March 2014 FAQs

Are there benefits to using genotype-guided warfarin dosing for INR control?

Introduction

Warfarin is a vitamin K antagonist that interferes with the generation of clotting factors II, VII, IX, and X in addition to the anticoagulant proteins C and S.1 It is used as an anticoagulant for prophylaxis and treatment of venous thromboembolism associated with atrial fibrillation and mechanical heart valves and of deep vein thrombosis and pulmonary embolism. The dosing for warfarin is individualized for each patient to maintain an International Normalized Ratio (INR) of 2 to 3, or a higher goal of 2.5 to 3.5 in the setting of mechanical valves. Patients that have an INR that is subtherapeutic are at risk for clot development, while those with supratherapeutic INR values are at risk for minor and major bleeding events. Each patient requires different doses to achieve the target INR, and it has been discovered that there are a variety of genes, specifically VKORC1 and CYP2C9, that are involved in the dosing variations needed among patients. In addition to various genotypes that make it difficult to predict a patient’s maintenance regimen, there are many foods and medications that interact with warfarin. Foods that contain high levels of vitamin K counteract the actions of warfarin and, therefore, patients are counseled to maintain a consistent amount in their diet to help keep their dose stable. Medications may interact with warfarin either to make the patient to be more prone to being supra- or subtherapeutic, depending on the interacting medication. Drug interactions are more easily manageable when involving a chronic medication; however, acute changes in the patient’s medication regimen, such as a short course of antibiotics, can cause drastic changes in the patient’s INR. In these cases, the warfarin dose may require adjusting in anticipation of the effects on the INR, or a different antibiotic may need to be selected to avoid this interaction. All of these factors require a patient to receive close follow-up every few days with a healthcare professional until their dose has been optimized to maintain a stable therapeutic INR. Once a stable dose of warfarin has been identified, the patient must be monitored every 4 to 6 weeks, with more frequent monitoring when outside factors are expected to lead to a change in INR.

Gene polymorphisms

As more pharmacogenomics services are being set up around the country, their use has been justified due to the narrow therapeutic index of warfarin and the inter-patient variability that occurs due to differences in genotypes.2 It has been hypothesized that choosing an initial warfarin dose based upon genotypes will lead to more time within the therapeutic INR range. This inter-patient variability has been linked to polymorphisms in the genes CYP2C9 and VKORC1.2,3,8 In a study designed specifically to look at variant alleles in the CYP2C9 genome, it was found that patients with CYP2C9*2 and CYP2C9*3 polymorphisms have an increased risk of being over-anticoagulated and thus are more likely to require lower doses of warfarin to maintain a therapeutic INR.4 Patients with VKORC1 AA genotypes also require a lower dose than patients with the GA or GG genotype.5 In 2007, the United States Food and Drug Administration (FDA) changed the labeling for warfarin, citing that up to one-third of patients metabolize warfarin differently depending upon their CYP2C9 and VKORC1 genotypes.3 At that time, the FDA stated additional studies were required to determine if pharmacogenomic testing should be required for patients being treated with warfarin. 6 In 2010, the FDA released a statement that encouraged practitioners to select a patient’s starting warfarin dose based upon the genotype if available, but did not recommend genetic testing.7 At this time, the Centers for Medicare and Medicaid Services (CMS) do not cover genotyping as a service for its patients.8 As more pharmacogenomics services have come available, the utility of these services has been assessed with some conflicting results.

Pharmacogenomic-guided warfarin dosing

The technique of warfarin dosing could potentially change with the use of pharmacogenomics. In some institutions, clinical algorithms or clinical judgment are used for warfarin dosing. Clinical algorithms may include patient factors such as age, race, smoking history, anthropometrics, amiodarone use, target INR, and indication.1 However, in the advent of pharmacogenomics, algorithms are being developed to include a patient’s CYP2C9 and VKORC1 genotypes in addition to other clinical variables. In 2009, an algorithm was developed by the International Warfarin Pharmacogenetics Consortium (IWPC) based on clinical and genetic data collected from 4043 patients and then validated in an additional 1009 patients.9 When the genotype-guided algorithm was compared with a clinical algorithm and a fixed-dose approach, it was significantly better at predicting more accurate initial doses, especially in those requiring weekly warfarin doses of 21 mg or less and 49 mg or more. While there are studies available that comment on the presence of the different genetics that affect warfarin dosing, there is one additional study that has evaluated the dosing of warfarin in the setting of known VKORC1 and CYP2C9 genotypes titled the CoumaGen-II trial.10 This study compared 2 pharmacogenomics-guided algorithms—a simple 1-step algorithm based loosely on the IWPC algorithm and a more complex 3-step algorithm with additional modifications to the IWPC algorithm—and found that the more complex protocol was noninferior but not superior to more simple protocol. The authors’ conclusions were that these protocols would aid in determining stable maintenance doses of warfarin, but noted that limitations in study design and sample size need to be considered when interpreting the results. Since there is still somewhat conflicting and limited information regarding prospective genotype-guided protocols, 2 new studies—COAG and EU-PACT—allow the impact of genotype-guided protocols to be better assessed.

The COAG and EU-PACT studies

In a study performed by Kimmel et al, named the Clarification of Optimal Anticoagulation through Genetics (COAG) trial, a dosing initiation algorithm, in addition to clinical factors was used for the first 5 days of warfarin therapy, followed by a standardized dosing-adjustment technique for the remaining 4 weeks.8 In another study, entitled the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT), patients that received genotype-guided therapy received loading doses days 1 through 3 based on their genotype, and then on days 4 and 5 the dose was determined based on a dose-revision algorithm that incorporated the clinical and genetic factors. From day 6 onwards, doses were then determined according to local clinical practices. 2

The COAG trial was a multicenter, double-blind, randomized, controlled trial with 1015 patients to determine if an initial dosing algorithm based on clinical variables and genotypes compared to clinical variables alone would increase the percentage of time in the INR therapeutic range of 2 to 3, with follow-up of up to 28 days of therapy.8 Patients included in the study were 18 years of age or older and being initiated on warfarin. Patients were randomized by study center and by self-reported race as black or non-black. Patients had their genotype determined immediately after blood-sample collection. In the genotype-guided group (n=514), a dosing initiation algorithm was used for the first 3 days followed by a dose-revision algorithm for the next 4 or 5 days. After 5 days of therapy, a standardized dosing-adjustment technique was used for the remaining 4 weeks. Patients in the control group (n=501) received dosing based on a clinically-guided algorithm. At the conclusion of the study, it was found that there was no statistical difference for the primary outcome, which was the amount of time spent in the therapeutic range from day 4 or 5 through day 28 (45.2% of the genotype-guided group vs 45.4% in the clinically-guided group; adjusted mean difference -0.2%, 95% confidence interval [CI], -3.4 to 3.1, p=0.91). A subgroup analysis determined that black patients spent less time in the therapeutic range when the genotype-guided protocol was compared to the clinically-guided group (35.2% vs 43.5%, respectively; adjusted mean difference -8.3%, p=0.01), showing a potential limitation of implementing the pharmacogenomics approach. There were no differences in percentage of time in the therapeutic range in the subgroup of nonblack patients, nor in terms of gender or number of genetic variants. This study was also unable to show a difference in the amount of time it took to achieve the first therapeutic INR. Additionally, this study failed to find a difference in the secondary outcomes such as rates of major bleeding, thromboembolism, or INR values of greater than 4. The authors’ overall conclusions were that using a genotype-guided protocol did not aid in gaining anticoagulation control within the first 4 weeks of therapy.

The EU-PACT trial was a single-blind, randomized, controlled trial with 455 patients who were over the age of 18 years and were being initiated on warfarin for atrial fibrillation or venous thromboembolism with a target INR of 2 to 3.2 The same primary end point was used as the COAG study (percentage of time spent within the therapeutic range); however, these patients were followed for the first 12 weeks of warfarin therapy rather than the first 4 weeks. Patients were genotyped after randomization stratified by their study center and indication for treatment. Patients that received genotype-guided therapy (n=211) received loading doses days 1 through 3 based on their genotype, and then on days 4 and 5 the dose was determined based on a dose-revision algorithm that integrated the INR from day 4. Both algorithms incorporated clinical and genetic factors. From day 6 onwards, doses were determined according to the local clinical practices. Patients in the control group (n=216) received standard dosing of warfarin. At the conclusion of the study, it was found that more patients were therapeutic 4 weeks after the initiation of warfarin in the genotype-guided group versus the control group (67.4% vs 60.3%; difference 7.0%; 95% CI, 3.3 to 10.6, p<0.001). Unfortunately, these differences were no longer evident at the endpoint of 3 months, with 74.5% of the genotype-guided group versus 72.9% of the control group in therapeutic range (95% CI, -3.8 to 6.6, p=0.61). Of the secondary endpoints, there was a statistically significant difference in the median time to reach the therapeutic INR range, with 21 days being required in the genotype-guided group compared to 29 days in the control group (hazard ratio for time to therapeutic INR, 1.43; 95% CI, 1.17 to 1.76, p<0.001). In addition, this study did not find any difference in secondary outcomes such as INR values of greater than 4.0 or less than 2.0, major and minor bleeding events, thromboembolic events, or number of warfarin dose adjustments. The authors concluded that genotype-guided protocols were associated with reduced time to reach a therapeutic INR and more time in the therapeutic INR range initially, though this difference did not persist at 3 months.

Summary

The COAG and EU-PACT studies both compared a genotype-guided protocol to the normal clinically guided protocols. While similar dosing strategies were used to evaluate the same outcomes, there were differences in the populations studied and the length of follow-up between the 2 trials. The COAG study followed a large and diverse population in the United States and followed patients for a period of 28 days. Alternatively, the EU-PACT study was conducted in Europe with the majority of patients being white and followed for 12 weeks after warfarin initiation. Both studies were conducted largely at academic medical centers, which likely had clinical specialists and pharmacists aiding in the management of patients, making it difficult to evaluate the efficacy of the algorithms alone. Also, in the absence of a true control group in the EU-PACT study (the control group used a non-pharmacogenomic algorithm rather than usual standard of care), it is difficult to truly evaluate the efficacy of the algorithm used compared to what occurs in general practice. At this time, these studies indicate that there may not be additional benefits to using genotype dosing for better therapeutic INR control; however, these dosing protocols may aid in better predicting maintenance doses and may help with getting to a therapeutic INR faster, and may have larger implications in certain subpopulations, such as African American patients. The addition of pharmacogenetic factors in the approach to warfarin dosing may not be as significant when clinical factors are already being taken into consideration.

References:

1. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G; American College of Chest Physicians. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e44S-88S.

2. Pirmohamed M, Burnside G, Eriksson N, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. 2013:12;369(24):2294-2303.

3. Zineh I, Pacanowski M, Woodcock J. Pharmacogenetics and Coumarin Dosing – Recalibrating Expectations. N Engl J Med. 2013:12;369(24):2273-2275.

4. Higashi MK, Veenstra DL, Kondo LM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcome during warfarin therapy. JAMA. 2002;287(13):1690-1698.

5. Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. 2005;106(7):2329-2333.

6. FDA Approves Updated Warfarin (Coumadin) Prescribing Information. FDA website. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108967.htm . Accessed January 29, 2014.

7. Coumadin (warfarin sodium) tablet and injection. FDA website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm201100.htm. Accessed January 29, 2014.

8. Kimmel SE, French B, Kasner SE, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med. 2013: 12;369(24):2283-2293.

9. International warfarin pharmacogenetics consortium, Klein TE, Altman RB, et al. N Engl J Med. 209;360(8):753-764.

10. Anderson JL, Horne BD, Steves SM, et al. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation. 2012;125(16):1997-2005.

Written by: Laura Means, PharmD

PGY1 Pharmacy Resident

March 2014

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Does perioperative use of selective serotonin reuptake inhibitors increase the risk of adverse outcomes?

Introduction

Mental illness can be defined as an alteration in an individual’s cognitive ability, mood, or behavior that impairs their daily life. Some of these mental illnesses include depression, anxiety, bipolar disorder, and post-traumatic stress disorder. Depression alone affects 26% of the US adult population. By the year 2020, depression will be second only to ischemic heart disease as a cause of disability throughout the world.1

One drug class that is used as a first-line treatment for mental illnesses such as depression and anxiety are the selective serotonin reuptake inhibitors (SSRIs).2 The SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. These agents work by inhibiting the reuptake of serotonin in the central nervous system. Although SSRIs are a good treatment option for depression and related conditions, they do have risks associated with their use. The labeling for these drugs currently carry a Food and Drug Administration (FDA) box warning for increased risk of suicide in children and young adults. Other concerning side effects with SSRIs are serotonin syndrome, QT prolongation, and increased risk of bleeding.

In recent years, there have been growing concerns with the perioperative use of SSRIs. The concern revolves around the issue of whether SSRIs are more helpful or harmful when used perioperatively. These concerns have arisen because studies have shown that SSRIs increased the risk for bleeding when taken alone or with aspirin, warfarin, nonsteroidal anti-inflammatory drugs (NSAIDs), or other anticoagulants.3-5 One study from 1999 showed that SSRIs used alone increased the risk of upper gastrointestinal (GI) bleeding.3 This study also showed that when SSRIs were combined with aspirin or NSAIDs, the risk of upper GI bleeding was greatly increased. A case control study showed that patients who were on SSRIs and a vitamin K antagonist had a higher risk of hospitalization from non-GI bleeding.4 A third study illustrated that SSRIs alone increased the risk of bleeding but did not have a much greater risk when SSRIs were combined with NSAIDs.5

Despite these reports of a potentially higher risk of bleeding, currently there are no formal guidelines on how to manage SSRIs perioperatively. It has been suggested to continue SSRI use throughout the perioperative period for most patients, with discontinuation only in patients at high risk for bleeding. 6 The available literature on the bleeding risks with perioperative SSRI is discussed below.

Literature Review

Several studies have been performed over the past decade evaluating SSRI use perioperatively and their impact on adverse bleeding outcomes in different types of surgeries, most commonly orthopedic and coronary artery bypass graft surgery. Studies evaluating outcomes in these 2 types of surgeries are summarized in Table 1.

Table 1. Outcomes following perioperative use of SSRIs.7-15

Similar to results described in Table 1, studies of other surgical procedures including breast cancer, breast augmentation, spinal fusion, cosmetic face-lift, and percutaneous endoscopic gastrostomy (PEG) placement have demonstrated conflicting effects of SSRIs on bleeding outcomes.16-20

The latest study, by Auerbach et al, also a retrospective study, had a large diverse population and included data from January 2006 to December 2008 from 375 hospitals.21 The study enrolled 530,419 patients who underwent elective major surgery. The primary outcomes were in-hospital mortality, length of stay, readmission at 30 days, bleeding events, transfusions, and incidence of ventricular arrhythmias. Target SSRI antidepressants included citalopram (14.2%), escitalopram (25.3%), fluoxetine (with [0.02%] and without olanzapine [17.8%]), paroxetine (16.3%), sertraline (26.5%), and fluvoxamine (0.3%). To distinguish between uninterrupted and interrupted SSRI use, administration of an SSRI was classified as the day before or the day of surgery and onward or as the day after (or later) surgery, respectively.

The SSRI user cohort consisted of 72,540 patients; there were 457,876 non-SSRI users.21 The study found that patients on SSRIs had a higher overall mortality (odds ratio [OR] 1.20, 95% confidence interval [CI] 1.07 to 1.36) versus non-SSRI users, for a number needed to harm (NNH) of 839. Patients on SSRIs were also found to have higher rates of bleeding (OR 1.09, 95% CI 1.04 to 1.15; NNH 424), 30-day readmission (OR 1.22, 95% CI 1.18 to 1.26; NNH 75), transfusion counts (OR 1.10, 95% CI 1.08 to 1.13), and length of stay (OR 1.02, 95% CI 1.02 to 1.03). With the exception of mortality, the outcomes remained significant among patients given an SSRI after surgery (interrupted use) or before surgery (uninterrupted use) compared to no use. For mortality, uninterrupted SSRI use was associated with worse outcomes (OR 1.25, 95% CI 1.11 to 1.41) compared with nonusers. The study also found that when SSRI use was stratified by depression or no depression, there was no increase in mortality, but the increased risk of bleeding and transfusion count compared to no SSRI use remained.

Although the study by Auerbach is the largest study to date, is it an observational trial, with weaknesses inherent to that design. The authors noted that it could not be determined how long prior to surgery an SSRI may have been held among those patients considered to have interrupted therapy, or if therapy was discontinued just prior to admission and restarted after discharge. The study also used data from an electronic billing system and not directly from medical records. The authors concluded that SSRI exposure resulted in poorer outcomes after major surgery. However, it remains unclear as to what timeframe to withhold therapy (e.g., early discontinuation or close to surgery) is needed.

A recent review conducted by Jeong and colleagues aimed to provide a summary of the current literature evaluating various bleeding outcomes in surgical patients taking serotonergic antidepressants and recommendations for SSRI management in surgical patients; however, the Auerbach study was not included in this review.22 Due to the inconsistent results of these studies, as demonstrated above, the authors do not recommend the routine practice of discontinuing SSRIs before surgery. However, based on the results of certain studies, discontinuation of SSRIs before breast and orthopedic surgery may be considered for patients with stable depression. Based on the pharmacokinetics of SSRIs and the life span of platelets, a general timeframe for SSRI discontinuation recommended by the authors is 2 weeks prior to surgery. However, a longer timeframe may be needed for patients receiving high doses or SSRIs associated with severe withdrawal. Evaluation of individual patient factors such as depression severity, suicide risk, type of surgery, concomitant medications, other risk factors for bleeding, type and dose of antidepressant, and health status must be undertaken when creating a plan for managing SSRI use prior to a surgical procedure.

Conclusion

Although many studies have been performed over the past decade on the potential risk of using SSRIs perioperatively, the results do not present a clear picture of how SSRIs should be managed in these situations. The latest study by Auerbach, with its large, diverse patient population, resolved some of the problems of earlier, smaller trials but some questions still remain. Ideally, large, prospective randomized clinical trials need to be completed in order to obtain a definitive answer as to whether SSRIs should be used perioperatively. Additionally, in an editorial accompanying the Auerbach study and a recent literature review, it was noted that the adverse consequences of stopping SSRI therapy, such as discontinuation syndrome, worsening depression, or increased postoperative pain, need to be considered.22,23 Based on the available evidence, the authors do not support the routine tapering and discontinuation of SSRI therapy prior to surgery. Tapering an SSRI over a 2-week (or longer) period preceding orthopedic and certain breast surgeries or in patients at high risk of bleeding can be considered according to the review by Jeong et al.22 Ultimately, however, it is up to the practitioner to weigh the risks and benefits of SSRI therapy to make the best decision for the patient before each surgery.

References

1. Center for Disease Control and Prevention. Mental health basics. http://www.cdc.gov/mentalhealth/basics.htm . Accessed August 1, 2013.

2. Hirsch M, Birnbaum RJ. Unipolar depression in adults and selective serotonin reuptake inhibitors (SSRIs): pharmacology, administration, and side effects. In: Roy-Byrne PP, Solomon D, eds. UpToDate.Waltham, MA: UpToDate; 2014 http://www.uptodate.com/contents/unipolar-depression-in-adults-and-selective-serotonin-reuptake-inhibitors-ssris-pharmacology-administration-and-side-effects?detectedLanguage=en&source=search_result&search=ssri&selectedTitle=1~150&provider=noProvider . Accessed February 26, 2014.

3. de Abajo FJ, Rodrıguez LA, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case control study. BMJ. 1999;319(7217):1106-1109.

4. Schalekamp T, Klungel OH, Souverein PC, de Boer A. Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors and coumarins. Arch Intern Med. 2008;168(2):180-185.

5. Tata LJ, Fortun PJ, Hubbard RB, et al. Does concurrent prescription of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs substantially increase the risk of upper gastrointestinal bleeding? Aliment Pharmacol Ther. 2005;22(3):175-181.

6. Muluk V, Macpherson DS. Perioperative medication management. In: Basow D, ed. UpToDate.Waltham, MA: UpToDate; 2014. http://www.uptodate.com/contents/perioperative-medication-management. Accessed January 27, 2014.

7. Dall M, Primdahl A, Damborg F, Nymark T, Hallas J. The association between use of serotonergic antidepressants and perioperative bleeding during total hip arthroplasty-cohort study. Basic Clin Pharmacol Toxicol . 2014 Feb 18. [Epub ahead of print].

8. Seitz DP, Bell CM, Gill SS, et al. Risk of perioperative blood transfusions and postoperative complications associated with serotonergic antidepressants in older adults undergoing hip fracture surgery. J Clin Psychopharmacol . 2013;33(6):790-798.

9. Tavakoli HR, DeMaio M, Wingert NC, et al.Serotonin reuptake inhibitors and bleeding risks in major orthopedic procedures. Psychosomatics. 2012;53(6):559-565.

10. Van Haelst IM, Egberts TC, Doodeman HJ, et al. Use of serotonergic antidepressants and bleeding risk in orthopedic patients. Anesthesiology. 2010;112(3):631-636.

11. Movig KL, Janssen MW, de Waal Malefijt J, Kabel PJ, Leufkens HG, Egberts AC. Relationship of serotonergic antidepressants and need for blood transfusion in orthopedic surgical patients. Arch Intern Med. 2003;163(19):2354-2358.

12. Tully PJ, Cardinal T, Bennetts JS, Baker RA. Selective serotonin reuptake inhibitors, venlafaxine and duloxetine are associated with in hospital morbidity but not bleeding or late mortality after coronary artery bypass graft surgery. Heart Lung Circ . 2012;21(4):206-214.

13. Xiong GL, Jiang W, Clare RM, et al. Safety of selective serotonin reuptake inhibitor use prior to coronary artery bypass grafting. Clin Cardiol. 2010;33(6): e94-e98.

14. Kim DH, Daskalakis C, Whellan DJ, et al. Safety of selective serotonin reuptake inhibitor in adults undergoing coronary artery bypass grafting. Am J Cardiol. 2009; 103(10):1391-1395.

15. Andreasen JJ, Riis A, Hjortdal VE, Jørgensen J, Sørensen HT, Johnsen SP. Effect of selective serotonin reuptake inhibitors on requirement for allogeneic red blood cell transfusion following coronary artery bypass surgery. Am J Cardiovasc Drugs . 2006;6(4):243-250.

16. Gartner R, Cronin-Fenton D, Hundborg, HH, et al. Use of selective serotonin reuptake inhibitors and risk of re-operation due to post-surgical bleeding in breast cancer patients: a Danish population-based cohort study.BMC Surg. 2010;10:3.

17. Basile FV,Basile AR, Basile VV. Use of selective serotonin reuptake inhibitors antidepressants and bleeding risk in breast cosmetic surgery. Aesthetic Plast Surg. 2013;37(3):561-566.

18. Harirchian S,Zoumalan RA, Rosenberg DB. Antidepressants and bleeding risk after face-lift surgery. Arch Facial Plast Surg. 2012;14(4):248-52.

19. Sayadipour A,Mago R, Kepler CK, et al. Antidepressants and the risk of abnormal bleeding during spinal surgery: a case–control study. Eur Spine J . 2012;21(10):2070-2078.

20. Richter JA,Patrie JT, Richter RP, et al. Bleeding after percutaneous endoscopic gastrostomy is linked to serotonin reuptake inhibitors, not aspirin or clopidogrel. Gastrointest Endosc. 2011;74(1):22-34.

21. Auerbach AD, Vittinghoff E, Maselli J, Pekow PS, Young JQ, Lindenauer PK. Perioperative use of selective serotonin reuptake inhibitors and risks for adverse outcomes of surgery. JAMA Intern Med. 2013;173(12):1075-1081.

22. Jeong BO, Kim SW, Kim SY, Kim JM, Shin IS, Yoon JS.Use of serotonergic antidepressants and bleeding risk in patients undergoing surgery. Psychosomatics. 2013 Dec 4. [Epub ahead of print].

23. Mrkobrada M, Hackam DG. Selective serotonin reuptake inhibitors and surgery: to hold or not to hold, that is the question. JAMA Intern Med. 2013;173(12):1082-1083.

Written by: Tuan Vu, PharmD candidate

University of Illinois at Chicago

March 2014

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What is the evidence for the use of albumin for treatment of intradialytic hypotension?

Introduction

Currently in the United States, about 530,000 individuals have end-stage renal disease (ESRD), and the majority of that population requires dialysis. 1 Although there are 2 different types of dialysis, hemodialysis and peritoneal, the majority of patients receive hemodialysis. Hemodialysis involves the removal of metabolic waste products from the circulation into the dialysate. For most dialysis patients, 9 to 12 hours of hemodialysis each week is necessary. A patient’s dialysis dose is determined by the following: patient size, residual kidney function, dietary protein intake, degree of anabolism or catabolism, comorbid conditions, urea nitrogen, and electrolytes. Patient criteria for receiving maintenance dialysis include the following: a creatinine clearance (CrCl) or glomerular filtration rate (GFR) < 10 mL/min per 1.73m2, refractory hyperkalemia, refractory expansion of extracellular volume, refractory acidosis, or a bleeding diathesis.

Intradialytic Hypotension

There are many complications associated with dialysis including hypotension, muscle cramps, and dialyzer-related anaphylactoid reactions. Intradialytic hypotension is the most predominant of these dialysis-related adverse effects. The 3 main criteria for intradialytic hypotension are a sudden fall in blood pressure, the need for an intervention, and symptoms such as headache, leg cramps, and nausea and vomiting.2 Potential interventions for this hypotension are a reduction in the ultrafiltration rate, placing the patient in the Trendelenburg position, and intravenous saline. The National Kidney Foundation Disease Outcomes Quality Initiative (K/DOQI) guideline defines intradialytic hypotension as a drop in systolic blood pressure by ≥ 20 mmHg or a decrease in mean arterial pressure by 10 mmHg with the following accompanying symptoms: abdominal discomfort, yawning, sighing, nausea, vomiting, muscle cramps, restlessness, dizziness, fainting, and anxiety.3 Another similar definition that has been used for this condition is a drop in blood pressure of at least 20 mmHg systolic or 10 mmHg diastolic, symptoms of end organ ischemia, and the need for intervention by the dialysis staff. 4

Previous studies have reported various incidence rates of intradialytic hypotension. K/DOQI estimates the incidence rate as being about 25% of all hemodialysis sessions.3 One study by Sands et al looked at a total of 44,801 hemodialysis treatments in 1,137 patients that took place at 13 outpatient hemodialysis centers.5 The defining criterion for intradialytic hypotension in this study was a greater than 30 mmHg drop in systolic blood pressure to less than 90 mmHg. The mean age of patients in this study was 62 years; 51% were black, 44% white, and 11% Hispanic. The mean body mass index (BMI) was 29 kg/m2. The overall incidence rate of intradialytic hypotension was 17.2%. However, the incidence rate was highly variable among both the patients and the centers. For example, 25.1% of patients never experienced an episode of intradialytic hemodialysis while 16.2% experienced it in more than 35% of their treatments. A moderate frequency rate (1% to 35% of treatments with a hypotensive episode) was experienced by 58.8% of patients.

Numerous risk factors were identified for intradialytic hypotension in this study by Sands et al.5 Risk factors found to be significant for intradialytic hypotension included age, female gender, diabetes, Hispanic ethnicity, longer duration of ESRD, a higher BMI, a higher ultrafiltration volume, the second and third weekly treatments of dialysis, a lower pre-hemodialysis systolic blood pressure, a higher difference between prescribed and achieved post-hemodialysis weight, and a higher dialysate temperature. This study also found that there was a statistically significant higher rate of mortality (22.4/100 patient-years; p=0.036), hospital admissions (1.5/patient-year; p=0.04), and hospital days (10.84/patient-year; p=0.0002) in patients who experienced intradialytic hypotensive episodes in > 35% of their treatments compared with patients with a low incidence of hypotensive episodes (<1% of treatments).

Treatment for Intradialytic Hypotension

Different treatments exist for the treatment and prevention of intradialytic hypotension. One nonpharmacologic method that can be tried in these patients is sodium restriction in order to reduce interdialytic weight gain and decrease the need for high ultrafiltration rates.4 In addition, increasing the dialysis time can reduce the need for high ultrafiltration rates. High ultrafiltration rates can not only cause problems in regards to intradialytic hypotension, but may also contribute to an increased risk of cardiovascular complications. It is thought that the mechanism behind this is similar to the reason why fluid overload exacerbates patients in heart failure.6 Some other nonpharmacologic treatment methods include not allowing patients to eat during dialysis and cooling the patient during the treatment, because an elevated body temperature may lead to peripheral vasodilation. The patient can be cooled during the treatment by cooling the dialysate (usually to between 35 and 35.5ºC, just below the patient’s core temperature).4 Some physicians hold blood pressure medications prior to hemodialysis in order to decrease the risk of intradialytic hypotension, but there is not much data to support this. It has been recommended to avoid short-acting antihypertensive medications just prior to dialysis. 4,7 The K/DOQI guideline recommendations for nonpharmacologic treatments are similar to these recommendations from published literature and include dialysate temperature modeling and isothermic dialysis, both of which involve keeping the dialysate temperature down, ultrafiltration modeling, dialysate calcium modeling, and dialysate sodium modeling.3 The evidence does not seem strong in support of calcium modeling, and there are many limitations with sodium modeling, especially in regards to postdialysis hypernatremia.

There are several different pharmacologic agents that have been used for intradialytic hypotension, including carnitine and midodrine.3 Carnitine has been used to decrease the incidence of muscle cramps and intradialytic hypotension in dialysis patients. However, evidence for its use is limited. A meta-analysis that looked at this intervention did not see a reduction in these complications with carnitine, in part due to the small number of studies available.8 Midodrine, in doses of 2.5 to 10 mg given 15 to 30 minutes prior to dialysis, has been suggested to prevent intradialytic hypotension.5,7 A meta-analysis reported midodrine to be effective in preventing hypotension during dialysis, although studies were small and of lesser quality.9 However, one individual study found that there was no benefit to adding midodrine (10 mg predialysis) if a patient was already receiving cool dialysate (at 35.5ºC) during dialysis.10

Literature Review

For acute treatment of intradialytic hypotension, intravenous administration of fluids for volume expansion is frequently done, often with normal saline. 11,12 Albumin has also been used as a pharmacologic intervention for intradialytic hypotension. Albumin works by increasing intravascular oncotic pressure, which can lead to a movement of fluids from the interstitial into the intravascular space.13 This fluid expansion may lead to an improvement in blood pressure. A 2010 Cochrane review by Fortin et al looked at the use of human albumin alone or in combination with crystalloid or nonprotein colloids for the treatment of intradialytic hypotension through volume expansion.14 The review specifically looked at the harms and benefits of these treatment methods. The criteria for symptomatic intradialytic hypotension in this study was a drop in systolic blood pressure by at least 10 mmHg or a systolic blood pressure of less than 100 mmHg in addition to symptoms associated with intradialytic hypotension. The selection criteria for this review were that the studies had to be randomized controlled trials, quasi-randomized controlled trials, or randomized crossover trials. The investigators only found one study that compared albumin with normal saline. No controlled trials were found comparing albumin versus hypertonic saline, nonprotein colloids, or a combination of nonprotein colloids and saline. The authors concluded that since no randomized or controlled studies were found that compared albumin to these other interventions, there is currently not enough data to support the use of albumin for the treatment of symptomatic intradialytic hypotension over crystalloids or nonprotein colloids. Based on a lack of evidence in support of albumin and the cost difference between albumin and saline, the authors believe that saline should be the first-line therapy for this condition.

The one study that was identified in the Cochrane review is a study by Knolls et al that compared albumin with 0.9% normal saline for the treatment of intradialytic hypotension.12 The study was a randomized, double-blind, crossover trial that studied 72 dialysis patients. The mean age of patients in the study was 65 years. Patients in the study were randomized to treatment with either sequence 1 or sequence 2. Sequence 1 consisted of 12.5 g of 5% albumin (250 mL) for their first episode of hypotension during the first dialysis sessions; normal saline (250 mL) was used for hypotension during the second dialysis session and during the third dialysis session. Sequence 2 consisted of normal saline, 5% albumin, and normal saline for hypotension during the first, second, and third dialysis sessions, respectively. Up to 750 mL of study solution could be given for each episode of intradialytic hypotension. Per the protocol if the patient experienced an episode of symptomatic hypotension then the dialysis session would be stopped, the patient would be placed in the Trendelenburg position, and study solution administered. If after the third infusion of study solution (the third round) the patient still did not recover, then the episode was considered a treatment failure and treatment was given at the discretion of the attending physician. If the symptomatic hypotension recurred during the same dialysis session after the blood pressure had become normotensive then the patient was not treated with another round of the study drug and the patient was treated at the discretion of the attending physician.

The primary outcome for the study was percentage of target ultrafiltration achieved.12 The secondary outcomes were postdialysis systolic blood pressure, postdialysis diastolic blood pressure, the volume of study fluid used, the time it took to restore blood pressure, the nursing time it took to treat the episode, treatment failures, recurrent hypotension, and the use of other interventions. The authors did not find any statistically significant differences between albumin and normal saline except for the need for additional saline to treat hypotension (16% with albumin versus 36% with normal saline, p=0.04); however, no difference was seen in the volume of additional normal saline fluid needed for albumin versus normal saline (231 mL versus 260 mL, p=0.74). The normal saline intervention took 9.9 minutes for the restoration of blood pressure versus 7.9 minutes in the albumin group (p=0.09). The authors concluded that for the treatment of intradialytic hypotension, albumin is not superior to normal saline.

In a another study by Emili et al, the authors investigated the use of human serum albumin for the treatment of intradialytic hypotension under a specific protocol.15 The protocol consisted of giving patients 200 mL of 0.9% normal saline (or 10 mL of 23% saline) over 2 to 3 minutes first to see if that would restore the patient’s blood pressure. If no response in blood pressure was seen, saline (0.9% and/or 23%) could be repeated at 5-minute intervals up to a preset fluid maximum. If normal saline did not work, 100 mL (25 g) of mannitol was given as a one-time dose to the patient, but not during the last 30 minutes of hemodialysis. Lastly, if the other interventions did not work, the patient was given 100 mL (25 g) of human serum albumin, which could be repeated once after 10 minutes. During 2559 dialysis sessions, 608 episodes of intradialytic hypotension occurred. Among 433 dialysis sessions where the protocol was used, the success rate (defined as reversal of hypotension with completion of dialysis and use of prescribed ultrafiltration) was 93%. Albumin was used in a total of 105 dialysis sessions (17%) with hypotension. Among 414 sessions where the protocol was completed, hypotension was successfully resolved with saline alone in 92%. Mannitol was needed in 3% and albumin in 3%; protocol failures occurred in 2% of patient. After the initiation of this protocol, the rate of albumin use at the hospital decreased from 22% of dialysis sessions with hypotension (prior to implementation of the protocol) to 6% with the protocol for 2559 dialysis sessions. This study found that almost all episodes of intradialytic hypotension were resolved by normal saline and that albumin was reserved for refractory cases and was effective in those cases that were resistant to normal saline and mannitol.

Discussion

Currently there is a lack of studies looking at albumin versus saline or intravenous fluids. What little information there is from the study by Knoll et al was not able to show albumin as being superior to normal saline for the treatment of symptomatic intradialytic hypotension. Even though there was a statistically significant difference between albumin and normal saline for the percentage of patients needing additional normal saline, the volume of saline used in either group was not significantly different. Also, even if the study by Knoll had shown albumin to be superior, it has limited generalizability since the population studied was older and the study size was small, at only 72 participants.

Conclusion

Based on the limited data that is currently available and the lack of mention of albumin in the K/DOQI guidelines, the evidence does not seem strong to support that treatment protocols be switched from normal saline to albumin for the treatment of symptomatic intradialytic hypotension. Further studies need to be done to compare the efficacy of albumin against normal saline, especially since it is a more expensive product. However, based on the study by Emili et al, albumin may still work as a treatment for refractory intradialytic hypotension.

References

1. Liu KD, Chertow GM. Chapter 281. Dialysis in the Treatment of Renal Failure. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York: McGraw-Hill; 2012. http://accessmedicine.mhmedical.com/content.aspx?bookid=331&Sectionid=40727070. Accessed February 12, 2014.

2. Henderson LW. Symptomatic intradialytic hypotension and mortality: an opinionated review. Semin Dial. 2012 May;25(3):320-325.

3. K/DOQI Workgroup. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis. 2005;45(4Suppl3):S1-153.

4. Reilly RF. Attending Rounds: A Patient with Intradialytic Hypotension. Clin J Am Soc Nephrol. 2014 Jan 2. [Epub ahead of print].

5. Sands JJ, Usvyat LA, Sullivan T, et al. Intradialytic hypotension: Frequency, sources of variation and correlation with clinical outcome. Hemodial Int. 2014 Jan 27. doi: 10.1111/hdi.12138.

6. Kalantar-Zadeh K, Regidor DL, Kovesdy CP, et al. Fluid retention is associated with cardiovascular mortality in patients undergoing long-term hemodialysis. Circulation. 2009;119(5): 671-679.

7. Agarwal R. How can we prevent intradialytic hypotension? Curr Opin Nephrol Hypertens. 2012 Nov;21(6):593-599.

8. Lynch KE, Feldman HI, Berlin JA, Flory J, Rowan CG, Brunelli SM. Effects of L-carnitine on dialysis-related hypotension and muscle cramps: a meta-analysis. Am J Kidney Dis. 2008;52(5):962-971.

9. Prakash S, Garg AX, Heidenheim AP, House AA. Midodrine appears to be safe and effective for dialysis-induced hypotension: a systematic review. Nephrol Dial Transplant. 2004;19(10):2553-2558.

10. Cruz DN, Mahnensmith RL, Brickel HM, Perazella MA. Midodrine and cool dialysate are effective therapies for symptomatic intradialytic hypotension. Am J Kidney Dis. 1999;33(5):920-926.

11. van Der Sande FM, Kooman JP, Leunissen KM. Strategies for improving hemodynamic stability in cardiac-compromised dialysis patients. Am J Kidney Dis. 2000;35(5):E19

12. Knoll GA, Grabowski JA, Dervin GF, O’Rourke K. A randomized, controlled trial of albumin versus saline for the treatment of intradialytic hypotension. J Am Soc Nephrol. 2004 Feb;15(2):487-492.

13. Lexi-Comp, Inc. (Lexi-DrugsTM). Lexi-Comp, Inc.; February 20, 2014.

14. Fortin PM, Bassett K, Musini VM. Human albumin for intradialytic hypotension in haemodialysis patients. Cochrane Database Syst Rev. 2010 Nov 10;(11): CD006758. doi: 10.1002/14651858.CD006758.pub2.

15. Emili S, Black NA, Paul RV, Rexing CJ, Ullian ME. A protocol-based treatment for intradialytic hypotension in hospitalized hemodialysis patients. Am J Kidney Dis. 1999 Jun;33(6):1107-1114.

Written by: Andrea Derlet, PharmD

PGY-1 Pharmacy Resident

University of Illinois at Chicago

March 2014

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