February 2014 FAQs
February 2014 FAQs
What are the key features of the new hypertension treatment guidelines?
What are the key features of the new hypertension treatment guidelines?
Over the last decade there has been increasing anticipation for an updated hypertension guideline following the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) released in 2003. The National Heart, Lung, and Blood Institute (NHLBI) initially commissioned the Eighth Joint National Committee (JNC 8) in 2008, but in 2013 NHLBI announced that they were no longer authoring guidelines and empowered other organizations to undertake the task.1 The NHLBI withdrew authorship of the JNC 8 guidelines prior to publication; however, the panel members appointed to JNC 8 released a revised set of evidence-based treatment guidelines for the management of high blood pressure (BP) in December 2013.2 While awaiting JNC 8, several other organizations published their own hypertension guidelines. In addition to JNC 8, the most recently published guidelines for high BP are from the American Heart Association (AHA)/American College of Cardiology (ACC)/Centers for Disease Control and Prevention (CDC) and the American Society of Hypertension (ASH)/International Society of Hypertension (ISH), released in November 2013 and December 2013, respectively.2,3 The new recommendations in each of these guidelines contain some key features that may significantly impact the management of high BP in adults.
Key features of available guidelines
In contrast to JNC 7, the JNC 8 guidelines are less comprehensive and focus on answering the panel’s 3 highest-ranked (critical) questions related to BP management.2
1. Does initiating antihypertensive therapy at specific BP thresholds improve health outcomes?
2. Does treatment with antihypertensive therapy to a specified BP goal lead to improved health outcomes?
3. Do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes?
There are 9 general recommendations made in JNC 8.2 For the general adult population less than 60 years of age, the panel recommends initiating pharmacologic treatment when BP is above 140/90 mm Hg. This is also the recommended goal BP for these patients. For patients 60 years of age and older it is recommended to initiate pharmacologic treatment when BP is above, and to a goal less than, 150/90 mm Hg. There is a caveat to this recommendation that those who have achieved tighter control than the stated goal and are tolerating their treatment without adverse effects can continue current treatment without adjustment. In the adult population with chronic kidney disease or diabetes the goal BP is less than140/90 mm Hg regardless of age.
The JNC 8 recommendations for initial pharmacologic treatment are summarized in the Table.2 If the goal BP is not reached within 1 month of treatment initiation there are several recommended strategies: the dose of the drug can be increased; a second or third agent from the recommended drug classes (thiazide-type diuretic, calcium channel blocker [CCB], angiotensin-converting enzyme inhibitor [ACEI], or angiotensin receptor blocker [ARB]) can be initiated; or the patient may be referred to a hypertension specialist. Lifestyle modification is strongly emphasized.
The ASH/ISH guidelines are focused on managing hypertension in the community setting.3 They are more comprehensive than JNC 8 and include background information on hypertension with definitions, diagnostic measures, information, and recommendations on pharmacological and non-pharmacological treatments, and a specific section on special issues in treating high BP in Black patients. While the ASH/ISH guidelines resemble JNC 8 in many ways there are some differences. The guidelines recommend 80 years as the age cutoff for the higher initiation and treatment BP goal of <150/90 mm Hg and the omission of a thiazide diuretic as an initial treatment option for non-Black adults under 60 years of age. ASH/ISH also provides additional recommendations for special populations with coronary artery disease (CAD), stroke, and heart failure (HF). Another area that the guidelines differ from JNC 8 is that they recommend initial treatment with 2 drugs for all patients with a BP >160/100 mm Hg.
The AHA/ACC/CDC guidelines provide less information than the ASH/ISH guidelines, but still more than JNC 8. These guidelines are similar to JNC 7 and maintain the goal BP of <140/90 mm Hg for the general population.4 They mention that lower goals may be targeted for special populations, but do not state a specific goal for these patients. AHA/ACC/CDC also makes specific pharmacologic treatment recommendations for patients with CAD/post-myocardial infarction and systolic or diastolic HF patients. They also provide detailed information on lifestyle modifications and information on antihypertensive agents.
Table. Guideline comparisons of goal BP and initial drug therapy for adults with hypertension 1-4 Guideline Population Goal BP(mm Hg) Initial Drug Treatment Options JNC 7 No compelling indication <140/90 Thiazide (most patients), ACEI or ARB, β-blocker, CCB, or combination Compelling disease indication (including diabetes and CKD) <130/80 Diabetes: 1st-ACEI or ARB, 2nd-thiazide, 3rd-β-blocker or CCB CKD: 1st-ACEI or ARB JNC 8 ≥60 y <150/90 Non-Black: thiazide, ACEI, ARB, or CCB Black: thiazide or CCB <60 y <140/90 Diabetes <140/90 Thiazide, ACEI, ARB, or CCB CKD <140/90 ACEI or ARB ASH/ISH <80 y <140/90 Non-Black (<60 y): ACEI or ARB Non-Black ( ≥60 y): CCB or thiazide (may consider ACEI or ARB) Black (all ages): CCB or thiazide CAD: β-blocker plus ACEI or ARB Stroke: ACEI or ARB HF: ACEI or ARB + β-blocker + diuretic + aldosterone antagonist ≥80 y <150/90 Diabetes <140/90 ACEI or ARB (black can consider CCB or thiazide) CKD <140/90 ACEI or ARB AHA/ACC/CDC General population <140/90 CAD/Post MI: β-blocker, ACEI Systolic HF: ACEI or ARB, β-blocker, aldosterone-antagonist, thiazide Diastolic HF: ACEI or ARB, β-blocker, thiazide Diabetes: ACEI or ARB, thiazide, β-blocker, CCB CKD: ACEI or ARB Stroke/TIA: thiazide or ACEI ACEI, angiotensin converting enzyme inhibitor; AHA/ACC/CDC, American Heart Association/American College of Cardiology/Centers for Disease Control and Prevention; ARB, angiotensin receptor blocker; ASH/ISH, American Society of Hypertension/International Society of Hypertension; CAD, coronary artery disease; CCB, calcium channel blocker; CKD, chronic kidney disease; HF, heart failure; JNC 7, Seventh National Joint Committee; JNC 8, Eighth Joint National Committee; MI, myocardial infarction; TIA, transient ischemic attack.
Controversies with new guidelines
There has been some controversy regarding the recommendation toward a more liberal BP goal in the population over 60 years of age as stated in JNC 8, and this recommendation was not supported in other recently released guidelines.2-4 The ASH/ISH guidelines chose a higher age cut-off for a less restrictive BP goal, and the AHA/ACC/CDC chose to maintain the general goal of <140/90 mm Hg for adult patients of all ages. These variations between guidelines in ages and BP goals, along with varied pharmacologic treatment recommendations may result in differences among healthcare professionals in the management of patients with high BP.
The healthcare community has long awaited the arrival of the updated JNC 8 hypertension guidelines and has now received 3 very recently published updates. Some of the guidelines suggest that a less stringent level of BP control may be sufficient to prevent poor health outcomes in certain patient populations. However, this is controversial and not uniformly recommended in all guidelines for the treatment of hypertension. There are also differences with initial pharmacological treatment recommendations for patients in the 3 guidelines and some are more comprehensive. It may, therefore, be necessary to review multiple guideline recommendations from the different organizations prior to making treatment decisions in clinical practice.
1. National Heart, Lung and Blood Institute. Clinical Practice Guidelines: Hypertension. http://www.nhlbi.nih.gov/guidelines/hypertension/. Accessed January 8, 2014.
2. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8) [published online ahead of print December 18, 2013]. JAMA. doi: 10.1001/jama.2013.284427.
3. Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens. 2014;16(1):14-26.
4. Go AS, Bauman, M, Coleman King SM, et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention [published online ahead of print November 15, 2013]. Hypertension. doi: 10.1161/HYP.0000000000000003.
Tamkeen Quraishi Abreu, Pharm.D.
PGY-1 Pharmacy Practice Resident
Loyola University Medical Center
How do the novel oral anticoagulants compare to low-molecular-weight heparin for prevention of venous thromboembolism in patients undergoing total hip or knee replacements?
How do the novel oral anticoagulants compare to low-molecular-weight heparin for prevention of venous thromboembolism in patients undergoing total hip or knee replacements?
The risk of venous thromboembolism (VTE) after major orthopedic surgery, particularly total hip replacement (THR), is the highest among all surgical procedures.1 Without prophylaxis, the 35-day rate of symptomatic VTE after THR and total knee replacement (TKR) is estimated to be 4.3%. Pharmacological prophylaxis is reported to decrease VTE in THR and TKR by approximately 50%, but it is associated with increased risk of bleeding. 2 Thus, prophylaxis must balance the risk of bleeding events with the benefit of VTE reduction.
Prior to the introduction of the novel oral anticoagulants (NOACs), pharmacologic VTE prophylaxis in patients undergoing THR or TKR was accomplished using low-molecular-weight heparin (LMWH), fondaparinux, low-dose unfractionated heparin (LDUH), adjusted-dose warfarin, or aspirin.3 Though these agents have been used commonly, there are disadvantages to their use. The LMWHs and fondaparinux have good efficacy, but are limited by cost and parenteral administration, which can lead to poor compliance.2 Heparin is a poor choice for outpatient care because of the frequency of administration. Warfarin is inexpensive and can be given orally, but requires frequent monitoring and presents limitations due to the numerous interactions with other drugs, herbal medications, and dietary products. Aspirin is advantageous for ease of use, but has lower efficacy in VTE prophylaxis compared to LMWH. 1
Due to the aforementioned issues, several clinical trials have investigated the safety and efficacy of the NOACs for VTE prophylaxis in major orthopedic surgery, including THR and TKR. Currently, only rivaroxaban (Xarelto) is approved for this indication, but both apixaban (Eliquis) and dabigatran (Pradaxa) have been studied in this setting. Table 1 outlines dosing recommendations and pertinent pharmacokinetic information for these agents specifically for VTE prophylaxis.4 As apixaban and dabigatran have yet to earn Food and Drug Administration (FDA) approval, the dosing with these agents is based on the clinical trials and Canadian labeling. The major studies for NOACs in orthopedic surgery are summarized in Table 2.
Table 1. Comparison of NOACs for VTE prophylaxis.1,4-7
Rivaroxaban Apixaban Dabigatran Class Factor Xa Inhibitor Factor Xa Inhibitor Direct Thrombin Inhibitor Dosing 10 mg once daily 2.5 mg twice daily 220 mg once daily Dosing adjustments CrCl <30 mL/min: contraindicated CrCl <15 mL/min: contraindicated CrCl 30-50 mL/min: 150mg dailya CrCl <30 mL/min: contraindicateda Bioavailability ~80% ~50% 6% t1/2 5-13 hrs ~13 hrs 12-17 hrs tmax 3 hrs 3-4 hrs 0.5-2 hrs Metabolic pathways CYP3A4, P-gp CYP3A4, P-gp P-gp
a Canadian labeling.
Abbreviations: CrCl, creatinine clearance; CYP, cytochrome P450; NOACs, novel oral anticoagulants; VTE, venous thromboembolism.
Table 2. Studies of NOACs in VTE prophylaxis.8-18
Trial Population (n) Intervention/Duration Outcomes b Rivaroxaban RECORD 18 THR patients (n = 4541) Rivaroxaban 10 mg once daily Enoxaparin 40 mg once daily 35 days Rivaroxaban more effective at reducing endpoint of DVT, nonfatal PE, or death at 36 days, compared to enoxaparin (1.1% vs. 3.7%, ARR 2.6%, 95% CI: 1.5 to 3.7, p<0.001) Major VTE (proximal DVT, nonfatal PE, death from VTE) less common with rivaroxaban (0.2% vs. 2.0%, ARR 1.7%, 95% CI: 1.0 to 2.5, p<0.001) Major bleeding similar between groups (0.3% vs. 0.1%, p=0.18) RECORD 29 THR patients (n = 2509) Rivaroxaban 10 mg once daily for 31-39 days Enoxaparin 40 mg once daily for 10-14 days Rivaroxaban more effective at reducing endpoint of DVT, nonfatal PE, or death up to day 32-40, compared to enoxaparin (2.0% vs. 9.3%, ARR 7.3%, 95% CI: 5.2 to 9.4, p<0.0001) Similar rates of on-treatment bleeding (6.6% vs. 5.5%, p=0.25) RECORD 310 TKR patients (n = 2531) Rivaroxaban 10 mg once daily Enoxaparin 40 mg once daily 14 days Rivaroxaban more effective at reducing endpoint of DVT, nonfatal PE, or death up to day 13-17, compared to enoxaparin (9.6% vs. 18.9%, ARR 9.2%, 95% CI: 5.9 to 12.4, p<0.001) Major VTE (proximal DVT, nonfatal PE, death from VTE) less common with rivaroxaban (1.0% vs. 2.6%, ARR 1.6%, 95% CI: 0.4 to 2.8, p=0.01) Major bleeding similar between groups (0.6% vs. 0.5%, p=0.77) RECORD 411 TKR patients (n = 3148) Rivaroxaban 10 mg once daily Enoxaparin 30 mg twice daily 14 days Rivaroxaban more effective at reducing endpoint of DVT, nonfatal PE, or death up to day 17, compared to enoxaparin (6.9% vs. 10.1%, ARR 3.2%, 95% CI: 0.71 to 5.67, p=0.0118) Major bleeding similar between groups (0.7% vs. 0.3%, p=0.1096) Apixaban ADVANCE12 TKR patients (n = 3195) Apixaban 2.5 mg twice daily Enoxaparin 30 mg twice daily 10-14 days Apixaban did not meet criteria for noninferiority for reduction in the endpoint of DVT, nonfatal PE, or death, compared to enoxaparin (9.0% vs. 8.8%, RR 1.02, 95% CI: 0.78 to 1.32, p=0.06) Composite of major bleeding and clinically relevant nonmajor bleeding lower with apixaban (2.9% vs. 4.3%, p=0.03) ADVANCE-213 TKR patients (n = 3057) Apixaban 2.5 mg twice daily Enoxaparin 40 mg once daily 10-14 days Apixaban more effective at reducing DVT, nonfatal PE, or all-cause death, compared to enoxaparin (15% vs. 24%, RR 0.62, 95% CI: 0.51 to 0.74, p<0.0001) Major or clinically relevant non-major bleeding similar (3.5% vs. 4.8%, p=0.09) ADVANCE-314 THR patients (n = 5407) Apixaban 2.5 mg twice daily Enoxaparin 40 mg once daily 35 days Apixaban more effective at reducing DVT, nonfatal PE, or all-cause death, compared to enoxaparin (1.4% vs. 3.9%, RR 0.36, 95% CI: 0.22 to 0.54, p<0.001) Major and clinically relevant nonmajor bleeding similar between arms (4.8% vs. 5.0%, p=0.72) Dabigatran RENOVATE I15 THR patients (n = 3494) Dabigatran 220 mg once daily Dabigatran 150 mg once daily Enoxaparin 40 mg once daily 28-35 days Dabigatran 220 mg noninferior to enoxaparin in reducing total VTE and death (6.0% vs. 6.7%, 95% CI: -2.9% to 1.6%) Dabigatran 150 mg noninferior to enoxaparin in reducing total VTE and death (8.6% vs. 6.7%, 95% CI: -0.6% to 4.4%) No difference in major bleeding rates (1.3 to 2%) REMODEL16 TKR patients (n = 2101) Dabigatran 220 mg once daily Dabigatran 150 mg once daily Enoxaparin 40 mg once daily 6-10 days Dabigatran 220 mg noninferior to enoxaparin in reducing total VTE and mortality (36.4% vs. 37.7%, 95% CI: ‑7.3 to 4.6) Dabigatran 150mg noninferior to enoxaparin in reducing total VTE and mortality (40.5% vs. 37.7%, 95% CI: ‑3.1 to 8.7) No difference in major bleeding (1.3% to 1.5%) RENOVATE II17 THR patients (n = 2055) Dabigatran 220 mg once daily Enoxaparin 40 mg once daily 28-35 days Dabigatran noninferior to enoxaparin in reducing total VTE and death (7.7% vs. 8.8%, 95% CI: -3.8% to 1.6%, p<0.0001) Similar rates of bleeding between groups (1.4% vs. 0.9%, p=0.4) REMOBILIZE18 TKR patients (n = 2596) Dabigatran 220 mg once daily Dabigatran 150 mg once daily Enoxaparin 30 mg twice daily 12-15 days Dabigatran 220 mg failed to meet the criteria for noninferiority to enoxaparin in preventing VTE (31% vs. 25%, p=0.02) Dabigatran 150 mg failed to meet the criteria for noninferiority to enoxaparin in preventing VTE (34% vs. 25%, p<0.001) Similar rates of bleeding
b All comparisons NOAC vs. active control.
Abbreviations: ARR, absolute risk reduction; CI, confidence interval; DVT, deep vein thrombosis; NOACs, novel oral anticoagulants; PE, pulmonary embolism; RR, risk ratio; THR, total hip replacement; TKR, total knee replacement; VTE, venous thromboembolism.
American College of Chest Physicians Recommendations
The American College of Chest Physicians (ACCP) provides recommendations for the prevention of VTE in orthopedic surgery patients.1 However, the guidelines do not identify a preferred agent, grading their recommendations for pharmacological prophylaxis similarly. They recommend:
· In patients undergoing THR or TKR, we recommend use of one of the following for a minimum of 10 to 14 days rather than no antithrombotic prophylaxis: LMWH, fondaparinux, apixaban, dabigatran, rivaroxaban, LDUH, adjusted-dose vitamin K antagonists, aspirin (all Grade 1B), or an intermittent pneumatic compression device (Grade 1C).
· For patients undergoing major orthopedic surgery, we suggest extending thromboprophylaxis in the outpatient period for up to 35 days from the day of surgery rather than for only 10 to 14 days (Grade 2B).
Comparison of the NOACs versus LMWH
No study to date has directly compared the NOACs to each other for thromboprophylaxis. A recently published systematic review identified other systematic reviews and evaluated the comparative efficacy of NOACs versus LMWH by using common endpoints among the studies.2 Table 3 summarizes this information.
Table 3. Factor Xa inhibitors versus LMWH.2
Outcome Total Studies (Patients) Events/Total Patients OR (95% CI) FXa inhibitors LMWH Mortality 10 (22,838) 31/12,384 26/10,454 0.95 (0.55-1.63) Symptomatic DVT 12 (22,877) 41/12,993 57/9,884 0.46 (0.3-0.7) Nonfatal PE 20 (26,998) 44/15,187 29/11,811 1.07 (0.65-1.73) Major bleeding 21 (31,424) 192/18,307 86/13,117 1.27 (0.98-1.65) Outcome Total Studies (Patients) Events/Total RR (95% CI) Dabigatran LMWH Mortality 4 (10,264) 10/6,508 2/3,756 1.54 (0.38-6.33) Symptomatic DVT 4 (10,264) 34/6,508 18/3,756 0.82 (0.17-3.99) Nonfatal PE 4 (10,264) 14/6,508 11/3,756 0.69 (0.31-1.54) Major bleeding 4 (10,264) 81/6,508 48/3,756 0.94 (0.58-1.52)
Abbreviations: CI, confidence interval; DVT, deep vein thrombosis; FXa, Factor Xa; LMWH, low-molecular-weight heparin; OR, odds ratio, PE, pulmonary embolism; RR, risk ratio.
Overall, the NOACs had similar efficacy and bleeding rates when compared to LMWH.2 The factor Xa inhibitors demonstrated a significantly greater reduction in symptomatic DVT after THR or TKR. Dabigatran did not demonstrate a difference in reducing any endpoint when compared to LMWH; however, large confidence intervals indicate variability in the mortality and symptomatic DVT results in these studies.
Recommendations and Considerations
Currently, the only NOAC approved for VTE prophylaxis following THR or TKR is rivaroxaban. However, apixaban is being reviewed for this indication and may be available for use for VTE prophylaxis soon. Additionally, dabigatran is another option that may see FDA approval. The recently conducted systematic review demonstrates similar rates of mortality, nonfatal pulmonary embolism (PE), and bleeding with factor Xa inhibitors or LMWH.2 Factor Xa inhibitors did show greater reduction in the incidence of symptomatic DVT. When comparing dabigatran and LMWH, there were no differences in any of the studied endpoints.
One concern with NOAC use is reversal of anticoagulation induced by these agents. Currently there are no specific reversal agents for the NOACs and the efficacy of various blood products for reversal is inconclusive. Please refer to this FAQ for more information: http://dig.pharm.uic.edu/faq/2011/oct/faq2.aspx. There is no routine monitoring required with the use of NOACs compared to adjusted-dose warfarin, potentially improving compliance and reducing costs associated with monitoring. However, as these medications are brand-only at this time, cost may be a limiting factor for some patients. The manufacturers of rivaroxaban, apixaban, and dabigatran do provide patient support programs for patients. This includes a free 10-day trial of rivaroxaban for federally-insured patients and reduced copays for privately-insured patients.19 For apixaban and dabigatran, they offer similar reduced copays for privately-insured and a free 30-day trial for federally-insured patients.20,21
The NOACs, rivaroxaban, apixaban, and dabigatran, are attractive options compared to LMWH due to ease of administration. Both factor Xa inhibitors demonstrated similar efficacy in terms of mortality and nonfatal PE and superiority in terms of symptomatic DVT when compared to enoxaparin.2 Additionally, they had similar rates of bleeding. Dabigatran did not show the same benefit as the factor Xa inhibitors, but can still be considered for use. However, with these agents, cost may be a limiting factor, even with patient support programs.
1. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9 th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2):e278S-e325S.
2. Adam SS, McDuffie JR, Lachiewicz PF, Ortel TL, Williams JW. Comparative effectiveness of new oral anticoagulants and standard prophylaxis in patients having total hip or knee replacement. Ann Int Med. 2013; 159(4):275-284.
3. Goldhaber SZ, Fanikos J. Prevention of deep vein thrombosis and pulmonary embolism. Circulation. 2004; 110(16): e445-e447.
4. Ageno W, Spyropoulos AC, Turpie AGG. Role of new anticoagulants for the prevention of venous thromboembolism after major orthopaedic surgery and in hospitalized acutely ill medical patients. Thromb Haemost. 2012;107(6): 1027-1034.
5. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2013.
6. Apixaban. Lexi-Comp Online. Lexi-Drugs. Hudson, OH: Lexi-Comp, Inc.; 2013. http://online.lexi.com/lco/action/home/switch. Accessed September 27, 2013.
7. Dabigatran. Lexi-Comp Online. Lexi-Drugs. Hudson, OH: Lexi-Comp, Inc.; 2013. http://online.lexi.com/lco/action/home/switch. Accessed September 27, 2013.
8. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-2775.
9. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomized controlled trial. Lancet. 2008;372(9632):31-39.
10. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786.
11. Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomized trial. Lancet. 2009;373(9679):1673-1680.
12. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361(6):594-604.
13. Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomized double-blind trial. Lancet. 2010;375(9717):807-815.
14. Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363(26):2487-2498.
15. Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomized, double-blind, non-inferiority trial. Lancet. 2007;370(9591):949-956.
16. Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5(11):2178-2185.
17. Eriksson BI, Dahl OE, Huo HM, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). A randomized, double-blind, non-inferiority trial. Thromb Haemost. 2011;105(4):721-729.
18. Ginsberg JS, Davidson BL, Comp PC, et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24(1):1-9.
19. Affordability and Access. Xarelto (rivaroxaban). http://www.xareltohcp.com/access-affordability/access-affordability.html . Accessed September 17, 2013.
20. Eliquis 360 Support. Eliquis (apixaban). http://www.eliquis.com/support-program.aspx. Accessed September 18, 2013.
21. Save on Your Prescription with PRADAXA Savings Card. Pradaxa (dabigatran etexilate) capsules. https://www.pradaxa.com/save-on-pradaxa.jsp. Accessed September 18, 2013.
Paul Wong, PharmD
University of Illinois at Chicago
Is there evidence to support the use of lidocaine to reduce pain associated with potassium infusions?
Is there evidence to support the use of lidocaine to reduce pain associated with potassium infusions?
Hypokalemia is a commonly encountered electrolyte abnormality and can be defined by a serum potassium level of less than 3.5 mEq/L, with mild hypokalemia having serum potassium levels ranging from 3 to 3.5 mEq/L and severe hypokalemia with serum levels less than 2.5 mEq/L.1 There are many different reasons for hypokalemia but some common causes include poor dietary intake of potassium, vomiting or diarrhea, and use of certain medications which can increase renal potassium losses or cause intracellular potassium shifting.2 Patients with mild hypokalemia often appear to be asymptomatic, while patients with moderate hypokalemia may present with weakness, cramping, malaise, and myalgias. Hypokalemia can sometimes lead to very serious complications and can even be fatal. Some common complications of hypokalemia include cardiac arrhythmias, increased risk of stroke, myopathy, hypomagnesemia, and nocturnal leg cramps.3 Therefore, it is important to correct potassium levels in symptomatic patients. This can be done by increasing dietary potassium (for patients with mild hypokalemia), taking oral potassium supplements, or by using intravenous (IV) potassium for severely hypokalemia patients.
Intravenous potassium supplementation is indicated for treatment of severe hypokalemia (less than 2.5 mEq/L), symptomatic hypokalemia, or for patients with gastrointestinal issues that would exclude them from using oral therapy.3 The recommended IV dosing is 20 to 40 mEq in 0.9% sodium chloride for mild to moderate hypokalemia (40 to 80 mEq in severe hypokalemia) with a maximum daily dose of 240 to 400 mEq/day. The infusion rate should be from 10 to 20 mEq/L with a maximum rate of 40 mEq/L. A central venous catheter is recommended for infusion rates greater than 10 mEq/hour and cardiac monitoring may be needed for some patients. The maximum concentration of potassium solutions is 80 mEq/L via peripheral vein and 120 mEq/L via central vein infusions.
Adverse effects of intravenous potassium
Phlebitis is a common occurrence in infusion therapy, especially with potassium chloride infusions.4 Phlebitis is the inflammation of the intima of the vein and is characterized by pain and tenderness along the vein. There are a several types of phlebitis, including mechanical, chemical, and bacterial. Chemical phlebitis can occur due to differences between the pH of the infusion solution and normal blood (pH 7.35 to 7.48). The more acidic the infusion solution is, the more likely phlebitis may develop. The osmolality of the infusion solution can also play a role in phlebitis. Solutions with osmolality greater than 600 mOsm/L (a hyperosmolar solution) can irritate the vein intima. Also, the infusion rate can be a major factor as well. A rapid infusion rate can irritate the vein more than an infusion administered at a slow rate, because of the rapid introduction of drug and solution to the vein wall. With a slow infusion, there is time for the drug and solution to be diluted by the blood, producing less vein irritation. In addition to causing pain and discomfort for the patient, phlebitis may result in more serious complications such as sepsis or thrombosis formation.
Since it is known that potassium chloride infusions can cause pain and phlebitis, primarily when administered via a peripheral vein, lidocaine has been used as a method to decrease the risk of this effect. This review summarizes the current literature available on the efficacy of adding lidocaine to potassium chloride infusions.
The concerns of pain and phlebitis from IV potassium chloride infusions led Morrill and Katz to conduct a double-blind, randomized, placebo-controlled study in 6 volunteer subjects.5 This study was published in 1988 and sought to observe the effects of lidocaine on pain associated with IV infusions of potassium chloride. Subjects received both a control solution, which contained 10 mEq potassium chloride in 50 mL of 5% dextrose in water, as well as the study solution, which contained the control solution with 10 mg of preservative-free lidocaine hydrochloride. The solutions were infused at separate times in different arms over 1 hour. Subjects were monitored before, during, and after the infusion and assessed for pain, swelling, erythema, induration, and infiltration. Pain was evaluated on a 7-point scale, with 1 being mild pain and 7 being severe pain. Results of this study showed that the mean pain score was 3.17 with the lidocaine/potassium infusion versus a mean pain score of 6.17 with the control solution. This difference was statistically significant (p<0.01). Furthermore, 2 subjects did not complete the infusion with potassium chloride because of severe pain. The infusion was stopped in another subject due to infiltration 10 minutes after the infusion began.
Another study was conducted by Lim and colleagues.6 This double-blind study enrolled 28 patients with hypokalemia.The patients were randomized into 1 of 2 groups. Group 1 patients received potassium chloride 20 mEq in 100 mL in dextrose 5% solution infused over 2 hours. Prior to the infusion, patients in this group were pretreated with a 3 mL bolus dose of lidocaine 1%. Patients in Group 2 were given the same potassium chloride infusion regimen but with a 3 mL saline bolus prior to the infusion. Patients were assessed every 30 minutes during the 2-hour infusion and were asked to rate their pain on a 4 point pain scale. Patients given potassium chloride without lidocaine pretreatment experienced more moderate to severe pain at the start of infusion (79%), during the infusion (72%), and after 2 hours (50%). On the other hand, none of the patients who received lidocaine pretreatment experienced any pain at the start of infusion and 14% and 22% had moderate to severe pain during the infusion and after 2 hours, respectively. The difference between the 2 groups was statistically significant (p<0.01). This study showed that the pretreatment with a bolus dose of lidocaine significantly reduced pain associated with administration of IV potassium chloride.
Similarly, a randomized, double-blind, placebo-controlled, crossover trial by Pucino et al enrolled 18 patients with hypokalemia. 7 Patients received 4 peripheral vein infusions (2 infusions per arm)—dextrose 5% (2 solutions), potassium chloride 20 mEq in 65 mL of diluent with lidocaine 50 mg, and potassium chloride 20 mEq in 65 mL without lidocaine—each given over a 2-hour period. Pain was measured by both a visual analog scale and also a verbal descriptor. Pain scores by either method were highest in the potassium chloride infusion without lidocaine, followed by potassium chloride infusion with lidocaine, and then dextrose 5% (p=0.0012 for pain perception between lidocaine and nonlidocaine potassium chloride infusions).
Limitations and safety concerns
Although the use of lidocaine was shown to reduce the pain associated with peripheral infusions of potassium chloride, the available studies have a number of limitations. Each published study enrolled a small number of patients and used varying methods to evaluate the efficacy of lidocaine. Also, solutions were infused over a short period of time (1 to 2 hours), contained a fairly high concentration of potassium (0.2 mEq/mL to 0.3 mEq/mL compared to the recommended 0.08 mEq/mL for peripheral infusions), and used varying doses of lidocaine.
In addition to these limitations, there are concerns about the safety of this practice. As of 2012, the list of high-alert medications issued by the Institution for Safe Medication Practices (ISMP) contains both lidocaine and potassium chloride.8 This list of high-alert medications is used to assist providers in becoming more aware of the common medications that may require special safeguard to reduce the risk of harmful errors. A medication error report analysis issued by ISMP described 3 previous incidents of medication errors that involved the use of lidocaine to reduce potassium chloride infusion pain. One incident involved a nurse accidentally using the wrong concentration of lidocaine, which led to the patient receiving a large amount of lidocaine. The patient had a pacemaker, which suppressed any cardiac adverse effects from the lidocaine toxicity. The other medication errors reported were similar in nature and were attributed to poor labeling and packaging of lidocaine.
On addressing the issue of the benefits and risks of adding lidocaine to potassium, ISMP states that all the safety issues need to be weighed out carefully. The addition of an extra step in the drug preparation process (i.e., the addition of a second drug to an infusion) may increase the potential for medication errors.8 Past statements from ISMP have recommended against the addition of lidocaine to IV potassium infusions because it may mask a vein injury (such as phlebitis or infection) as well as mask symptoms of a potassium chloride overdose by preventing the burning sensation that often occurs when too much potassium is administered. Consideration must also be given to the potential for cardiac effects from lidocaine in patients with symptomatic hypokalemia.
In conclusion, although there are a few studies that show improved patient tolerance when administering potassium infusions with lidocaine, these studies are small and of limited quality. Per ISMP, other steps can be taken to reduce pain associated with potassium chloride infusions, including use of oral replacement agents, decreasing the concentration of the infusion, slowing the infusion rate, and using a large bore vein for administration as appropriate.
1. Brophy DF, Frumin J. Chapter 60. Disorders of Potassium and Magnesium Homeostasis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=7984069. Accessed January 17, 2014.
2. UpToDate [database online]. Philadelphia, PA: Wolters Kluwer Health; 2013. http://www.uptodate.com/contents/clinical-manifestations-and-treatment-of-hypokalemia?detectedLanguage=en&source=search_result&search=hypokalemia&selectedTitle=1~150&provider=noProvider. Accessed January 17, 2014.
3. Dynamed [database online]. Ipswich (MA): EBSCO Information Services. http://web.ebscohost.com/dynamed/detail?vid=6&sid=b7c25aaf-9385-4e42-815a-eedd28f8d081%40sessionmgr115&hid=114&bdata =JnNpdGU9ZHluYW1lZC1saXZlJnNjb3BlPXNpdGU%3d#db=dme&AN=115951. Accessed January 17, 2014.
4. Perucca R. Peripheral venous access devices. In: Alexander M, Corrigan A, Gorski L, Hankins J, Perucca R, eds. Infusion Nursing: An Evidence-Based Approach. 3rd ed. St Louis, MO: Saunders Elsevier; 2010:456-479.
5. Morrill GB, Katz MD. The use of lidocaine to reduce the pain induced by potassium chloride infusion. J Intraven Nurs . 1988;11(2):105-108.
6. Lim, ET, Kloo ST, Tweed WA. Efficacy of lignocaine in alleviating potassium chloride infusion pain. Anaesth Intensive Care . 1992;20(2):196-198.
7. Pucino F, Danielson BD, Carlson JD, et al. Patient tolerance to intravenous potassium chloride with and without lidocaine. Drug Intell Clin Pharm . 1988;22(9):676-679.
8. Cohen MR. Should lidocaine be added to IV potassium infusions to prevent burning sensation? Hosp Pharm. 2004;39(4):308:310-311.
Joseph Truong, PharmD Candidate, 2014