Medication Management

18.1 Medication Management

Jay S. Kersh

Generally speaking, the goal of medical therapy is to restore and/or maintain homeostasis. These goals may be achieved with pharmacotherapy targeted at either the disease mechanism or by treating secondary symptoms. The ultimate goal of pharmacotherapy is to reduce morbidity and mortality. Some beneficial medications may be harmful in the perioperative period. Preparation for surgery requires a critical appraisal of medication regimens in order to minimize harm.

A patient’s state of compensation of chronic medical conditions is assessed during a preoperative encounter. A careful review of medications is performed. Necessary medications need to be started, restarted, or doses changed. Decisions are made to continue or discontinue medications for an appropriate amount of time before surgery. The goal is to reduce adverse outcomes from potential interactions or from known pharmacologic effects such as anticoagulation. It must be considered that the discontinuation of a medication(s) may put the patient at risk for increased morbidity and mortality. It is becoming clear that many medications that had previously been recommended to be stopped before surgery can be safely continued perioperatively (Table 18.1).

REBOUND PHENOMENON AND WITHDRAWAL SYNDROMES

Many medications used to treat chronic medical conditions cause physiologic changes with long-term use. There may be secondary effects such as cardiac remodeling associated with beta blockers and ACEIs in addition to the primary antihypertensive effect. These positive long-term changes can be challenged by the acute re-emergence of tachycardia, hypertension, and myocardial ischemia upon discontinuation of these medications (1). This phenomenon is known as rebound after medication discontinuation. Furthermore, acute beta-blocker withdrawal can alter thyroid hormone metabolism, exacerbating an already complicated situation. Careful medication documentation and appropriate instructions and plans can prevent or minimize rebound.

Opiates and benzodiazepines used chronically can lead to tolerance and addiction. Tolerance leads to escalating doses of the medication in order to achieve a desired clinical result. When medications are discontinued abruptly for surgery, avoidable medical complications and patient discomfort can occur.

TABLE 18.1 Preoperative Medication Instructions

Drug Class	Examples	Action
Anticoagulants	Warfarin, apixaban	See Chapter 18.2
Anticonvulsants	Phenytoin, levetiracetam	Continue as prescribed
Antidepressants	SSRI, TCA, MAOI	Continue as prescribed
Antihypertensives	Metoprolol, amlodipine	Continue as prescribed
Antiplatelets	Clopidogrel	Discontinue unless highrisk stent period (2) (see Chapters 3.2 and 3.3)
Aspirin		Continue, if taken for secondary prophylaxis for all except intraspinal and intracranial procedures
Asthma/COPD medications	Albuterol, salmeterol, tiotropium	Continue as prescribed
Cardiac medications	Amiodarone, digoxin	Continue as prescribed
COX-2 inhibitors	Celecoxib	Continue as prescribed
Diuretics	Furosemide, bumetanide	Discontinue DOS
Diuretics, non-loop	Spironolactone, hydrochlorothiazide	Continue as prescribed
Erectile dysfunction medications	Cialis, sildenafil	Discontinue for 24 hours
Eye drops	Timolol, acetazolamide	Continue as prescribed
Herbs/vitamins/minerals	Vitamin D, gingko, St. John’s wort	Discontinue
Hormones except estrogen	Thyroid replacement, prednisone, oral contraceptives	Continue as prescribed
Hypoglycemic drugs	Metformin	Discontinue DOS
Insulins	Humalog, Lispro, Lantus	Discontinue short-acting, continue long-acting
NSAIDs	Naproxen, diclofenac	Discontinue for 5 half-lives
Opioids	Oxycontin, codeine	Continue as prescribed
Reflux medications	Omeprazole, lansoprazole	Continue as prescribed
Statins	Atorvastatin	Continue as prescribed
Topical (creams, ointments)		Discontinue DOS
SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressants; MAOI, monoamine oxidase inhibitors; COPD, chronic obstructive pulmonary disease; COX, cyclooxygenase; DOS, day of surgery; NSAIDs, nonsteroidal anti-inflammatory drugs.

MEDICATIONS THAT POTENTIALLY COMPLICATE ANESTHETICS

Psychiatric medications, such as monoamine oxidase inhibitors (MAOIs), SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), antipsychotics, and benzodiazepines may require alteration of the anesthetic plan. Either effective anesthetic drug doses may be significantly altered, or potential drug-drug interactions may be a concern with the possibility of hypertensive crisis, serotonin syndrome, or neuroleptic malignant syndrome. Care must be taken to accurately document the use of these drugs, during the preoperative assessment.

There are many medications that have corresponding parenteral formulations that can be easily substituted (such as beta blockers and benzodiazepines) in the perioperative period. Some drugs, such as statins and antidepressants, do not have nonenteral formulations. When there is a clear benefit for continuing oral-only drugs, the medication is taken as scheduled. Most medications are resumed as soon as possible postoperatively.

MEDICATIONS THAT POTENTIALLY COMPLICATE SURGERY

Anticoagulants

Warfarin is the most commonplace oral anticoagulant in use, with increasing utilization of newer anticoagulants with fewer drug-drug or drug-food interactions, such as oral direct factor X inhibitors apixaban and rivaroxaban. See Chapters 18.2 and 18.3 for a discussion of anticoagulants.

Aspirin (ASA) and Antiplatelet Agents

ASA and clopidogrel are the two most commonly encountered irreversible antiplatelet agents used to prevent thrombotic occlusion of coronary and peripheral arteries. See Chapters 3.2, 3.3 and 18.3.

Corticosteroids and Disease-modifying Antirheumatic Drugs (DMARDs)

Corticosteroids are typically continued perioperatively, but DMARDs are discontinued. Abrupt discontinuation of corticosteroids can lead to life-threatening adrenal crisis. Historically, DMARDs were thought to significantly impair wound healing, while increasing the risk of surgical site infection. Currently, there is
emerging evidence that DMARDs may not be as detrimental to surgical wound healing and infection as previously thought (3,4,5).

REFERENCES

1. Hopper I, Samuel R, Hayward C, et al. Can medications be safely withdrawn in patients with stable chronic heart failure? Systematic review and meta-analysis. J Card Fail. 2014;20: 522-532.

2. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2016;134:e123-e155.

3. Ito H, Kojima M, Nishida K, et al. Postoperative complications in patients with rheumatoid arthritis using a biological agent—A systematic review and meta-analysis. Mod Rheumatol. 2015;25:672-678.

4. Grennan DM, Gray J, Loudon J, et al. Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery. Ann Rheum Dis. 2001;60:214-217.

5. Dixon WG, Watson K, Lunt M, et al. Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum. 2006;54:2368-2376.

18.2 Anticoagulants and Bridging Therapy

Suparna Dutta

Amir K. Jaffer

Approximately 2.5 million people in the United States take chronic anticoagulants (1). Anticoagulant therapy is recommended for prevention of thromboembolic events in those who have had venous thromboembolic events (VTE), and those with atrial fibrillation (AF) or mechanical heart valves. Management of chronic anticoagulant therapy can be challenging before surgery. Continuation of medications can lead to perioperative bleeding, while premature stoppage can predispose to a thromboembolic event. A patient- and surgery-specific strategy, with a clear understanding of the medications leads to the best decisions for perioperative management.

ANTICOAGULANTS

Unfractionated Heparin

Heparin blocks the intrinsic and common pathways of the coagulation cascade.
UFH has a rapid onset and clearance, allowing for easy titration.
UFH is safe to use in patients with renal insufficiency or failure.
UFH can only be administered parenterally.
A highly variable dose-response relationship necessitates monitoring with frequent measurements of aPTT when using treatment dosing.
UFH has a narrow therapeutic window, with a goal aPTT between 60 and 90.
The main complication of UFH is heparin-induced thrombocytopenia (HIT). HIT is caused by antibodies against platelet factor 4 and heparin complexes, and
is associated with a low or dropping platelet count, with or without thrombosis. Management of HIT entails stopping all heparin products, and using alternative modes of anticoagulation with direct thrombin inhibitors, such as argatroban (2).

Low-Molecular-Weight Heparins and Synthetic Pentasaccharides

The LMWH include: dalteparin (Fragmin), enoxaparin (Lovenox), tinzaparin (Innohep), and nadroparin (Fraxiparine). These medications are manufactured derivatives of UFH that preferentially inhibit factor Xa more than factor IIa.
Fondaparinux (Arixtra) is a synthetic pentasaccharide that selectively inhibits factor Xa mediated via antithrombin III.
LMWH and fondaparinux are administered subcutaneously.
These medications have a more predictable effect than UFH, but dosing is limited by weight and use is limited in renal insufficiency or failure.
These drugs have greater bioavailability than UFH and a longer duration of anticoagulation effect, allowing for once- or twice-daily administration.
Unlike UFH, there is better correlation between LMWH dose and anticoagulant response, thus coagulation monitoring is not necessary.
Checking factor Xa levels may be necessary in obese patients (weight >130 kg) due to the concern for suboptimal absorption (3).

Vitamin K Antagonists

Vitamin K antagonists (VKA), most commonly warfarin, are orally administered.
Warfarin and other VKAs prevent activation of vitamin K-dependent coagulation factors, including factors II (prothrombin), VII, IX, and X.
These medications can be used in patients with renal and liver diseases, and there is no weight limit for dosing (3).
VKAs have several limitations, making their use difficult and cumbersome in the clinical setting:
- Warfarin has a slow onset and offset, thus requiring initial bridging therapy with a parenteral anticoagulant (e.g., LMWH) before achieving target therapeutic levels. Its offset of 36 to 42 hours can pose a problem if immediate surgical interventions are required (4).
- PT/INR is used to evaluate the target level of anticoagulation. Warfarin has a narrow therapeutic window and exhibits a variable and unpredictable dose response. It is associated with several food and drug interactions, and variable dietary vitamin K intake causes fluctuating levels of anticoagulation with a laboratory control that is very difficult to standardize.
- Achieving an optimal INR requires frequent testing, regular monitoring, and numerous contacts with a healthcare provider for modifications (3).

Direct Oral Anticoagulants

DOACs are newer drugs used in the prevention of VTE or stroke for patients with nonvalvular AF, and are recommended as first-line treatment of deep venous thrombosis (DVT) or pulmonary embolus (PE) in noncancer patients (5). They are not approved for use in patients with prosthetic heart valves (4).
The DOACs include direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban).
These drugs have favorable qualities compared to other anticoagulants, such as ingestion via oral route, a quick time to peak effect (1 to 3 hours), a simple dosing regimen, and fewer drug and dietary interactions. They are as effective as conventional anticoagulants and are not implicated with HIT.
Renal excretion is the predominant elimination pathway for DOACs, and dosing differs according to a patient’s renal function and the clinical indications for use.
There is an increased risk of bleeding in patients older than 75 years.
There is currently no identified antidote to reverse their anticoagulation effect.
Additional drawbacks include the lack of a routine test to reliably measure their anticoagulant effect.
- With direct thrombin inhibitors, such as dabigatran, both PT and aPTT can be prolonged. However these tests should not be used to assess the level of anticoagulation. Better options include the thrombin time. A normal thrombin time indicates that no or only minimal dabigatran is present.
- Factor Xa inhibitors, such as rivaroxaban and apixaban can also affect the PT and aPTT. Anti-factor Xa assays are the best option to evaluate the level of anticoagulation with these drugs.
The DOACs are considerably more expensive than VKAs or heparin. Some studies suggest their use is cost-effective if the cost of coagulation monitoring and management of excess thromboembolic and bleeding events are considered (3).

PERIOPERATIVE MANAGEMENT OF ANTICOAGULANTS

Heparins

Preoperative management:

UFH has a biologic half-life of 45 minutes. Therapeutic dose intravenous UFH is continued until 4 to 5 hours before the procedure. If subcutaneous UFH is used, the last dose can be given the evening before the procedure.
LMWH is discontinued 24 hours before procedures, based on a half-life of 3 to 5 hours. One-half of the total dose is given on the morning of the day before surgery (6). Studies have shown a residual anticoagulant effect at 24 hours after stopping therapeutic-dose LMWH so this method ensures that no significant residual anticoagulant is present at the time of surgery (3).

Warfarin/VKAs

Preoperative management:

The perioperative management of warfarin and other VKAs is challenging because of their long half-lives. The American College of Chest Physicians (ACCP) recommend stopping VKAs 5 days before surgery to allow clearance of the drug and restoration of functional clotting factors to normal or near-normal levels (3).

Postoperative management:

Warfarin can generally be resumed 12 to 24 hours after surgery, assuming adequate hemostasis. It will take several days for the INR to reach the therapeutic range (3).

DOACs

Preoperative management:

The timing of cessation of DOACs before an elective procedure should consider factors such as the type of procedure and its bleeding risk (Table 18.2), the type of anesthetic (general, centroneuraxial, or regional) and the patient’s renal function (6,7).

DOACs are stopped 4 to 5 half-lives before procedures with high bleeding risk, or before centroneuraxial anesthesia to ensure minimal residual anticoagulant effect. These drugs are stopped 2 to 3 half-lives before low bleeding risk procedures.

TABLE 18.2 Surgical Bleed Risk

Surgeries with high bleeding risk (7):

Urologic: Transurethral prostate resection, bladder resection, tumor ablation, nephrectomy, or kidney biopsy; in part due to untreated tissue damage (after prostatectomy) and endogenous urokinase release
Pacemaker or implantable cardioverter-defibrillator device implantation (separation of infraclavicular fascial layers and lack of suturing of unopposed tissues within the device pocket may predispose to hematoma development)
Colonic polyp resection, typically of large (i.e., >1-2 cm) sessile polyps, in which bleeding may occur at the transected stalk following hemostatic plug release
Surgery and procedures in highly vascular organs, such as the kidney, liver, and spleen
Bowel resection in which bleeding may occur at the bowel anastomosis site
Major surgery with extensive tissue injury (e.g., cancer surgery, joint arthroplasty, reconstructive plastic surgery)
Cardiac, intracranial, or spinal surgery
Vascular surgery (aortic aneurysm repair, peripheral artery bypass)

Surgeries with low bleeding risk (6):

Abdominal hernia repair
Abdominal hysterectomy
Arthroscopic surgery lasting <45 minutes
Axillary node dissection
Bronchoscopy with or without biopsy
Carpal tunnel repair
Cataract and noncataract eye surgery
Central venous catheter removal
Cholecystectomy
Cutaneous and bladder/prostate/thyroid/breast/lymph node biopsies
Dilatation and curettage
Gastrointestinal endoscopy ± biopsy, enteroscopy, biliary/pancreatic stent without sphincterotomy, endosonography without fine-needle aspiration
Hemorrhoidal surgery
Hydrocele repair
Noncoronary angiography

The half-life of DOACs increases as creatinine clearance decreases. Patients on P-glycoprotein or cytochrome P450 inhibitors or inducers (such as amiodarone, azithromycin, carvedilol, tacrolimus, ritonavir, itraconazole) may need further adjustments in discontinuation times (4).

Postoperative management:

DOACs have a rapid onset of action (1 to 3 hours) and therapeutic levels are reached within a few hours of administration. The risk of bleeding increases if treatment is resumed soon after surgery, especially after major surgeries (e.g., hip or knee replacements). In general, NOAC resumption is delayed at least 24 hours after low bleeding risk procedures. If procedures have a high bleeding risk, therapeutic dosing is delayed 48 to 72 hours once adequate hemostasis is achieved (4).

RAPID REVERSAL OF ANTICOAGULANTS

Heparins

The anticoagulant effect of UFH can last up to 3 hours. Intravenous protamine, 1 mg, will neutralize 100 units of heparin administered in the previous 4 hours (3).
LMWH has a plasma half-life 2 to 4 times as long as UFH. Protamine will neutralize the antithrombin effect of LMWH but incompletely reverses factor Xa inhibition. Protamine, 1 mg, will neutralize 1 mg of enoxaparin and 100 units of dalteparin, given within the previous 8 hours (3).

Warfarin/VKAs

Reversal of the anticoagulant effects of warfarin includes stopping therapy, administering vitamin K, fresh frozen plasma (FFP), or prothrombin complex concentrates (PCC).

DOACs

The most common strategy for the reversal of DOACs is the passage of time. Vitamin K does not reverse the anticoagulant effect of DOACs, and FFP and PCC are of unproven benefit.
Activated charcoal may theoretically reduce absorption of DOACs if recently ingested.
Because dabigatran is approximately 35% protein bound, hemodialysis has been used successfully. Rivaroxaban has no reversal agent and because it is highly protein bound, dialysis is impractical (3).

PERIOPERATIVE BRIDGING

The concept of bridging in patients on chronic oral anticoagulation is based on the need to stop longer-acting drugs to avoid an increased risk of bleeding during surgery and the desire to use short-acting anticoagulants to minimize time off anticoagulants.
Therapeutic dosing of LMWH or UFH is recommended for bridging. Low or prophylactic dose bridging has not been established as effective in preventing thromboembolism in AF. However, in moderate-risk patients with a history of VTE, prophylactic bridging can be considered, especially postoperatively (1).

In What Situations Is Perioperative Bridging Required?

The ACCP guidelines from 2012 recommend that patients who have low bleeding risk procedures do not need their anticoagulant discontinued, and bridging is not indicated (grade 2C).⁷ These recommendations have been validated for procedures such as cataract surgery, pacemaker and dermatologic procedures (1).
The ACCP guidelines categorize patients into low, moderate, and high risk for thromboembolism (Table 18.3). Patients at low thrombotic risk do not require bridging, and those at a high risk should be bridged. The ACCP has no recom-mendations
for patients in the moderate-risk category, and advises that decisions regarding anticoagulation be made after careful consideration of patient and surgery-specific factors (Table 18.3) (7).

TABLE 18.3 Risk of Thromboembolism and Bridging Recommendations (7)

Risk Category	Conditions	Risk of VTE/Year	Bridging Recommendations
High risk	Heart valves: MV prosthesis, older (caged ball or tilting disc) AV prosthesis AF: recent CVA or TIA (≤6 months), CHA₂DS₂-VASc^* 5-6, rheumatic valvular disease VTE: VTE ≤3 months, severe thrombophilia (protein C or S or antithrombin III deficiency, antiphospholipid antibodies)	>10%	Bridge perioperatively
Moderate risk	Heart valves: bileaflet AV and at least one of the following: AF, prior CVA/TIA, HTN, DM, HF or >75 years old AF: CHA₂DS₂-VASc 3-4 ^aVTE: VTE within 3-12 months, nonsevere thrombophilia (heterozygous factor V or factor II mutations), recurrent VTE, presence of active cancer (treated <6 months or palliative)	5-10%	Decision depends on individual patient-related and surgeryrelated factors
Low risk	Heart valves: bileaflet AV without AF and no other risk factors for stroke AF: CHA₂DS₂-VASc 0-2 VTE: prior, single VTE >12 months, no other risk factors	<5%	No bridging indicated
^aSee comments in text regarding BRIDGE trial. ^*CHA₂DS₂-VASc, see Table 18.5. MV, mitral valve; AV, aortic valve; AF, atrial fibrillation; CVA, cerebrovascular accident; TIA, transient ischemic attack; VTE, venous thromboembolism; HTN, hypertension; DM, diabetes; HF, heart failure