September 2012 FAQs
September 2012 FAQs Heading link
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Do selective serotonin reuptake inhibitors increase the risk of upper gastrointestinal bleeds?
Do selective serotonin reuptake inhibitors increase the risk of upper gastrointestinal bleeds?
Introduction
Selective serotonin reuptake inhibitors (SSRIs), a widely prescribed class of oral antidepressants, have been associated with an increased risk of gastrointestinal (GI) bleeding over the past decade.1 A combination of mechanisms and aggravating factors may be responsible, but studies provide conflicting evidence on the clinical importance of this reaction.
Mechanisms and aggravating factors
Serotonergic neurotransmission, which affects mood and contributes to vasoconstriction, is the target of action for SSRI antidepressants.2 Specifically, SSRIs bind to SERotonin Transporter (SERT), blocking its role to remove serotonin from the synaptic cleft and return it to the nerve terminal. With regard to coagulation, platelets release serotonin in response to vascular injury and exposure to proaggregatory factors such as adenosine diphosphate (ADP) and epinephrine.3,4 Serotonin then binds to receptors on adjacent platelets and contributes to platelet aggregation, as well as promotes vasoconstriction.2,3 Even without the presence of these proaggregatory factors, serotonin is a weak platelet activator.2 However, SSRIs allosterically inhibit about 90% of the activity of SERT in platelets, and this reduction in serotonin is the basis for the proposed mechanism of GI bleeding caused by SSRIs.5
Of note, there does not appear to be an association between SSRIs and other types of bleeding such as intracranial hemorrhage, menstrual bleeding, or surgical bleeding.1 Therefore, a possible second mechanism may be responsible for the specificity of this side effect to the upper GI tract. Animal studies have shown a dose-dependent increase in gastric acid secretion with the administration of paroxetine. Sertraline and fluoxetine have also been shown to increase gastric acidity in an animal study. In humans, the side effects of SSRIs that are GI-related are quite common and may be a result of this direct increase in gastric acid secretion. Finally, it is known that serotonin is synthesized in serotonergic neurons in the central nervous system, but 90% of all serotonin is stored within enterochromaffin cells in the GI tract.3 A combination of increased gastric acidity and impairment in platelet aggregation may be responsible for upper GI bleeding with SSRIs.
Some of the SSRIs are prone to drug-drug interactions involving the cytochrome (CYP) P450 enzyme system.1 Fluoxetine, fluvoxamine, and paroxetine inhibit several of these enzymes, such as CYP 1A2, 2D6, 3A4, and 2C9, thereby increasing the serum concentrations of concomitant medications that may be associated with bleeding risk. Examples of affected medications include antiplatelet agents such as clopidogrel or aspirin and anticoagulants such as warfarin.
Similarly, several studies have examined the risk of upper GI bleeds with the combination of non-steroidal anti-inflammatory drugs (NSAIDs) and SSRIs. 1 Mort et al analyzed 4 retrospective studies and found the risk of upper GI bleed was increased with the combination of NSAIDs and SSRIs compared to either drug individually. In a systematic review and meta-analysis published by Loke et al, 4 observational studies showed a pooled risk of upper GI bleed with serotonin alone of 2.36 (95% CI, 1.44-3.85) and a pooled risk of 6.33 (95% CI, 3.40-11.80) when NSAIDs and SSRIs were combined. However, according to 2 recent case-control studies, the risk of bleed was not increased with the combined use of NSAIDs and SSRIs.6,7
Studies also show a higher affinity to SERT is associated with an increased risk of developing serious GI bleeding.3,4 The most potent SSRIs are clomipramine, fluoxetine, sertraline, and paroxetine. Citalopram, fluvoxamine, doxepin, and the serotonin-norepinephrine reuptake inhibitor, venlafaxine, are considered to have intermediate affinity.3
Literature Review
Several epidemiological and case-control studies have been performed to evaluate this theoretical adverse effect due to SSRIs (Table 1). It should be noted, however, that these studies were quite heterogeneous. Only 1 prospective study thus far has found a significant risk of bleed with SSRI use. 4
Table 1. Epidemiological and case-control studies for SSRIs and GI bleeding association
Citation Design/Sample Outcomes and conclusion de Abajo et al 19998 - Population based case-control study
- 1651 patients with UGIB and 248 with ulcers
- 10,000 matched controls
- RR 3.0; 95% CI, 2.1-4.4 for GI bleeding with SSRIs
- RR 0.8; 95% CI, 0.1-2.4 for GI bleeding and non-SSRI antidepressants
- SSRI + NSAIDs increased the risk of UGIB more than either class alone – RR 15.6; 95% CI, 6.6-36.6
- No association with ulcer
Dunn et al 20009 - Prospective cohort study by prescription-event monitoring
- 103 events in 237609 patient-months of exposure
- Rate Ratio of UGIB 1.30; 95% CI, 0.75-2.27 vs. non-SSRI use
- Rate Ratio of UGIB for SSRI vs. venlafaxine 0.75; 95% CI, 0.5-1.7
van Walraven et al 200110 - Retrospective cohort study
- 317,824 elderly subjects observed for >130,000 patient-years
- Stronger serotonin reuptake inhibition was more likely to be associated with GI bleeds vs. weaker reuptake; RR 1.10; 95% CI, 1.02-1.19
- Risk was seen in older patients and in patients with previous GI bleeding
Dalton et al 200311 - Population based cohort study
- SSRI use more than tripled the risk of hospitalization related to UGIB; risk returned to baseline when SSRI therapy was discontinued.
- The risk was increased with aspirin or NSAID use.
- Less potent drugs that inhibit serotonin reuptake had an increased risk as well, but antidepressants that do not affect reuptake did not increase the risk of GI bleeds.
Meijer et al 200412 - Nested case-control
- 196 patients hospitalized for a primary diagnosis of abnormal bleeding
- 972 matched controls for age and sex
- Significantly greater risk of hospitalization for drugs of intermediate and high potency for serotonin reuptake inhibition vs. low potency (OR 1.9; 95% CI, 1.1-3.5 and OR 2.6, 95% CI 1.4-4.8)
Tata et al 200513 - Case-control study
- 11,261 cases with UGIB
- 53,156 controls matched by gender, age and general practice
- SSRI and NSAID use associated with increased risk of bleeding
- Combination of SSRI and NSAID use did not greatly increase the risk
Weissinger et al 200614 - Retrospective, case-control
- 579 cases (admitted with GI hemorrhage)
- 1000 controls matched by age and sex
- SSRI use was associated with LGIB, but not UGIB
- SSRI with NSAID or aspirin use resulted in increased risk of bleeding
Helin-Salmivaara et al 200715 - Matched case-control study on non-institutionalized residents
- 9191 patients with serious upper GI events
- 41,780 individually matched controls
- Risk of serious UGIB was greater with SSRI and SSRI + NSAID combination compared to control
- Risk of SSRI + NSAID was higher than NSAID alone
Ziegelstein et al 200716 - Retrospective study
- 158 patients with ACS received an SSRI
- Propensity score-matched group of patients who did not
- All patients were treated with a glycoprotein IIb/IIIa inhibitor and almost all also received aspirin, clopidogrel, and heparin
- Hospitalized patients treated with SSRIs were more likely to experience abnormal bleeding
de Abajo et al 200817 - Nested case-control study
- 1,321 patients with UGIB
- 10,000 control subjects matched for age, sex, and calendar year of the index date
- Patients with GI bleeding used significantly more SSRIs or venlafaxine
- NSAID use enhanced the association between SSRI and bleeding
Lewis et al 200818 - Prospective case-control study
- 359 case subjects hospitalized for UGIB, perforation, or benign gastric outlet obstruction
- 1889 control subjects recruited from same region
- Moderate to high affinity SSRI use was associated with significantly increased odds of hospitalization for upper GI toxicity (adjusted OR 2.0; 95% CI, 1.4-3.0).
Opatrny et al 200819 - Case-control study
- 4,028 cases of GI hemorrhage
- 40,171 controls
- SSRIs and venlafaxine were associated with risk of bleeding
- TCAs not associated with risk of bleeding
Vidal et al 20086 - Prospective population-based case-control study
- 2813 incident cases of UGIB
- 7193 matched controls
- UGIB in patients taking SSRIs + NSAIDs no different than NSAIDs alone
- SSRI dose and affinity for SERT did not increase the bleeding risk
Targownik et al 20097 - Population-based matched case-control analysis
- 1,552 patients admitted to the hospital with a primary diagnosis of UGIB
- 68,590 matched outpatient controls with no history of UGIB
- SSRI use increased bleeding risk
- SSRI + NSAID did not increase bleeding risk more than NSAID alone
- PPI therapy decreased bleeding risk related to SSRIs
Dall et al 200920 - Population-based case-control study
- 3652 cases with a first discharge diagnosis of serious UGIB
- 36,502 controls matched for age and sex
- Significantly increased risk of UGIB for current, recent, and past users of SSRIs
- Risk of bleeding with SSRI was not dependent on dose or gender, but was higher with recent initiation and age >55
- The risk of UGIB was elevated with fluoxetine, sertraline, and citalopram but not with other SSRIs, venlafaxine, or TCAs
- SSRI + NSAID use with and without aspirin had an elevated odds of UGIB
Barbui et al 200921 - Case-control study
- 11,025 case patients were admitted for bleeding abnormalities
- Matched with 21,846 eligible control subjects
- 1008 were admitted for GIbleeding
- Matched with 1990 eligible control subjects
- Antidepressants increased the risk of GI bleeding but did not increase the risk of any bleeding
- SSRIs or TCAs did not increase the risk of GI bleeding
Carvajal et al 20114 - Prospective case-control study
- 581 cases of primary diagnosis of acute UGIB
- 1358 controls matched by sex, age, date of admission within 3 months
- No significant risk for UGIB was found (adjusted OR 1.06; 95% CI, 0.57-1.96)
- Risk of bleeding remained nonsignificant in those who did not self-medicate with NSAIDs and in those who took a high-affinity SSRI
Verdel et al 201122 - Population-based case-control study
- 28,289 cases of hospitalization for bleeding (gastrointestinal, intracranial, or in the female genital tract).
- 50,786 matched controls
- Current use of antidepressant drugs was associated with all 3 types of bleeding
- No clear association was found between the degree of affinity for SERT or the serotonin receptor and the risk of any of the 3 types of bleeding
ACS, acute coronary syndrome; CI, confidence interval; GI, gastrointestinal; LGIB, lower gastrointestinal bleed; NSAID, non-steroidal anti-inflammatory drug; OR, odds ratio; RR, relative risk; SERT, SERotonin Transporter; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; UGIB, upper gastrointestinal bleed.
Timeline of Bleeding
Although SSRIs can increase gastric acidity immediately after administration, bleeds are not likely to occur immediately upon initiation.1 Platelet impairment due to depletion of serotonin stores may be delayed by several weeks. An actual bleed is more likely to occur if the patient has a primary pathology for bleeding, such as a gastric mucosal lesion, prior to the administration of SSRIs or if one develops during administration. Once the drug is discontinued and gastric acidity normalizes, the risk will likely end.
Management
Based on the available literature and knowledge of the potential mechanisms and aggravating factors, there is no need to pre-emptively change the management of the depressed patient based on this potential adverse reaction alone. If the patient has serious and important primary pathology for ulceration, consideration may be taken to initiate a different class of antidepressant if possible. Even in patients with aggravating factors such as liver disease, ulcerative disease, NSAID use, or anticoagulation, SSRIs should not be avoided if these are the best choice for the patient.1 Careful and frequent monitoring through occult blood in stool testing and of symptoms such as unexplained, abnormal bleeding should suffice to avoid serious bleeding events. Hematologic laboratory monitoring may not be sensitive enough to detect abnormalities and should not be relied upon alone. Proton-pump inhibitors have been shown to mitigate the risk of bleeding events in patients taking SSRIs, so these may be an option for management of patients with other risk factors who are initiating therapy with an SSRI or who complain of GI symptoms after therapy initiation.
Conclusion
Although multiple studies have been published in the past decade examining the potential increased risk of upper GI bleeding with the use of SSRIs, the quality and heterogeneity of these studies prevent a clear conclusion from being made. Many confounding factors, such as concomitant medications and baseline comorbidities, may be the cause of such conflicting evidence. While therapy should not be changed in those individuals who require SSRIs on the basis of bleeding risk alone, health care providers should closely monitor patients for signs and symptoms of upper GI bleeds.
References
1. Andrade C, Sandarsh S, Chethan KB, Nagesh KS. Serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms. J Clin Psychiatry. 2010;71(12):1565-1575.
2. Bismuth-Evenzal Y, Gonopolsky Y, Gurwitz D, Iancu I, Weizman A, Rehavi M. Decreased serotonin content and reduced agonist-induced aggregation in platelets of patients chronically medicated with SSRI drugs. J Affect Disord. 2012;136(1-2):99-103.
3. Athimulam S, Sharma N, Khan SA. Upper gastrointestinal bleeding in a patient receiving selective serotonin reuptake inhibitor. BMJ Case Rep. 2011; pii: bcr0120113741. doi: 10.1136/bcr.01.2011.3741.
4. Carvajal A, Ortega S, Del Olmo L, et al. Selective serotonin reuptake inhibitors and gastrointestinal bleeding: a case-control study. PLoS One. 2011;6(5):e19819.
5. de Abajo FJ, Montero D, Rodríguez LA, Madurga M. Antidepressants and risk of upper gastrointestinal bleeding. Basic Clin Pharmacol Toxicol. 2006;98(3):304-310.
6. Vidal X, Ibáñez L, Vendrell L, et al. Risk of upper gastrointestinal bleeding and the degree of serotonin reuptake inhibition by antidepressants: a case-control study. Drug Saf. 2008;31(2):159-168.
7. Targownik LE, Bolton JM, Metge CJ, Leung S, Sareen J. Selective serotonin reuptake inhibitors are associated with a modest increase in the risk of upper gastrointestinal bleeding. Am J Gastroenterol. 2009;104(6):1475-1482.
8. de Abajo FJ, Rodríguez LA, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. BMJ. 1999;319(7217):1106-1109.
9. Dunn NR, Pearce GL, Shakir SA. Association between SSRIs and upper gastrointestinal bleeding. SSRIs are no more likely than other drugs to cause such bleeding. BMJ. 2000;320(7246):1405-1406.
10. van Walraven C, Mamdani MM, Wells PS, Williams JI. Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. BMJ. 2001;323(7314):655-658.
11. Dalton SO, Johansen C, Mellemkjaer L, Nørgård B, Sørensen HT, Olsen JH. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med. 2003;163(1):59-64.
12. Meijer WE, Heerdink ER, Nolen WA, Herings RM, Leufkens HG, Egberts AC. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants. Arch Intern Med. 2004;164(21):2367-2370.
13. 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.
14. Wessinger S, Kaplan M, Choi L, et al. Increased use of selective serotonin reuptake inhibitors in patients admitted with gastrointestinal haemorrhage: a multicentre retrospective analysis. Aliment Pharmacol Ther. 2006;23(7):937-944.
15. Helin-Salmivaara A, Huttunen T, Grönroos JM, Klaukka T, Huupponen R. Risk of serious upper gastrointestinal events with concurrent use of NSAIDs and SSRIs: a case-control study in the general population. Eur J Clin Pharmacol. 2007;63(4):403-408.
16. Ziegelstein RC, Meuchel J, Kim TJ, Latif M, Alvarez W, Dasgupta N, Thombs BD. Selective serotonin reuptake inhibitor use by patients with acute coronary syndromes. Am J Med. 2007;120(6):525-530.
17. de Abajo FJ, García-Rodríguez LA. Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-inflammatory drugs and effect of acid-suppressing agents. Arch Gen Psychiatry. 2008;65(7):795-803.
18. Lewis JD, Strom BL, Localio AR, et al. Moderate and high affinity serotonin reuptake inhibitors increase the risk of upper gastrointestinal toxicity. Pharmacoepidemiol Drug Saf. 2008;17(4):328-335.
19. Opatrny L, Delaney JA, Suissa S. Gastro-intestinal haemorrhage risks of selective serotonin receptor antagonist therapy: a new look. Br J Clin Pharmacol. 2008;66(1):76-81.
20. Dall M, Schaffalitzky de Muckadell OB, Lassen AT, Hansen JM, Hallas J. An association between selective serotonin reuptake inhibitor use and serious upper gastrointestinal bleeding. Clin Gastroenterol Hepatol. 2009;7(12):1314-1321.
21. Barbui C, Andretta M, De Vitis G, et al. Antidepressant drug prescription and risk of abnormal bleeding: a case-control study. J Clin Psychopharmacol. 2009;29(1):33-38.
22. Verdel BM, Souverein PC, Meenks SD, Heerdink ER, Leufkens HG, Egberts TC. Use of serotonergic drugs and the risk of bleeding. Clin Pharmacol Ther. 2011;89(1):89-96.
Written by:
Michelle Bryson, PharmD
University of Illinois at Chicago
September 2012
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What are the data supporting the approval of the new, purified omega-3 lipid agent (icosapent ethyl)?
What are the data supporting the approval of the new, purified omega-3 lipid agent (icosapent ethyl)?
Introduction
In late July, Amarin Corporation announced that it had received approval from the Food and Drug Administration (FDA) for its icosapent ethyl (Vascepa) capsules.1 This new medication is an ultra-pure omega-3 fatty acid product, which contains primarily eicosapentaenoic acid (EPA, ≥ 96%) in a 1-g capsule. The capsules are indicated as an adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridemia, defined as triglycerides greater than or equal to 500 mg/dL.
Recommendations for omega-3 fatty acids
The American Heart Association (AHA) has long endorsed the consumption of fish products and vegetables containing plant-derived omega-3 fatty acids because of their cardiovascular health benefits.2 Specifically, the AHA recommends that patients without documented coronary heart disease (CHD) eat a variety of (preferably oily) fish at least twice a week and include oils and foods rich in alpha-linolenic acid (eg, flaxseed, canola and soybean oils, flaxseed and walnuts) in their diets. For those with CHD, the organization recommends consumption of at least 1 g of EPA plus docosahexaenoic acid (DHA), given as fatty fish products or as a dietary supplement in consultation with a physician. In addition, AHA recommends that for patients with documented elevated triglyceride levels, 2 to 4 g of EPA plus DHA per day be given with oversight from a physician.
How icosapent ethyl differs from omega-3-acid ethyl esters (Lovaza)
Until recently, omega-3-acid ethyl esters (Lovaza) was the only other prescription omega-3 fatty acid product on the market.3 This product contains 84% EPA plus DHA ethyl esters and is approved for the same indication as icosapent ethyl.1,3,4 The 2 products differ, however, in that icosapent ethyl is purely an EPA-containing product and lacks DHA. This is important because data have shown that although both EPA and DHA reduce triglyceride levels, it is the DHA component that is primarily responsible for elevations in low-density lipoprotein (LDL) levels.4 In addition, the DHA component has also been associated with elevations in high-density lipoprotein (HDL) levels and in LDL particle size.
The lack in elevation of LDL levels may be viewed as a benefit by some; however, the true clinical significance of this lipid effect is yet to be determined.4 This is because DHA increases LDL particle size, and larger LDL particles are considered less atherogenic than smaller, dense LDL particles, suggesting that the shift may not be detrimental.
The MARINE and ANCHOR trials
Approval of icosapent ethyl was based on data from the MARINE clinical trial.5 This trial was a randomized, placebo-controlled, double-blind, parallel-group study of 229 adult patients with very high fasting triglyceride levels, between 500 and 2000 mg/dL. Patients treated for 12 weeks with the recommended daily dose of 4 g demonstrated a statistically significant placebo-adjusted median triglyceride reduction of 33.1% (p<0.0001) and did not show an increase in LDL cholesterol levels compared with placebo. In addition, treatment with icosapent ethyl 4 g/d showed statistically significant placebo-adjusted median reductions from baseline in non-HDL cholesterol levels (17.7%), total cholesterol (16.3%), very low density lipoprotein (VLDL) cholesterol (28.6%), and apolipoprotein B (8.5%).
The efficacy of icosapent ethyl was also evaluated in the ANCHOR trial.6 This trial was a phase 3, multicenter, placebo-controlled, randomized, double-blinded, 12–week clinical trial in high-risk statin-treated patients (n=702) with triglyceride levels between 200 and <500 mg/dL despite having LDL levels in the range of 40 to 100 mg/dL. After 12 weeks, treatment with icosapent ethyl 4 g/d resulted in a significant median placebo-adjusted percent change from baseline in triglyceride levels of 21.5% (p<0.0001). In addition, median placebo-adjusted reductions in LDL (6.2%), non-HDL cholesterol (13.6%), apolipoprotein B (9.3%), total cholesterol (12.0%), VLDL (24.4%), lipoprotein-associated phospholipase A2 (19.0%), and high-sensitivity C-reactive protein (22.0%) were also observed with use of icosapent ethyl 4 g/d.
Safety considerations
In both the MARINE and ANCHOR trials, treatment-emergent adverse events were similar among those treated with icosapent ethyl as compared with placebo. 5,6 In the MARINE trial, any treatment-emergent event occurred in 35% of the 4 g/d group versus 37% in the placebo group.5 Diarrhea, nausea, and eructation were the most commonly observed events. In the ANCHOR trial, any treatment-emergent event occurred in 45.5% of the 4 g/d group versus 48.1% in the placebo group.6 Diarrhea, nausea, nasopharyngitis, and arthralgia occurred in >3% of patients, and only arthralgia occurred in a larger percentage of patients treated with icosapent ethyl as compared with placebo.
The labeling for icosapent ethyl has few contraindications and warnings/precautions.1 The drug is contraindicated in patients with a known hypersensitivity to the agent, and warnings include monitoring hepatic function in those with hepatic impairment and using the agent cautiously in patients with a fish allergy and/or shellfish allergy. In addition, some data suggest that omega-3 fatty acids may prolong bleeding time, so patients receiving icosapent ethyl with other drugs that affect coagulation should be monitored periodically.
Summary
The approval of icosapent ethyl now offers clinicians another prescription option for the management of extremely high triglyceride levels. This agent has been shown not to adversely affect LDL levels; however, the clinical implications of this effect remain to be seen. As of August 2012, no head-to-head studies comparing this product with the other prescription omega-3 product have been published, and no outcome data are available evaluating the effects of icosapent ethyl on cardiovascular morbidity or mortality. Therefore, additional data are needed before firm conclusions can be drawn about proper selection between agents.
References
1. Vascepa [package insert]. Bedminster, NJ: Amarin; 2012.
2. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2003;23(2):e20-e30.
3. Lovaza [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2010.
4. Davidson MH, Kling D, Maki KC. Novel developments in omega-3 fatty acid-based strategies. Curr Opin Lipidol. 2011;22(6):437-444.
5. Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial). Am J Cardiol. 2011;108(5):682-690.
6. Ballantyne CM. Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR Study). Am J Cardiol. 2012; doi:10.1016/j.amjcard.2012.05.031.
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What are the recommendations for use of the meningococcal vaccines Menomune, Menactra, and Menveo?
What are the recommendations for use of the meningococcal vaccines Menomune, Menactra, and Menveo?
Background
Neisseria meningitidis causes approximately 1000 cases of meningococcal disease in the United States annually.1 Serogroups Y, C, and B are responsible for most cases, followed by W-135.2 The meningococcal tetravalent polysaccharide vaccine MPSV4, also known by the trade name Menomune-A,C,Y,W-135, was approved for use in the United States in 1981 for ages 2 years and older.3 It provided well-established protection against serogroups A and C in school-aged children and adults. The serogroups Y and W-135 were shown to help elicit bactericidal antibody responses. Currently, there is no vaccine against serogroup B, which is most prevalent in infants, accounting for >50% of meningococcal cases. In 2005, a meningococcal tetravalent conjugate vaccine, MCV4, was licensed for use in the United States after displaying noninferiority to MPSV4, as well as a fourfold increase in bactericidal antibody production. It is also known by the trade name Menactra. Menveo, another MCV4 conjugated meningococcal vaccine, was approved by the Food and Drug Administration (FDA) in 2010.4 It is approved for use in ages 2 to 55 years, while Menactra is approved for use in ages 9 months to 55 years. 5 Menomune, the original meningococcal vaccine, is the only one approved for use in persons older than 55 years.6 Epidemiological trends and efforts toward optimizing protection during ages when meningococcal rates peak (ages 16 through 21 years) have led to recent updated recommendations on the use of the 3 available meningococcal vaccines.2
Comparison of MPSV4 and MCV4
Both MPSV4 (Menomune) and MCV4 (Menactra and Menveo) are tetravalent mixtures of meningococcal polysaccharide antigens serogroups A, C, Y, and W-135, but MCV4 vaccines contain these same serogroup polysaccharides conjugated to a diphtheria protein carrier.7 Conjugation of the polysaccharides to protein carriers (diphtheria toxoids) allows for a more robust response through stimulation of T-lymphocytes.3 Compared to the polysaccharide vaccine (MPSV4), immunogenicity elicited by the conjugate vaccines (MCV4) is characterized by a longer and anamnestic response. The conjugate vaccines are also believed to better reduce bacterial carriage in the nose and throat as compared to the polysaccharide vaccine.8 Currently, MCV4 is preferred for ages 9 months to 55 years, and MPSV4 may be used for those older than 55 years. However, MPSV4 may be used in persons 2 to 55 years who have a contraindication to MCV4 vaccines. MCV4 vaccines are now considered interchangeable after data showed the 2 MCV4 vaccines resulted in similar titer levels 3 years after a primary dose, as well as similar titer levels after a booster dose regardless of which product was administered for the primary dose.9 Table 1 provides basic comparisons of the 3 meningococcal vaccines.
Table 1. Comparison of meningococcal vaccines.7
Characteristics Meningococcal Vaccine Type Generic name Meningococcal Polysaccharide Vaccine A/C/Y/W-135 (MPSV4) Meningococcal Conjugate Vaccine A/C/Y/W-135 (MCV4) Meningococcal Conjugate Vaccine A/C/Y/W-135 (MCV4) Brand name Menomune-A/C/Y/W-135 Menactra Menveo Indications 2 years and older in those needing protection: military basic trainees, outbreak settings, college students 9 months to 55 years in those needing protection: military basic trainees, outbreak settings, adolescents 11 to 18 years of age or college students Age 2 to 55 years in those needing protection: military basic trainees, outbreak settings, adolescents 11 to 18 years of age or college students Concentration 50 mcg of each serogroup polysaccharide per 0.5 mL 4 mcg of each serogroup polysaccharide per 0.5 mL 10 mcg of serogroup A and 5 mcg each of serogropus C, Y and W-135 polysaccharides per 0.5 mL Dose 0.5 mL as a single dosea Ages 9 through 23 months: 2 doses of 0.5 mL, 3 months apart Ages 2 through 55 years: a single dose of 0.5 mLa 0.5 mL as a single dosea Route of administration Subcutaneous Intramuscular Intramuscular Packaging Single-dose, 10-dose vials (contain thimerosal preservative) Single-dose vials Package of 5 vials of lyophilized MenA powder and 5 vials of MenCYW-135 liquid Storage 2° to 8°C 2° to 8°C 2° to 8°C Stability Discard multidose vial within 35 days of reconstitution n/a Discard within 8 hours after reconstitution a Dose for persons with no risk factors for meningococcal disease. See “Meningococcal vaccine updates for management of patients with risk factors for meningococcal disease.
The Advisory Committee on Immunization Practices (ACIP) meningococcal vaccine recommendations:
Use of MCV4 in children 10
- Children ages 9 months to 10 years at increased risk, including those who:
- Have complement deficiencies (eg, C5-C9, properidin, factor H, or factor D)
- Travel to or residents of countries in which meningococcal disease is hyperendemic or epidemic
- Are part of an outbreak of a vaccine-preventable serogroup
- Have human immunodeficiency virus (HIV) infection
- Children ages 2 to 10 years and have anatomic or functional asplenia
- Children ages 2 to 10 years with no increased risks for acquiring meningococcal disease are not recommended to receive the meningococcal vaccine 9
Use of MCV4 in adolescents 10
- All adolescents ages 11 to 18 years
- Preferred age of primary vaccination is 11 or 12 years
- Preferred age of booster is 16 years
Use of MCV4 or MPSV4 in adults 11
- College freshmen living in a dormitory if not previously vaccinated or did not receive booster dose
- Military recruits
- Those with a damaged spleen or asplenia
- Those with terminal complement deficiency
- Microbiologists who are routinely exposed to N meningitidis
- Those traveling to areas where the disease is common
- Adults over 21 years with no increased risks for acquiring meningococcal disease are not recommended to receive the meningococcal vaccine11
Meningococcal vaccine updates
In 2010, ACIP updated meningococcal conjugate vaccine recommendations to include the following: a 2-dose primary series spaced 2 months apart for persons ages 2 through 54 years with a reduced response to a single dose/risk factors for meningococcal disease and addition of a booster dose to adolescent scheduling.11 In 2011, meningococcal vaccination of children ages 9 through 23 months with Menactra was approved by the FDA, and ACIP recommended those in this age group with risk factors for meningococcal disease also receive a 2-dose primary series.12 The difference with this recommendation compared to those older than 23 months is that the 2-dose spacing is 3 months apart as opposed to 2 months apart. Data showed that serum bactericidal activity (SBA), a measure of immune response to vaccination, was increased with a 2-dose primary series in patients with HIV, asplenia, and complement component deficiency.11 These persons areat greater risk for developing meningococcal infection, with the risk being greater in persons with asplenia or complement component deficiency than in those with HIV. For patients ages 2 through 54 with reduced immune responses, a booster dose should be administered every 5 years upon completion of the 2-dose primary series.
The rationale for the booster dose in adolescent scheduling stems from waning immunity as evidenced by serologic data and trends in meningococcal epidemiology and vaccine effectiveness.11 The meningococcal vaccine was initially recommended by ACIP to be given at ages 11 or 12 years, with the expectations that persons receiving the vaccine would be protected through ages 16 to 21 years, when they are at greatest risk for meningococcal disease.3 However, despite decreases in meningococcal disease since 2000, there is still a peak incidence at age 18 years.12 Meningococcal conjugate vaccine efficacy lasts approximately 5 years, not 10 years as originally thought. Studies of booster doses of Menactra found they elicited higher geometric mean antibody titers and comparable adverse reactions compared to a primary dose of Menactra. It was also estimated that administering a booster dose has similar economic consequences as a single dose administered at age 11 or 15 years, but may prevent twice as many meningococcal cases and deaths. Upon review of these data, ACIP made the recommendation to routinely administer a booster dose of meningococcal conjugate vaccine at age 16 years, after the primary vaccination of all persons at ages 11 or 12 years. The minimum interval of time between doses is 8 weeks.13 The booster dose may be given using either of the available conjugate vaccines, regardless of which one was used for the primary vaccination. 9 If an adolescent received their first dose at age 16 years or later, a booster dose is not necessary.
State laws on meningococcal vaccination
Some states mandate that students attending college have proof of meningococcal vaccination.9 Schools and colleges may also require it as a condition of enrollment, particularly if a student is going to live on campus. Beginning January 1, 2012, the state of Texas requires all college students to be vaccinated against bacterial meningitis, with documentation that the vaccine was given in the past 5 years but no sooner than 10 days prior to the first day of enrollment. Students living off-campus or who are older than 30 years of age are exempt from the requirement. Some students may also be exempt if they have special documentation from a physician or a signed affidavit. A complete listing of state mandates can be found at http://www.immunize.org/laws/#menin.14
Vaccine for serogroup B meningococcal infection
Despite advances in meningococcal vaccination, protection against serogroup B strains—the strains responsible for a majority of cases of meningococcal disease in infants—has not been developed into a vaccine.15 The difficulty in developing a meningococcal vaccine effective against serogroup B antigen strains is due to the serogroup B polysaccharide similarity to human neural cell glycopeptide, which prevents the polysaccharide from being immunogenic. A randomized phase 2b trial investigated the safety and immunogenicity of a multicomponent vaccine against novel meningococcal serogroup B antigens in over 1800 infants.16 The vaccine was given in 2 different schedules either as part of routine vaccination series or separately. Efficacy was measured by percentage of infants who had a human complement serum bactericidal activity titer >5 against 3 meningococcal serogroup B strains 30 days after vaccine administration. In all groups, >99% of the infants reached this endpoint for 2 components of the vaccine, and approximately 80% reached this endpoint for the third component. The authors concluded the vaccine was immunogenic and had minimal interference with routine vaccination schedules. Limitations include that the endpoint was surrogate; meningococcal disease prevention was not measured. Also, the study did not measure duration of immunogenicity. However, this trial is a promising step toward protection of infants from the serogroup of meningococcal disease they are most commonly infected with, as well as a step toward complete coverage of all 5 serogroups of meningococcal disease.
Conclusion
Three meningococcal vaccines that cover meningococcal serogroups A, C, Y, and W-135 are available, including a polysaccharide vaccine and 2 conjugate vaccines. For all persons under 55 years of age with indications to receive the vaccine, the conjugate vaccine is preferred due to its ability to elicit a more robust immunogenic response. The meningococcal conjugate vaccine is now approved for use in infants from ages 9 to 24 months with risk factors for meningococcal disease. Recent updates by ACIP include recommendations for those with risk factors for the disease and/or compromised immune function (eg, complement deficiency, asplenia, or travel to areas where the disease is prevalent) to receive a 2-dose primary series and for a booster vaccination to be given in all adolescents. There is not a vaccine against serogroup B, but recent studies of an experimental vaccine against serogroup B show promising results.
References
1. Centers for Disease Control and Prevention. Meningococcal disease: help prevent it. http://www.cdc.gov/features/meningococcal/. Updated April 23, 2012. Accessed August 6, 2012.
2. Pollard AJ. Meningococcal infections. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012. http://www.accessmedicine.com/content.aspx?aID=9121092. Accessed August 6, 2012.
3. Centers for Disease Control and Prevention. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2005;54(RR-7):1-21.
4. Menveo [package insert]. Cambridge, MA: Novartis; 2011.
5. Menactra [package insert]. Swiftwater, PA: Sanofi Pasteur Inc; 2011.
6. Menomune [package insert]. Swiftwater, PA: Sanofi Pasteur Inc; 2012.
7. Grabenstein JD. Immunofacts: Vaccines and Immunologic Drugs – 2011 (36th revision). St. Louis, MO: Wolters Kluwer Health; 2010.
8. Immunization Action Coalition. Ask the experts: meningococcal disease. Updated April 2012. http://www.immunize.org/askexperts/experts_men.asp. Accessed August 17, 2012.
9. Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP). Licensure of a meningococcal conjugate vaccine for children aged 2 through 10 years and updated booster dose guidance for adolescents and other persons at increased risk for meningococcal disease. 2011. MMWR. 2011;60(30):1018-1019.
10. Centers for Disease Control and Prevention Advisory Committee on Immunization Practices. Vaccines for children program: Vaccines to prevent meningococcal disease. June 22, 2011. Centers for Disease Control and Prevention Website. http://www.cdc.gov/vaccines/programs/vfc/downloads/resolutions/06-11mening-mcv.pdf. Accessed August 6, 2012.
11. Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP). Updated recommendations for use of meningococcal conjugate vaccines. MMWR. 2011;60(03):72-76.
12. Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP). Recommendations of the advisory committee on immunization practices (ACIP) for use of quadrivalent meningococcal conjugate vaccine (MenACWY-D) among children aged 9 through 23 months at increased risk for invasive meningococcal disease. MMWR. 2011;60(40):1391-1392.
13. Centers for Disease Control and Prevention. Meningococcal: who needs to be vaccinated? November 16, 2011. http://www.cdc.gov/vaccines/vpd-vac/mening/who-vaccinate.htm. Accessed August 17, 2012.
14. Immunization Action Coalition. State information: State mandates on immunization and vaccine-preventable diseases. Updated June 2, 2011. http://www.immunize.org/laws/#menin. Accessed August 18, 2012.
15. Cohn AC, Messonnier NE. Inching toward a serogroup B meningococcal vaccine for infants. JAMA. 2012;307(6):614-615.
16. Gossger N, Snape MD, Yu L-M, et al; for the European MenB Vaccine Study Group. Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial. JAMA. 2012;307(6):573-582.
- Children ages 9 months to 10 years at increased risk, including those who: