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Primary Care Corner with Geoffrey Modest MD: Bridge therapy for patients on warfarin and invasive procedures

10 Jun, 15 | by EBM

By: Dr. Geoffrey Modest 

A pretty common primary care conundrum is what to do with patients who are on warfarin but have impending surgery: stop the warfarin and hope they don’t get a pulmonary embolus, or do bridge therapy (there are several different ways to do the bridging: for those at high risk of venous thromboembolism –VTE, full-dose bridging is often done: stopping the warfarin 5 days prior to surgery, starting low molecular-weight heparin soon thereafter, stopping that for the surgery, and then restarting the heparin soon after the surgery (can be 1 day in those at low risk of post-op bleeding, longer if at higher risk); can do prophylactic low-dose heparin post-op; or can do intermediate (about 1/2 full-dose) for those with higher risk (eg VTE within the past month). Warfarin is resumed 12-24 hours post-op and usually takes 4-6 days to achieve target anticoagulation. A recent study in JAMA Internal Medicine looked at the outcome of 1178 patients in a retrospective cohort study in a large HMO (Kaiser Permanente Colorado) from 2006-2012 who were on warfarin for a VTE and had surgery with or without bridging (see doi:10.1001/jamainternmed.2015.1843​). They looked at the 30-day occurrence of clinically relevant bleeding, recurrent VTE, and all-cause mortality. Details:

 –1178 patients: mean age 66, 46% men, 56% on warfarin for deep venous thrombosis (dvt) and 44% for pulmonary embolism, 10 % with laboratory-confirmed thrombophilia (Protein S or C deficiency, antithrombin deficiency, antiphospholipid antibody syndrome, factor V Leiden, prothrombin 20210 mutation, increased factor VIII).

–Per the American College of Chest Physicians guidelines (AT9 guidelines, see CHEST 2012; 141(2)(Suppl):e326S–e350S), 79% of patients were considered low risk for VTE recurrence at the time of surgery, 18% moderate and 3% high risk (see below for risk stratification), and bridge therapy was done, respectively, in 29%, 34%. and 63% of the surgeries. 73% used therapeutic doses in the bridge therapy and 28% used prophylactic doses

–Procedures done: 37% GI endoscopies, 14% orthopedic, 10% spinal/intracranial, 9% abdominal. Of the surgeries, bridge therapy was performed more often for orthopedic and nonmajor abdominal or thoracic procedures


–clinically relevant bleeding within 30 days occurred in 15 patients (2.7%) in the bridge therapy group , but only in 2 patients (0.2%) without bridge therapy [(HR=17.2 (3.9-75.1)]

–high VTE risk group–5.6% with bridge therapy, 4.8% without. nonsignificant

–moderate VTE risk group–4.6% with bridge therapy, 0% without. p=0.004

–low VTE risk group–2.0% with bridge therapy, 0.1% without. p<0.001

–no significant difference in bleeding between those receiving therapeutic vs prophylactic doses in the bridge therapy

–no significant difference between groups in the rate of recurrent VTE in the bridge vs non-bridge groups (0 vs 3 patients, p=0.53)

–high VTE risk group–0% with bridge therapy, 0% without. nonsignificant

–moderate VTE risk group–0% with bridge therapy, 0.5% without. nonsignificant

–low VTE risk group–0% with bridge therapy, 0.2% without. nonsignificant

—no deaths in either group

General comments:

–it makes sense to stratify patients by surgical risk of bleeding: low risk (eg dental work)-continue with warfarin and therapeutic INR; moderate to high risk- stop the warfarin 5 days before the surgery (per AT9)

–the rationale for bridge therapy is two-fold: to decrease the amount of time the patient is not anticoagulated overall (around 7-10 days), but especially to do so in the high risk post-op period for VTE, since surgery leads to a more hypercoagulable state.

–the 2012 AT9 guidelines classifies the risk of recurrent VTEs in the post-op period as high (>10%/yr –eg, VTE within 3 months, severe thrombophilia), moderate (5-10%/yr –eg, VTE in past 3-12 months, non-severe thrombophilia such as heterozygous for factor V  Leiden or prothrombin gene mutation) and low (<5%/yr — eg, VTE>12 months previous and no other risk factors). This risk stratification is based on the annual risk of recurrent VTE in patients with mechanical heart valve, chronic atrial fibrillation or VTE who were either on no anticoagulation or less-effective treatment (eg aspirin).  ie, there is only indirect evidence to establish these risk categories for those with VTE on therapeutic anticoagulation.

So, this study is large but limited by being retrospective, and only a small % of the patients were high risk. However, it is impressive that bridge therapy made no difference in VTE occurrence in the much larger moderate and low risk groups, though there was a much higher risk of clinically relevant bleeding. We really need a prospective study, randomizing patients in the different risk categories to bridge therapy or not.  A prospective study could also sort out if there were other risk factors to consider which might favor bridge therapy, including those with a recent VTE (the risk is highest in the first 4 weeks post-VTE, 0.3-1.3%/day, decreasing to 0.03-0.2%/day over the next 4-12 weeks), or in those with several previous recurrences. also, we should note that this study did not include patients anticoagulated for atrial fibrillation or other indications (and it would be great to have good data on that… currently,  AT9 considers those in atrial fib with CHADS2 score of 0-2 as low risk, 3-4 as moderate, and 5-6 as high risk. Also high risk is if there is rheumatic heart disease or stroke/TIA within the past 3 months). But at least the current study gives some pretty strong support for withholding bridge therapy in those who are at least a few months out from their VTE event and who are in low or moderate VTE risk.


Primary Care Corner with Geoffrey Modest MD: New pre-op evaluation recommendations

21 Nov, 14 | by EBM

Two new recommendations for perioperative cardiovascular disease evaluation and management for patients undergoing noncardiac surgery were just released, one from the US and one from Europe (will limit review to common pre-operative primary care issues).

The US guidelines (see doi:10.1016/j.jacc.2014.07.944) reviews the risk factors for perioperative cardiovascular mortality, including the traditional ones (see paper for details):

–MI within the past 6 months, and esp. within the past 2 months

–heart failure, esp. decompensated, and more so in those with reduced ejection fraction

–cardiomyopathies present special management issues, though data on postoperative outcomes is limited and with mixed results

–valvular heart disease, noting the utility of preop echocardiography in those with suspected moderate or greater degrees of valvular disease and that recent advances in preoperative and operative monitoring/therapy have significantly reduced the risk of cardiac events — even those with severe AS and valve area <1cm2 now have only a slight increase in cardiac mortality (2.1% vs 1% at 30 days)

–arrhythmias typically need monitoring but more recent trials suggest they confer less cardiac risk — though their presence should trigger evaluation for underlying cardiopulmonary disease, especially if sustained or are associated with hemodynamic compromise

–high-grade conduction abnormalities such as complete A-V block may require pacing, but even left or right bundle-branch blocks only rarely progress perioperatively.

–also noted: preoperative natriuretic peptide has been found to be an independent risk factor, though requires further prospective studies, and other biomarkers have been incorporated into some of the risk models, including C-reactive protein and creatinine

There are 3 risk calculators noted in the paper, including:




For cardiac testing recommendations:

–first, evaluate functional status, a reliable predictor of cardiac events, with the increased risk if patients unable to perform at least 4 METs of activity (e.g., climbing a flight of stairs or walking up a hill, walking on level ground at 4 mph, or performing heavy work around the house).  There are also formal instruments to evaluate (e.g. Duke Activity Status Index).

–those patients to undergo nonemergent surgery and are unable to perform 4 METs activity should have pharmacologic stress testing, with potential revascularization if abnormal.

–other evaluations include 12-lead EKG if known cardiovascular disease, significant arrhythmia, peripheral arterial disease, cerebrovascular disease, or significant structural heart disease, “except for those undergoing low-risk surgery” and (lower level of certainty) if asymptomatic patients without known  cardiovascular disease. In all recommendations, not necessary if low-risk surgery. If doing EKG, should be within 1-3 months prior to surgery in stable patients. So, current imperative to do EKG within one month of cataract surgery seems quite unnecessary!!

–for patients with potential LV dysfunction on clinical evaluation, reasonable to do echo (in clinically stable, okay if echo done within past year).

–in those with stents: if drug-eluting, best to delay elective noncardiac surgery for 1 year (and at least 180 days). With bare metal stents, delay at least 30 days.

For perioperative therapy:

–only do coronary revasc if indicated according to existing recommendations, don’t do just for perioperative management.

–new recommendations for b-blockers (after discrediting the Dutch DECREASE trials for improprieties, as well incorporating the results of the new POISE-II trial): continue them if they were used chronically before surgery, may be reasonable to begin them in those with intermediate or high risk        myocardial ischemia in preop risk stratification (paying close attention to adverse effects: hypotension, bradycardia, etc.), may be reasonable in those with 3 or more risk factors (diabetes, heart failure, CAD, renal insufficiency, stroke), and if going to use them, begin more than 1 day prior to surgery.         –statins should be continued in patients already on them, and are reasonable if patient undergoing vascular surgery (who should probably have been on them anyway…).

–don’t give alpha-2 agonists (e.g. clonidine) perioperatively. Some studies suggest that calcium blockers (esp. diltiazem) may have benefit, but no recommendation. Can continue ACE-I or ARBs perioperativley.

–for antiplatelet drugs: those with recent stents should continue with dual antiplatelet therapy unless risk of bleeding outweighs benefit; in those without stents, may be reasonable to continue aspirin unless risk outweighs benefit; don’t initiate aspirin prior to surgery if no stent.

–anticoagulants: can continue in surgery with minimal bleeding risk (cataracts, minor derm procedures). For those on warfarin, bridging therapy (heparin) useful if high risk (mechanical mitral valve, or aortic valve plus another risk factor, such as afib, prior thromboemboli, LV dysfunction). Important  ​issue with the newer thrombin inhibitors is that they are not reversible. So stop them at least 48 hours prior to surgery.

The European recommendations (see doi: 10.1093/eurheartj/ehu282​) seem pretty similar on my less intense review. They do suggest a resting echo in asymptomatic patients without signs of cardiac disease but undergoing high-risk surgery. For b-blockers, they specifically recommend atenolol or bisoprolol. indications similar to US recs, though more strongly point out that these should not be fixed dose, but titrated to resting heart rate of 60-70 and systolic bp>100mmHg, and should be started more than one day prior to surgery (as with US recs), though they suggest preferably 7-30 days before. For statins, they suggest trying to start 2 weeks before surgery, with same indications as with US recs. ACE/ARBs, if indicated (e.g. pt with heart failure) should begin at least 1 week prior to surgery. They do seem a bit more aggressive in some issues:  e.g., consider pre-op routine carotid artery imaging in patients undergoing vascular surgery. Most of other recommendations are pretty similar to the US ones.



Primary Care Corner with Geoffrey Modest MD: Aspirin for noncardiac surgery not help

24 Apr, 14 | by EBM

recent followup study to the original POISE trial in the lancet, which found that pre-op b-blockers (metoprolol) did not improve post-surgical outcomes after noncardiac surgery in high risk vascular patients (risks outweighed benefits). NEJM had recent article on aspirin (see doi: 10.1056/NEJMoa1401105). in this trial 10K patients from 23 countries at risk for vascular complications (>45yo, with history of at least one of: CAD, PAD, stroke, major vasc surgery, or over age 70 with high risk of CAD) and about to undergo noncardiac surgery were assigned either aspirin vs placebo or clonidine vs placebo. for the aspirin group, they assessed 2 subgroups, those who were not previously on aspirin (initiation stratum, 5628 pts) and those previously on aspirin (continuation stratum, 4382 pts). those in the initiation group were given ASA 200mg just before surgery and 100mg/d after for 30 days. those in the continuation group stopped their regular aspirin 7 days before surgery, then received 200mg aspirin pre-op and then 100 mg/d for 7 days, then continued their regular aspirin regimen. primary outcome=composite of death or nonfatal MI at 30 days. results:

–baseline: age 69, 53% male, 33% with hx of vascular disease, 65% received prophylactic anticoagulation for 3 days post-op
–primary outcome in 7% in the aspirin group and 7.1% in placebo (non-significant)
–major bleeding in 4.6% in aspirin group and 3.8% placebo (significant with HR 1.23)
–no diff between the aspirin strata (somewhat more acute kidney injury in the continuation stratum and decreased risk of stroke in  the initiation stratum. no diff in MI

so, rationale for study is that post-surgical period is assoc with MI and with platelet activation (which might predispose to coronary artery thrombosis and might be prevented with ASA). one concern in this study design was that there are some observational data of increased thrombotic risk if stop aspirin before surgery. this was not found in this study. another issue, not commented upon directly, is whether low-dose aspirin is sufficient. this comes up with diabetics. for example, the well-designed POPADAD study (see doi:10.1136/bmj.a1840) looked at very high risk patients (diabetes and peripheral arterial disease) and found that ASA 100mg/d did not prevent cardiovascular events or mortality, and at that time raised the question whether low-dose aspirin was sufficient in diabetics who have really sticky platelets (and, i believe, led to downgrading of am diab assn recommendations from “recommend aspirin” to “consider aspirin”). so, higher dose aspirin, other antiplatelet drug. to me there are a couple of take-home messages: low-dose aspirin is not sufficient to cover high risk patients with noncardiac surgery (and increases bleeding), so should not be used; and it appears to be safe in this large study to just stop the aspirin a few days before surgery, without worrying about rebound thrombosis.

a separate report looked at giving clonidine 0.2 mg just before surgery and then for next 3 days, with rationale that there is marked activation of the sympathetic nervous system during and after noncardiac surgery, and this should be blocked centrally with clonidine. if anything, in this trial clonidine was worse than placebo (signif increase in nonfatal cardiac arrest) and more hypotension (48% vs 37%)



Primary Care Corner with Dr. Geoff Modest: Preop testing–Many studies, little evidence

3 Feb, 14 | by EBM

agency for healthcare research and quality (AHRQ) just came out with their synthesis of the data on routine preoperative testing (see link: ).  assessed literature on kids and adults of routine testing vs no testing or ad hoc testing, and routine vs per-protocol testing (per-protocol testing is testing a subset, eg EKG for those > 50yo, or hct in premenopausal women).  57 studies reviewed (14 comparative and 43 cohort). results:


good news: data for cataract surgery is the best: routine pre-op testing (EKG, metabolic panel or glucose, cbc) has no effect on total perioperative complications.


bad news: insufficient evidence for all other procedures and insufficient evidence comparing routine and per-protocol testing. no evidence regarding quality of life or satisfaction, resource utilization, or harms of testing.  and, results of cataract surgery pre-op is not applicable to other patients undergoing other higher risk procedures. even tonsillectomy/adenoidectomy in kids — just one retrospective, flawed study, so unable to draw conclusions.


the issue is that there just are not enough good studies (though 4581 citations assessed). many studies done, but poor quality. good studies need to look at real benefits/risks, including positive outcomes by testing (fewer medical complications, appropriate changes in perioperative management) vs risks (false positives or irrelevant findings, leading to further testing with attendant complications — medical and psychological; unnecessary delays in surgery; unnecessary radiation exposure; cost).



Primary Care Corner with Geoffrey Modest: Perioperative beta blocker Gdlns outdated…

5 Aug, 13 | by EBM

BMH open access with impressive meta-analysis on the use of perioperative b-blockade to prevent deaths in non-cardiac surgery(see the issue here is that much of the push for b-blockade came from profound mortality benefit found in the DECREASE family of trials (6 dutch trials, which have largely been conclusively discredited because of “fictitious methods”, “factitious adjudication committee”, and in one case “the entire study dataset had been fabricated”).  even though these trials were exposed and discredited 2 years ago, the European Society of Cardiology and American Heart Association guidelines  still endorse periop b-blockade; 2009 recs for AHA is to initiate perioperative b-blockage with dose titration in pts undergoing vascular and ischemia on pre-op testing, vascular surgery and established  CAD, vascular surgery and more than one risk factor, and intermediate-risk surgery and CAD or more than one risk factor.  the meta-analysis:

–11 RCTs met eligibility criteria, using bisoprolol, metoprolol, atenolol and propranolol. some diff on when ititiated b-blockers — from 37 days to 30 min prior to surgery and continued 5 to 30 days after.

–10,529 pts in 9 trials assessed all-cause mortality and found 162 deaths in 5264 pts on b-blockers and 129 in 5265 pts on placebo (increased mortality of 27%), with little heterogeneity between trials

–6 RCTs assessed MI — 27% decrease in non-fatal MI with b-blockade, BUT 73% increase in stroke and 51% increase in hypotension. (i sent out the POISE trial a couple of years ago: see orDOI:10.1016/S0140-6736(08)60601-7, which was by far the largest, well-done trial of the group, finding dramatic increase in strokes)

–so, by the authors calculation: refraining from the european cardiol guidelines would likely prevent up to 10K iatrogenic deaths/yr in the UK)

so, though we don’t have all the data we would like (eg, the studies included wide range of surgeries, such as abd, ortho, urolog, gynecolog, plastic — so not  sure if benefit might be different with different surgeries), we are likely traversing the “do no harm” boundary. the issue for us guys is that the guidelines, though old and predating the rather striking exposure of the DECREASE trials, are still standing and it is often hard for primary care or surgeons to buck them.  for example, i had a patient a couple of years ago, for whom the surgeon insisted on b-blockers even though i sent him the POISE study, so i had to do it to have the surgery done… ie, we need updated guidelines.

also, when looking at outcomes, all are not equal.  i, personally, would prefer a nonfatal MI to a stroke.


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