, and one cardiologist, an FDA advisor, expressed concern that there was a 5-fold variability in plasma levels on the 150-mg dose. with regard to this marked plasma variability, one of the company's own scientists commenting on the potential safety issues from not checking plasma levels was rebuffed by a company official noting in a 2012 internal email that "the publication [of this result] will [do] more harm than be useful for us, neither in the market but especially harmful in the discussions in the regulatory bodies", and further, "the world is crying for this information -- but the tricky part is that we have to tailor the message smart."  and "this will make any defense of no monitoring [of plasma levels] to [health authorities] extremely difficult and undermine our efforts to compete with other [new oral anticoagulants]. "

    ​--and, one of the concerns with bleeding with dabigatran​ is that there is no antidote, unlike vitamin K with warfarin overdoses [there now is a reversal agent available]

For 2 of the most relevant BMJ articles, see: dabigatran bleeding and regulators bmj 2014 in dropbox, or doi: 10.1136/bmj.g4517, and dabigatran info withheld bmj 2014 in dropbox, or doi: 10.1136/bmj.g4670

the big issue here, as mentioned in several prior blogs including a few on dabigatran​ is that we are increasingly propelled into an era of privatization and deregulation, beginning with the Reagan presidency and leading to the situation now where almost all of the studies in major medical journals are funded by the drug companies (in the 1970’s the vast majority were publicly-funded), a large percentage of guidelines now are from specialty societies (as opposed to the recent past when the NIH led most of the guideline development) and many of the leading specialists are directly supported by drug companies, and where the cash-strapped FDA is increasingly making drug companies do further studies instead of independent groups. My own bias is that we should be very hesitant in the current climate to be early-adopters of new medications, unless there is a compelling need (for example, I think there is a compelling case for the new oral hep c drugs, or new and better-tolerated hiv meds)

also, a recent report from 2015 which looked at Medicare claims from 2010-2011, looking at those with newly diagnosed atrial fibrillation who were put on dabigatan or warfarin within 60 days of the diagnosis (see dabigatran inc bleeding jamainternmed2015 in dropbox, or JAMA Intern Med. 2015;175(1):18-24). they found that dabigatran (vs warfarin) was associated with 

    --higher risk of any bleeding event, with HR 1.30 (1.20-1.41)

    --higher risk of major bleeding, with HR 1.58 (1.36-1.83) 

    --higher risk for GI bleeding, with HR 1.85 (1.64-2.07)

    --though, lower risk of intracranial hemorrhage, with HR 0.32 (0.20-0.50)  [the incidence of intracranial bleeds was about 1/11th that of GI bleeding, though intracranial bleeds have more morbidity/mortality; no clear explanation of why this difference. Though see above about RE-LY trial and reporting issues]

    --and, the results of increased bleeding were especially in African-Americans and those with chronic kidney disease

see http://gmodestmedblogs.blogspot.com/2014/11/dabagratan-again.html  for more info

so, bottom line: I’m just not sure I trust the NOACs given all of the above. I have continued with warfarin, with no real issues/adverse events (with the one exception of a patient controlled on 1mg of warfarin, admitted to the hospital for chest pain, seen by cardiology, but patient had missed a dose of warfarin that day and her INR was a little low, and the cardiol fellow increased the warfarin to 2mg, noting it was “only 1 mg more”, and one week later she bled out from a GI hemorrhage. Now, I always check in with my warfarin patients when discharged from the hospital just to make sure things were not changed too much, and provide very close followup)