Every year, 5% to 20% of US residents contract the flu, 200,000 are hospitalized for it, and 36,000 die of influenza-related complications. The economic impact, including direct medical costs and lost earnings, exceeds $87 billion.¹ Despite this, less than half of eligible US residents were vaccinated in the 2012–2013 season, with uninsured people more than twice as likely to forgo vaccination.^2,3

Several studies have shown that influenza vaccination reduces the need for outpatient encounters and hospitalizations and lowers the incidence of death from acute myocardial infarction, the rate of all-cause mortality, and even the incidence of therapies administered by implantable defibrillators.^4–6 In the 2012–2013 influenza season, vaccination prevented an estimated 3.2 million medically attended illnesses and almost 80,000 hospitalizations; 70% of hospitalizations prevented were in children age 6 months to 4 years and in adults over age 65.⁷

After the 2009 H1N1 pandemic, which disproportionately killed previously healthy adults, the US Centers for Disease Control and Prevention (CDC) expanded its vaccination recommendations to include everyone above the age of 6 months, with few contraindications.⁸

In addition, recent years have seen a great expansion in vaccine options, changes in the at-risk demographics, and continued widespread resistance to certain antiviral agents, with implications for practice in primary care.

Here, we review the barriers and the new options for treatment and prevention of influenza.

HEMAGGLUTININ AND NEURAMINIDASE

Influenza infection is caused by one of the circulating strains of influenza virus A or B.

The major viral surface glycoproteins are hemagglutinin and neuraminidase. Hemagglutinin plays an important role in viral attachment to host cells and is the major immunogen in the influenza vaccine. Neuraminidase contains an active enzymatic site that cleaves the newly formed budding influenza viruses from host-cell sialic acid residues and allows them to be released from the cell membrane to infect other respiratory epithelial cells. It is the target of currently recommended antiviral drugs.

VACCINE PRODUCTION

Throughout the year, 130 influenza centers around the world sample circulating strains and share their data with five World Health Organization (WHO) Collaborating Centers for Reference and Research on Influenza. The WHO analyzes the circulation patterns, predicts the strains most likely to be circulating in the next influenza season, and shares these strains with manufacturers of the vaccine.

Pharmaceutical companies then begin an elaborate process of producing and distributing hundreds of millions of doses of vaccine worldwide. The production traditionally uses millions of fertilized chicken eggs to produce strain-specific influenza hemagglutinin. Individual vaccine strains are combined into the final product after being inactivated by chemical or physical splitting of the viral envelope with or without subsequent purification of the hemagglutinin particles.

Before 2013, the WHO’s yearly recommendations included two strains of influenza A and a single strain of influenza B. In 2013, new quadrivalent vaccines that include protection against a second strain of influenza B were approved.

The WHO strain-selection process allows manufacturers about 6 months to produce the vaccine. In a typical year, the worldwide demand is about 400 million doses. The theoretical maximal annual worldwide capacity, given current techniques, is fewer than 1 billion doses, which is well short of the 10 billion doses necessary to allow for the double vaccination needed in a pandemic.⁹ Newly approved recombinant manufacturing techniques offer greater production efficiency, while novel methods of intradermal administration increase vaccine immunogenicity, decreasing the amount of viral antigens used per dose.

INACTIVATED VS LIVE-ATTENUATED

In addition to intramuscular inactivated influenza vaccine, a live-attenuated vaccine in the form of an intranasal spray (FluMist) became available in 2003. This form is generally favored in children, as it avoids the discomfort of an injection. It contains live, weakened, cold-adapted influenza strains that reproduce in the relatively colder temperatures of the exterior nares but cannot survive in the warmer temperatures of the lung and proximal airways. It is approved for healthy people 2 to 49 years of age, and some evidence suggests that it may be more effective than inactivated influenza vaccine in children,¹⁰ although its utility is limited by multiple contraindications (see below).

INFLUENZA VACCINE INDICATIONS AND CONTRAINDICATIONS

Vaccination for influenza is recommended for all persons 6 months of age and older, an expansion from pre-2009 guidelines that did not recommend vaccination for healthy adults age 19 to 49 who were not in contact with people at high risk of influenza-related complications.⁸ Many new vaccine formulations have become available in recent years, each with specific benefits, risks, and target populations (Table 1).

Contraindications to inactivated vaccine

The only firm contraindication to inactivated influenza vaccine is previous severe allergic reaction to influenza vaccine or any of its components. Those with moderate to severe acute illness are advised to wait until their condition improves before being vaccinated. People who have had Guillain-Barré syndrome and those with egg allergy are discussed in MISAPPREHENSIONS THAT POSE BARRIERS TO VACCINATION, below. There is no risk of influenza infection from inactivated influenza vaccine.

Contraindications to live-attenuated influenza vaccine

Unlike inactivated influenza vaccine, the live-attenuated vaccine does result in shedding of vaccine-strain virus from the vaccinated host, with the theoretical potential for transmission of the virus from the vaccine recipient to other people, as well as the potential for influenza-like illness in vaccine recipients.^11,12 Based on reported events, the former is estimated to occur in 10 to 20 per 1 million vaccinations, although these cases have never been proven to be caused by a cold-adapted vaccine-strain rather than by coincidental transmission of circulating wild-type viral strains.¹³

Despite this exceedingly small risk of viral transmission, live-attenuated influenza vaccine has multiple contraindications, including age less than 2 years and more than 49 years, disease- or drug-related compromised immune status, pregnancy, egg allergy, and history of allergic reaction to the formulation. These limit its use and are important to review in detail before prescribing.¹⁴

Use of neuraminidase inhibitors within 2 days before or 2 weeks after receiving live-attenuated influenza vaccine may interfere with replication of the cold-adapted strain and decrease the vaccine’s effectiveness.¹⁴

EFFECTIVENESS OF INFLUENZA VACCINATION IN OLDER ADULTS

The effectiveness of influenza vaccination depends on the age and health status of the person being vaccinated, as well as on the quality of the match between the vaccine and the circulating influenza viruses.

In the 2012–2013 season, the adjusted vaccine effectiveness was 56% overall, 47% for influenza A H3N2, and 67% for influenza B. However, in people age 65 and older, the overall adjusted vaccine effectiveness was 27%, and only 9% for influenza A H3N2.¹⁵ Thus, even though the vaccine-virus match was considered good, the vaccine was suboptimally effective in the older group. This may be an argument for using the recently approved high-dose vaccine in that age group. Although the high-dose vaccine has been shown to be significantly more immunogenic in older adults, it is too early to know if it is clinically more effective in preventing influenza in this age group.

Despite the lower-than-expected effectiveness in preventing influenza in the 2012–2013 season in people age 65 and older, several well-designed studies found that influenza vaccination prevented severe disease, including one study that found vaccination to be 89% effective in reducing influenza-associated hospitalizations in the 2010–2011 flu season.^4,16

The limited effectiveness of vaccination in the older age group reminds us of the importance of early recognition and treatment of patients at high risk of influenza-related complications (see Table 2). It is also a call for greater compliance with vaccination in younger people, with a goal of achieving the 80% vaccination rate that has been calculated as adequate to achieve herd immunity.¹⁷

MISAPPREHENSIONS THAT POSE BARRIERS TO VACCINATION

Concern about potential adverse effects is the most common reason for refusing influenza vaccination, even among health care workers.¹⁸ However, the only commonly encountered adverse effect of the intramuscular inactivated influenza vaccine is injection-site pain.

‘Catching the flu from a flu shot’

Many people think that they can “catch the flu from a flu shot” (or think that they actually did), but vaccine-acquired influenza is not possible with the inactivated influenza vaccine,¹⁹ and it is only a theoretical, undocumented consideration with the live-attenuated vaccine.

Various respiratory viruses other than influenza also cause viral upper-respiratory infections during the influenza season. These infections may coincide with influenza vaccination and are frequently misconstrued as a side effect of the influenza vaccine or as evidence of vaccine ineffectiveness.

Unnecessary concerns about simultaneous vaccinations

Patients and doctors are often concerned about simultaneous administration of multiple vaccines and choose to spread out indicated vaccinations over multiple visits. This practice increases patients’ risk of illness from vaccine-preventable diseases. Research shows that simultaneous administration does not alter the safety or effectiveness of vaccination.^20–22 The CDC recommends simultaneous administration of all indicated live and inactivated vaccinations in order to reduce barriers to vaccination.²⁰

Fear of Guillain-Barré syndrome

Guillain-Barré syndrome, an acute ascending polyneuropathy, has been blamed on influenza vaccination in cases that developed after the 1976 influenza A (H1N1) epidemic.

Most cases are self-limiting but require intensive treatment and supportive care. Full recovery occurs in 60% of cases, though some people experience persistent symptoms. The mortality rate is less than 5%.²³

After the 1976 influenza pandemic, approximately 400 cases of Guillain-Barré syndrome arose in 45 million vaccine recipients, or about 1 case per 100,000 people.²⁴ Multiple subsequent population analyses concluded that the actual incidence of Guillain-Barré syndrome attributable to influenza vaccination is negligible, at less than 1 case in 1 million vaccinations. Against this, we should compare the real risk of illness and death from influenza infection, which itself is a risk factor for Guillain-Barré syndrome.²⁵

Should a person with a history of Guillain-Barré syndrome be revaccinated against influenza? The risk was evaluated in a large retrospective analysis of cases identified in the Kaiser Permanente Northern California Database from 1995 to 2006.²⁶ Five hundred fifty cases of Guillain-Barré syndrome were identified, of which 18 had arisen within 6 weeks of the patient receiving a flu shot. Four hundred five doses of inactivated influenza vaccine were subsequently given to 105 patients who had a history of Guillain-Barré syndrome, two of whom had developed the syndrome within 6 weeks of receiving the shot. There were no documented episodes of recurrent Guillain-Barré syndrome in any of these patients. Only 6 of 550 patients with a history of the disease developed it again; none of these 6 had received the influenza vaccine in the preceding 2 months, and only 1 had been exposed to the measles-mumps-rubella vaccine in the 4 months before vaccination.

Nevertheless, expert opinion recommends lifelong avoidance of any immunization that had been given within 6 weeks before the onset of symptoms of Guillain-Barré syndrome.²⁷

Overstated concern about egg allergy

Anaphylactic reactions can occur after influenza vaccination in people who have severe egg allergy, and concern about these reactions unfortunately prevents many otherwise eligible people with mild allergy from being vaccinated.

These reactions are much less common than feared. In a well-designed prospective cohort study of 367 patients with a history of egg allergy and positive skin-prick tests, including 132 with a history of severe allergy and 4 with a history of mild allergic symptoms arising in response to previous influenza vaccinations, none developed anaphylaxis.²⁸

The same authors reviewed 26 studies in more than 4,000 egg-allergic patients, of whom more than 500 had a history of severe egg-associated reactions, and likewise found no cases of influenza vaccine-associated anaphylaxis. They concluded that the inactivated influenza vaccine is safer than the egg-derived mumps-measles-rubella vaccine, for which precautions for egg allergy no longer exist.²⁸

People with a history of more serious reactions, ranging from stomach upset to anaphylaxis, can be safely vaccinated with a recombinant vaccine or referred to an allergist for further testing. People who experience hives as their only reaction to egg exposure should receive full-dose vaccination but then be observed for a half hour afterward.

The recombinant trivalent influenza vaccine Flublok was approved in 2013 for people age 18 to 49. It is the first commercially available influenza vaccine produced in a continuous insect cell line using a baculovirus vector. No eggs are used in its production, and it is approved for use in patients with egg allergy of any severity.

People who have a history of more serious reactions, including abdominal pain, nausea, vomiting, dizziness, or wheezing can be vaccinated with the recombinant vaccine or referred to an allergy specialist.

Despite this new option, understanding of alternative immunization guidelines for people with egg allergies, available on the CDC website²⁹ remains important, as the availability of the recombinant trivalent influenza vaccine remains limited in the 2013–2014 influenza season.

Misconception about mercury toxicity

Thimerosal is an ethylmercury-containing preservative used in multidose antiviral vaccines, including some influenza vaccines.³⁰ It is designed to prevent bacterial and fungal colonization of the vaccine vial while not reducing vaccine effectiveness or causing toxicity.

Contemporary understanding of mercury neurotoxicity is based largely on studies of methylmercury, including long-term, low-dose exposure in remote communities in the Faroe Islands and the Seychelles through regular consumption of fish and whale meat.^31,32 These exposure studies had conflicting results: those in the Faroe Islands demonstrated toxicity, but the Seychelles studies actually showed better neurologic test scores at higher mercury levels, a trend the authors attributed to the beneficial effects of maternal fish consumption.

The results of the methylmercury studies have been extrapolated to ethylmercury (contained in thimerosal), although the two chemicals have vastly different pharmacologic properties. For example, methylmercury has a longer half-life and greater transport across the blood-brain barrier.³³ A direct comparison found that ethylmercury is less toxic than methylmercury, although an increase in ethylmercury concentration of only 20% resulted in similar toxicity profiles.³⁴ These studies were performed at concentrations of mercury thousands of times higher than those resulting from vaccination: nearly 150,000 times greater than those in an average adult or 15,000 times greater than those in a 1-year-old child from the typical 25-μg thimerosal dose allowed in contemporary influenza vaccines.

Despite much negative publicity, no link has been shown between thimerosal and autism.³⁰ Multiple regulatory, scientific, and medical organizations including the US Food and Drug Administration (FDA), the WHO, the National Institutes of Health, the CDC, the American Academy of Pediatrics, and the American Congress of Obstetricians and Gynecologists (ACOG) have evaluated the data on the safety of thimerosal in vaccines and have agreed that it is safe. However, most of them urged vaccine manufacturers to eliminate mercury from vaccines as a precaution.^30,35 Thimerosal has subsequently been eliminated from all childhood vaccines except for influenza vaccine, with no resulting decrease in childhood autism diagnoses.³⁶

Considering that no harm from thimerosal at FDA-approved doses has been documented, and considering the real risk of influenza-related complications, particularly in young children and pregnant women, we recommend vaccination using whatever vaccine formulation is locally available for all patients, including children age 6 months and older and pregnant women. Nevertheless, given that mercury is being eliminated from childhood vaccines and that preservative-free single-dose vials are increasingly available in the United States, it seems reasonable to use thimerosal-free formulations for children, expectant mothers, and patients concerned about exposure if these formulations are readily available. Influenza vaccination should not be delayed if a thimerosal-free formulation is not readily available.

NEW VACCINE FORMULATIONS

Recent years have seen a dramatic expansion in influenza vaccine options (Table 1).

Quadrivalent vaccines

Quadrivalent vaccines protect against two strains of influenza A and two strains of influenza B, whereas earlier formulations included only one influenza B strain. Vaccination against either influenza B strain offers only limited cross-protection against the other B strain, and previous formulations involved assumptions about which strain would predominate in any given year. The CDC estimates that switching to quadrivalent vaccines will prevent up to 970,000 cases of influenza, 8,200 hospitalizations, and 485 deaths per year.³⁷

Intradermal vaccine

The newly available Fluzone Intradermal vaccine contains smaller doses of hemagglutinin but is still effective because antigen-presenting dendritic cells in the skin reduce the required amount of vaccine antigen necessary for inducing protection.³⁸ This may provide an advantage in the event of vaccine shortage. Also, since it is given in needles only 1.5 mm long, it may appeal to people who are afraid of needles.

The stronger immune reaction with intradermal administration causes more redness, induration, and tenderness at the injection site than with intramuscular administration.³⁹ Patients should not be surprised by this reaction and can be advised to apply ice packs for symptomatic relief.

High-dose vaccine

A high-dose vaccine was approved in 2009 for use in adults age 65 and older. It contains 60 μg of hemagglutinin, compared with 15 μg in standard-dose vaccines, and has been shown to improve seroconversion rates. It remains to be seen if this translates into better clinical outcomes in older adults.⁴⁰ Further studies will be necessary before we can recommend high-dose vaccines to other people with weakened immune response, such as those undergoing chemotherapy or those infected with human immunodeficiency virus (HIV).

Cell-based vaccines

Flucelvax was the first cell-based influenza vaccine. However, unlike the recombinant trivalent influenza vaccine, which uses no eggs in its manufacturing process, Flucelvax production starts with egg-derived influenza strains that are subsequently propagated in liquid culture of animal cells. It may therefore contain traces of egg protein, and it has not been studied in people with egg allergy.⁴¹

An advantage of the cell-based production technique is the use of fewer or no eggs at all, which may result in greater manufacturing efficiency. Also, it is a closed process that reduces the risk of bacterial contamination as well as reliance on antibiotics or preservatives, such as thimerosal, in the manufacturing process.⁴²

CHEMOPROPHYLAXIS WITH NEURAMINIDASE INHIBITORS

The mainstays of influenza prevention are seasonal vaccination and appropriate infection-prevention practices. In addition, in patients at high risk of influenza-related complications (Table 2),⁴³ postexposure chemoprophylaxis with a neuraminidase inhibitor, ie, oseltamivir (Tamiflu) or zanamivir (Relenza), is an effective preventive strategy, especially in years when the match between vaccine and circulating virus strains is suboptimal.^44,45

Neuraminidase inhibitors are competitive inhibitors of the active site of the influenza glycoprotein neuraminidase, responsible for viral release from infected respiratory epithelial cells. Rates of resistance to neuraminidase inhibitors have been less than 1% in the United States in recent years, while resistance to the adamantanes amantadine (Symmetrel) and rimantadine (Flumadine) can be as high as 92%, depending on the virus isolate. Thus, their use for treatment or prophylaxis of influenza is not currently recommended by the CDC.⁴⁶

Chemoprophylaxis with any agent may promote emergence of resistant strains, can cause adverse reactions, and should never be considered a substitute for vaccination.

ANTI-INFLUENZA AGENTS

Two neuraminidase inhibitors, oseltamivir and zanamivir, are approved by the FDA for preventing and treating uncomplicated influenza. Treatment must be instituted within 2 days of onset of symptoms to be effective.

Oseltamivir is available as an oral capsule or powder for liquid suspension. Its most common adverse effects are gastrointestinal upset including diarrhea, nausea, and vomiting.⁴⁴

Zanamivir is only available in the form of a dry powder inhaler because of the drug’s poor oral bioavailability, and only 4% to 17% of the inhaled dose is systemically absorbed.⁴⁵ There is a theoretical benefit in targeted delivery of zanamivir to the primary organ affected by influenza, and gastrointestinal side effects are less common with this drug.^44,45 Unfortunately, the zanamivir inhaler requires complicated assembly and dexterity for administration (see the video on YouTube⁴⁷), which may make it unreliable in certain patient groups, especially handicapped and elderly patients. Administration has been associated with bronchospasm, resulting in a more than 20% reduction in the forced expiratory volume in 1 second, and it is contraindicated in patients with underlying reactive airway disease such as chronic obstructive pulmonary disease or asthma.⁴⁵

Table 3 lists the doses and duration of therapy for oseltamivir and zanamivir in adults with normal renal function, as well as approximate costs. No generic formulations of neuraminidase inhibitors are currently available, and outpatient use may not be covered by medical insurance. Several other neuraminidase inhibitors are either under development or at various stages in the FDA approval process.

EFFECTIVENESS OF ANTI-INFLUENZA DRUGS

Treatment with oseltamivir has been shown to reduce the duration of symptoms by approximately 1 day if initiated within 36 hours of onset of illness and 1.5 to 2 days if initiated within 24 hours.^48,49 Trials and meta-analyses of zanamivir show similar effectiveness, though some suggest that symptoms were alleviated as much as 3 days sooner than in controls in a subgroup of patients who were febrile at presentation.^50,51 Dual neuraminidase inhibitor therapy in an attempt to prevent emergence of resistance seems logical but was actually found to be less effective than monotherapy, according to a 2010 study.⁵²

The effectiveness of neuraminidase inhibitors in reducing influenza-related complications and mortality rates has been controversial in recent years, as these outcomes were not addressed in initial studies that secured FDA approval. Several meta-analyses differ in their assessments of available data quality and conclusions. A 2009 Cochrane review questioned the completeness and the veracity of the data from manufacturer-funded trial data, much of which was unpublished and not made available to reviewers, and it concluded that a reduction of complications could not be supported by the available data.⁵³ Hernán and Lipsitch,⁵⁴ in a 2011 review, calculated that oseltamivir reduces the risk of lower respiratory tract complications by 28% in patients with influenza-like symptoms and by 37% in patients with confirmed influenza infection.

Additional trials and better access to available data are needed to settle the question of the effectiveness of neuraminidase inhibitors in reducing complications of influenza. Meanwhile, they remain strongly recommended by major health organizations, including the CDC and the WHO, which lists oseltamivir on its “model list of essential medicines.”

VIRAL RESISTANCE TO NEURAMINIDASE INHIBITORS

Viral resistance to neuraminidase inhibitors occurs through multiple mechanisms and may arise without selective pressure from exposure to these drugs.⁵⁵

Oseltamivir possesses a hydrophobic moiety that requires viral neuraminidase to undergo a complex reconfiguration to expose the active site prior to binding. Any mutation affecting its ability to undergo this structural rearrangement can promote resistance by decreased oseltamivir access to the active site.

Zanamivir has a structural homology to the neuraminidase active site and requires no such reconfiguration. Additionally, mutations promoting resistance to zanamivir may actually decrease viral fitness; thus, resistance to zanamivir is significantly less common than to oseltamivir.⁵⁵

About 2,000 influenza virus isolates currently circulating in the United States were tested for resistance; only 1% of the 2009 influenza A H1N1 isolates demonstrated resistance to oseltamivir, and none to zanamivir.⁵⁶

The CDC regularly updates the resistance patterns of circulating influenza strains at www.cdc.gov/flu/weekly/index.htm.

SPECIAL CONSIDERATIONS

Pregnancy

Pregnant women may be at higher risk of severe influenza complications. This was especially true during the 2009 H1N1 pandemic, when pregnant women had a five times higher risk of death from influenza-related complications. Additionally, fever during pregnancy is an independent risk factor for adverse outcomes in the offspring.⁵⁷ Maternal vaccination against influenza effectively protects the infant for the first 6 months of life, when vaccination is not recommended because of a poor immune response.⁵⁸

Live-attenuated influenza vaccine is contraindicated during pregnancy. Given the documented risks to the mother from influenza and no documented harm from preservatives in multiuse vaccine vials, the Advisory Committee on Immunization Practices (ACIP) and ACOG do not state a preference for thimerosal-containing or thimerosal-free vaccine for any group, including pregnant women. Pregnant women should be vaccinated with whatever inactivated influenza vaccine formulation is available at the earliest opportunity in the beginning of the influenza season, regardless of the trimester of pregnancy.

Pregnant women are at high risk of influenza-related complications and should be considered for postexposure antiviral prophylaxis or early treatment with a neuraminidase inhibitor. However, both of the approved neuraminidase inhibitors are in pregnancy safety category C, indicating possible adverse effects in animal studies and a lack of safety data in pregnant humans. As with all category C medications, the risks and benefits must be considered, taking into account maternal comorbidities, vaccination status, effectiveness of the season’s influenza vaccine, and the virulence of circulating influenza strains.

As oseltamivir is associated with nausea and gastrointestinal side effects and as zanamivir has less systemic absorption, it may be reasonable to prescribe zanamivir for women already experiencing severe pregnancy-related nausea.

Immunocompromised people

Inactivated influenza vaccine is recommended and live-attenuated influenza vaccine is contraindicated for all immunocompromised people. Generally speaking, any form of immune compromise will decrease the immunogenicity of the vaccine. Additional considerations vary depending on the cause and severity of the immunocompromised status.

HIV-infected patients have higher seroconversion rates when vaccinated with the high-dose vaccine than with the standard-dose vaccine; however, as in adults over age 65, the clinical benefit has yet to be evaluated.⁵⁹ The efficacy of vaccination is predictably related to the CD4 cell count, as T cells are necessary to mount a response.⁶⁰ No documented benefit is gained from booster influenza vaccination in this group of patients.

Cancer patients should receive inactivated influenza vaccine every year. Postexposure chemoprophylaxis should be considered, and early treatment with a neuraminidase inhibitor is recommended in patients undergoing chemotherapy.

Solid-organ transplant recipients face a risk of organ rejection if they contract influenza infection, in addition to a higher risk of influenza-related complications.⁶¹ Transplant recipients should receive inactivated influenza vaccine as soon as it becomes available at the beginning of every influenza season. Additional research is necessary to evaluate the safety and effectiveness of the high-dose influenza vaccine in this patient group.

MORE OPTIONS, GREAT BENEFIT

Influenza remains a significant source of morbidity and mortality in the United States, and emerging pandemic strains as well as the aging population pose the risk of increased disease burden. New vaccine options offer hope of greater safety, improved efficacy, and higher vaccination rates though broader appeal to individuals. The actual differences in protection between various vaccine options are insignificant relative to the overall benefit of vaccination.

Health care providers should inquire about patients’ understanding and address their concerns about vaccination. Giving an available influenza vaccine within approved indications should not be delayed if alternative vaccine options are not readily available.

In addition to vaccination, patients at high risk of complications should be advised early in the influenza season to inform their doctors about potential exposure to influenza or the development of flu-like symptoms for consideration of early treatment or postexposure prophylaxis with a neuraminidase inhibitor.

Every year, 5% to 20% of US residents contract the flu, 200,000 are hospitalized for it, and 36,000 die of influenza-related complications. The economic impact, including direct medical costs and lost earnings, exceeds $87 billion.¹ Despite this, less than half of eligible US residents were vaccinated in the 2012–2013 season, with uninsured people more than twice as likely to forgo vaccination.^2,3

Several studies have shown that influenza vaccination reduces the need for outpatient encounters and hospitalizations and lowers the incidence of death from acute myocardial infarction, the rate of all-cause mortality, and even the incidence of therapies administered by implantable defibrillators.^4–6 In the 2012–2013 influenza season, vaccination prevented an estimated 3.2 million medically attended illnesses and almost 80,000 hospitalizations; 70% of hospitalizations prevented were in children age 6 months to 4 years and in adults over age 65.⁷

After the 2009 H1N1 pandemic, which disproportionately killed previously healthy adults, the US Centers for Disease Control and Prevention (CDC) expanded its vaccination recommendations to include everyone above the age of 6 months, with few contraindications.⁸

In addition, recent years have seen a great expansion in vaccine options, changes in the at-risk demographics, and continued widespread resistance to certain antiviral agents, with implications for practice in primary care.

Here, we review the barriers and the new options for treatment and prevention of influenza.

HEMAGGLUTININ AND NEURAMINIDASE

Influenza infection is caused by one of the circulating strains of influenza virus A or B.

The major viral surface glycoproteins are hemagglutinin and neuraminidase. Hemagglutinin plays an important role in viral attachment to host cells and is the major immunogen in the influenza vaccine. Neuraminidase contains an active enzymatic site that cleaves the newly formed budding influenza viruses from host-cell sialic acid residues and allows them to be released from the cell membrane to infect other respiratory epithelial cells. It is the target of currently recommended antiviral drugs.

VACCINE PRODUCTION

Throughout the year, 130 influenza centers around the world sample circulating strains and share their data with five World Health Organization (WHO) Collaborating Centers for Reference and Research on Influenza. The WHO analyzes the circulation patterns, predicts the strains most likely to be circulating in the next influenza season, and shares these strains with manufacturers of the vaccine.

Pharmaceutical companies then begin an elaborate process of producing and distributing hundreds of millions of doses of vaccine worldwide. The production traditionally uses millions of fertilized chicken eggs to produce strain-specific influenza hemagglutinin. Individual vaccine strains are combined into the final product after being inactivated by chemical or physical splitting of the viral envelope with or without subsequent purification of the hemagglutinin particles.

Before 2013, the WHO’s yearly recommendations included two strains of influenza A and a single strain of influenza B. In 2013, new quadrivalent vaccines that include protection against a second strain of influenza B were approved.

The WHO strain-selection process allows manufacturers about 6 months to produce the vaccine. In a typical year, the worldwide demand is about 400 million doses. The theoretical maximal annual worldwide capacity, given current techniques, is fewer than 1 billion doses, which is well short of the 10 billion doses necessary to allow for the double vaccination needed in a pandemic.⁹ Newly approved recombinant manufacturing techniques offer greater production efficiency, while novel methods of intradermal administration increase vaccine immunogenicity, decreasing the amount of viral antigens used per dose.

INACTIVATED VS LIVE-ATTENUATED

In addition to intramuscular inactivated influenza vaccine, a live-attenuated vaccine in the form of an intranasal spray (FluMist) became available in 2003. This form is generally favored in children, as it avoids the discomfort of an injection. It contains live, weakened, cold-adapted influenza strains that reproduce in the relatively colder temperatures of the exterior nares but cannot survive in the warmer temperatures of the lung and proximal airways. It is approved for healthy people 2 to 49 years of age, and some evidence suggests that it may be more effective than inactivated influenza vaccine in children,¹⁰ although its utility is limited by multiple contraindications (see below).

INFLUENZA VACCINE INDICATIONS AND CONTRAINDICATIONS

Vaccination for influenza is recommended for all persons 6 months of age and older, an expansion from pre-2009 guidelines that did not recommend vaccination for healthy adults age 19 to 49 who were not in contact with people at high risk of influenza-related complications.⁸ Many new vaccine formulations have become available in recent years, each with specific benefits, risks, and target populations (Table 1).

Contraindications to inactivated vaccine

The only firm contraindication to inactivated influenza vaccine is previous severe allergic reaction to influenza vaccine or any of its components. Those with moderate to severe acute illness are advised to wait until their condition improves before being vaccinated. People who have had Guillain-Barré syndrome and those with egg allergy are discussed in MISAPPREHENSIONS THAT POSE BARRIERS TO VACCINATION, below. There is no risk of influenza infection from inactivated influenza vaccine.

Contraindications to live-attenuated influenza vaccine

Unlike inactivated influenza vaccine, the live-attenuated vaccine does result in shedding of vaccine-strain virus from the vaccinated host, with the theoretical potential for transmission of the virus from the vaccine recipient to other people, as well as the potential for influenza-like illness in vaccine recipients.^11,12 Based on reported events, the former is estimated to occur in 10 to 20 per 1 million vaccinations, although these cases have never been proven to be caused by a cold-adapted vaccine-strain rather than by coincidental transmission of circulating wild-type viral strains.¹³

Despite this exceedingly small risk of viral transmission, live-attenuated influenza vaccine has multiple contraindications, including age less than 2 years and more than 49 years, disease- or drug-related compromised immune status, pregnancy, egg allergy, and history of allergic reaction to the formulation. These limit its use and are important to review in detail before prescribing.¹⁴

Use of neuraminidase inhibitors within 2 days before or 2 weeks after receiving live-attenuated influenza vaccine may interfere with replication of the cold-adapted strain and decrease the vaccine’s effectiveness.¹⁴

EFFECTIVENESS OF INFLUENZA VACCINATION IN OLDER ADULTS

The effectiveness of influenza vaccination depends on the age and health status of the person being vaccinated, as well as on the quality of the match between the vaccine and the circulating influenza viruses.

In the 2012–2013 season, the adjusted vaccine effectiveness was 56% overall, 47% for influenza A H3N2, and 67% for influenza B. However, in people age 65 and older, the overall adjusted vaccine effectiveness was 27%, and only 9% for influenza A H3N2.¹⁵ Thus, even though the vaccine-virus match was considered good, the vaccine was suboptimally effective in the older group. This may be an argument for using the recently approved high-dose vaccine in that age group. Although the high-dose vaccine has been shown to be significantly more immunogenic in older adults, it is too early to know if it is clinically more effective in preventing influenza in this age group.

Despite the lower-than-expected effectiveness in preventing influenza in the 2012–2013 season in people age 65 and older, several well-designed studies found that influenza vaccination prevented severe disease, including one study that found vaccination to be 89% effective in reducing influenza-associated hospitalizations in the 2010–2011 flu season.^4,16

The limited effectiveness of vaccination in the older age group reminds us of the importance of early recognition and treatment of patients at high risk of influenza-related complications (see Table 2). It is also a call for greater compliance with vaccination in younger people, with a goal of achieving the 80% vaccination rate that has been calculated as adequate to achieve herd immunity.¹⁷

MISAPPREHENSIONS THAT POSE BARRIERS TO VACCINATION

Concern about potential adverse effects is the most common reason for refusing influenza vaccination, even among health care workers.¹⁸ However, the only commonly encountered adverse effect of the intramuscular inactivated influenza vaccine is injection-site pain.

‘Catching the flu from a flu shot’

Many people think that they can “catch the flu from a flu shot” (or think that they actually did), but vaccine-acquired influenza is not possible with the inactivated influenza vaccine,¹⁹ and it is only a theoretical, undocumented consideration with the live-attenuated vaccine.

Various respiratory viruses other than influenza also cause viral upper-respiratory infections during the influenza season. These infections may coincide with influenza vaccination and are frequently misconstrued as a side effect of the influenza vaccine or as evidence of vaccine ineffectiveness.

Unnecessary concerns about simultaneous vaccinations

Patients and doctors are often concerned about simultaneous administration of multiple vaccines and choose to spread out indicated vaccinations over multiple visits. This practice increases patients’ risk of illness from vaccine-preventable diseases. Research shows that simultaneous administration does not alter the safety or effectiveness of vaccination.^20–22 The CDC recommends simultaneous administration of all indicated live and inactivated vaccinations in order to reduce barriers to vaccination.²⁰

Fear of Guillain-Barré syndrome

Guillain-Barré syndrome, an acute ascending polyneuropathy, has been blamed on influenza vaccination in cases that developed after the 1976 influenza A (H1N1) epidemic.

Most cases are self-limiting but require intensive treatment and supportive care. Full recovery occurs in 60% of cases, though some people experience persistent symptoms. The mortality rate is less than 5%.²³

After the 1976 influenza pandemic, approximately 400 cases of Guillain-Barré syndrome arose in 45 million vaccine recipients, or about 1 case per 100,000 people.²⁴ Multiple subsequent population analyses concluded that the actual incidence of Guillain-Barré syndrome attributable to influenza vaccination is negligible, at less than 1 case in 1 million vaccinations. Against this, we should compare the real risk of illness and death from influenza infection, which itself is a risk factor for Guillain-Barré syndrome.²⁵

Should a person with a history of Guillain-Barré syndrome be revaccinated against influenza? The risk was evaluated in a large retrospective analysis of cases identified in the Kaiser Permanente Northern California Database from 1995 to 2006.²⁶ Five hundred fifty cases of Guillain-Barré syndrome were identified, of which 18 had arisen within 6 weeks of the patient receiving a flu shot. Four hundred five doses of inactivated influenza vaccine were subsequently given to 105 patients who had a history of Guillain-Barré syndrome, two of whom had developed the syndrome within 6 weeks of receiving the shot. There were no documented episodes of recurrent Guillain-Barré syndrome in any of these patients. Only 6 of 550 patients with a history of the disease developed it again; none of these 6 had received the influenza vaccine in the preceding 2 months, and only 1 had been exposed to the measles-mumps-rubella vaccine in the 4 months before vaccination.

Nevertheless, expert opinion recommends lifelong avoidance of any immunization that had been given within 6 weeks before the onset of symptoms of Guillain-Barré syndrome.²⁷

Overstated concern about egg allergy

Anaphylactic reactions can occur after influenza vaccination in people who have severe egg allergy, and concern about these reactions unfortunately prevents many otherwise eligible people with mild allergy from being vaccinated.

These reactions are much less common than feared. In a well-designed prospective cohort study of 367 patients with a history of egg allergy and positive skin-prick tests, including 132 with a history of severe allergy and 4 with a history of mild allergic symptoms arising in response to previous influenza vaccinations, none developed anaphylaxis.²⁸

The same authors reviewed 26 studies in more than 4,000 egg-allergic patients, of whom more than 500 had a history of severe egg-associated reactions, and likewise found no cases of influenza vaccine-associated anaphylaxis. They concluded that the inactivated influenza vaccine is safer than the egg-derived mumps-measles-rubella vaccine, for which precautions for egg allergy no longer exist.²⁸

People with a history of more serious reactions, ranging from stomach upset to anaphylaxis, can be safely vaccinated with a recombinant vaccine or referred to an allergist for further testing. People who experience hives as their only reaction to egg exposure should receive full-dose vaccination but then be observed for a half hour afterward.

The recombinant trivalent influenza vaccine Flublok was approved in 2013 for people age 18 to 49. It is the first commercially available influenza vaccine produced in a continuous insect cell line using a baculovirus vector. No eggs are used in its production, and it is approved for use in patients with egg allergy of any severity.

People who have a history of more serious reactions, including abdominal pain, nausea, vomiting, dizziness, or wheezing can be vaccinated with the recombinant vaccine or referred to an allergy specialist.

Despite this new option, understanding of alternative immunization guidelines for people with egg allergies, available on the CDC website²⁹ remains important, as the availability of the recombinant trivalent influenza vaccine remains limited in the 2013–2014 influenza season.

Misconception about mercury toxicity

Thimerosal is an ethylmercury-containing preservative used in multidose antiviral vaccines, including some influenza vaccines.³⁰ It is designed to prevent bacterial and fungal colonization of the vaccine vial while not reducing vaccine effectiveness or causing toxicity.

Contemporary understanding of mercury neurotoxicity is based largely on studies of methylmercury, including long-term, low-dose exposure in remote communities in the Faroe Islands and the Seychelles through regular consumption of fish and whale meat.^31,32 These exposure studies had conflicting results: those in the Faroe Islands demonstrated toxicity, but the Seychelles studies actually showed better neurologic test scores at higher mercury levels, a trend the authors attributed to the beneficial effects of maternal fish consumption.

The results of the methylmercury studies have been extrapolated to ethylmercury (contained in thimerosal), although the two chemicals have vastly different pharmacologic properties. For example, methylmercury has a longer half-life and greater transport across the blood-brain barrier.³³ A direct comparison found that ethylmercury is less toxic than methylmercury, although an increase in ethylmercury concentration of only 20% resulted in similar toxicity profiles.³⁴ These studies were performed at concentrations of mercury thousands of times higher than those resulting from vaccination: nearly 150,000 times greater than those in an average adult or 15,000 times greater than those in a 1-year-old child from the typical 25-μg thimerosal dose allowed in contemporary influenza vaccines.

Despite much negative publicity, no link has been shown between thimerosal and autism.³⁰ Multiple regulatory, scientific, and medical organizations including the US Food and Drug Administration (FDA), the WHO, the National Institutes of Health, the CDC, the American Academy of Pediatrics, and the American Congress of Obstetricians and Gynecologists (ACOG) have evaluated the data on the safety of thimerosal in vaccines and have agreed that it is safe. However, most of them urged vaccine manufacturers to eliminate mercury from vaccines as a precaution.^30,35 Thimerosal has subsequently been eliminated from all childhood vaccines except for influenza vaccine, with no resulting decrease in childhood autism diagnoses.³⁶

Considering that no harm from thimerosal at FDA-approved doses has been documented, and considering the real risk of influenza-related complications, particularly in young children and pregnant women, we recommend vaccination using whatever vaccine formulation is locally available for all patients, including children age 6 months and older and pregnant women. Nevertheless, given that mercury is being eliminated from childhood vaccines and that preservative-free single-dose vials are increasingly available in the United States, it seems reasonable to use thimerosal-free formulations for children, expectant mothers, and patients concerned about exposure if these formulations are readily available. Influenza vaccination should not be delayed if a thimerosal-free formulation is not readily available.

NEW VACCINE FORMULATIONS

Recent years have seen a dramatic expansion in influenza vaccine options (Table 1).

Quadrivalent vaccines

Quadrivalent vaccines protect against two strains of influenza A and two strains of influenza B, whereas earlier formulations included only one influenza B strain. Vaccination against either influenza B strain offers only limited cross-protection against the other B strain, and previous formulations involved assumptions about which strain would predominate in any given year. The CDC estimates that switching to quadrivalent vaccines will prevent up to 970,000 cases of influenza, 8,200 hospitalizations, and 485 deaths per year.³⁷

Intradermal vaccine

The newly available Fluzone Intradermal vaccine contains smaller doses of hemagglutinin but is still effective because antigen-presenting dendritic cells in the skin reduce the required amount of vaccine antigen necessary for inducing protection.³⁸ This may provide an advantage in the event of vaccine shortage. Also, since it is given in needles only 1.5 mm long, it may appeal to people who are afraid of needles.

The stronger immune reaction with intradermal administration causes more redness, induration, and tenderness at the injection site than with intramuscular administration.³⁹ Patients should not be surprised by this reaction and can be advised to apply ice packs for symptomatic relief.

High-dose vaccine

A high-dose vaccine was approved in 2009 for use in adults age 65 and older. It contains 60 μg of hemagglutinin, compared with 15 μg in standard-dose vaccines, and has been shown to improve seroconversion rates. It remains to be seen if this translates into better clinical outcomes in older adults.⁴⁰ Further studies will be necessary before we can recommend high-dose vaccines to other people with weakened immune response, such as those undergoing chemotherapy or those infected with human immunodeficiency virus (HIV).

Cell-based vaccines

Flucelvax was the first cell-based influenza vaccine. However, unlike the recombinant trivalent influenza vaccine, which uses no eggs in its manufacturing process, Flucelvax production starts with egg-derived influenza strains that are subsequently propagated in liquid culture of animal cells. It may therefore contain traces of egg protein, and it has not been studied in people with egg allergy.⁴¹

An advantage of the cell-based production technique is the use of fewer or no eggs at all, which may result in greater manufacturing efficiency. Also, it is a closed process that reduces the risk of bacterial contamination as well as reliance on antibiotics or preservatives, such as thimerosal, in the manufacturing process.⁴²

CHEMOPROPHYLAXIS WITH NEURAMINIDASE INHIBITORS

The mainstays of influenza prevention are seasonal vaccination and appropriate infection-prevention practices. In addition, in patients at high risk of influenza-related complications (Table 2),⁴³ postexposure chemoprophylaxis with a neuraminidase inhibitor, ie, oseltamivir (Tamiflu) or zanamivir (Relenza), is an effective preventive strategy, especially in years when the match between vaccine and circulating virus strains is suboptimal.^44,45

Neuraminidase inhibitors are competitive inhibitors of the active site of the influenza glycoprotein neuraminidase, responsible for viral release from infected respiratory epithelial cells. Rates of resistance to neuraminidase inhibitors have been less than 1% in the United States in recent years, while resistance to the adamantanes amantadine (Symmetrel) and rimantadine (Flumadine) can be as high as 92%, depending on the virus isolate. Thus, their use for treatment or prophylaxis of influenza is not currently recommended by the CDC.⁴⁶

Chemoprophylaxis with any agent may promote emergence of resistant strains, can cause adverse reactions, and should never be considered a substitute for vaccination.

ANTI-INFLUENZA AGENTS

Two neuraminidase inhibitors, oseltamivir and zanamivir, are approved by the FDA for preventing and treating uncomplicated influenza. Treatment must be instituted within 2 days of onset of symptoms to be effective.

Oseltamivir is available as an oral capsule or powder for liquid suspension. Its most common adverse effects are gastrointestinal upset including diarrhea, nausea, and vomiting.⁴⁴

Zanamivir is only available in the form of a dry powder inhaler because of the drug’s poor oral bioavailability, and only 4% to 17% of the inhaled dose is systemically absorbed.⁴⁵ There is a theoretical benefit in targeted delivery of zanamivir to the primary organ affected by influenza, and gastrointestinal side effects are less common with this drug.^44,45 Unfortunately, the zanamivir inhaler requires complicated assembly and dexterity for administration (see the video on YouTube⁴⁷), which may make it unreliable in certain patient groups, especially handicapped and elderly patients. Administration has been associated with bronchospasm, resulting in a more than 20% reduction in the forced expiratory volume in 1 second, and it is contraindicated in patients with underlying reactive airway disease such as chronic obstructive pulmonary disease or asthma.⁴⁵

Table 3 lists the doses and duration of therapy for oseltamivir and zanamivir in adults with normal renal function, as well as approximate costs. No generic formulations of neuraminidase inhibitors are currently available, and outpatient use may not be covered by medical insurance. Several other neuraminidase inhibitors are either under development or at various stages in the FDA approval process.

EFFECTIVENESS OF ANTI-INFLUENZA DRUGS

Treatment with oseltamivir has been shown to reduce the duration of symptoms by approximately 1 day if initiated within 36 hours of onset of illness and 1.5 to 2 days if initiated within 24 hours.^48,49 Trials and meta-analyses of zanamivir show similar effectiveness, though some suggest that symptoms were alleviated as much as 3 days sooner than in controls in a subgroup of patients who were febrile at presentation.^50,51 Dual neuraminidase inhibitor therapy in an attempt to prevent emergence of resistance seems logical but was actually found to be less effective than monotherapy, according to a 2010 study.⁵²

The effectiveness of neuraminidase inhibitors in reducing influenza-related complications and mortality rates has been controversial in recent years, as these outcomes were not addressed in initial studies that secured FDA approval. Several meta-analyses differ in their assessments of available data quality and conclusions. A 2009 Cochrane review questioned the completeness and the veracity of the data from manufacturer-funded trial data, much of which was unpublished and not made available to reviewers, and it concluded that a reduction of complications could not be supported by the available data.⁵³ Hernán and Lipsitch,⁵⁴ in a 2011 review, calculated that oseltamivir reduces the risk of lower respiratory tract complications by 28% in patients with influenza-like symptoms and by 37% in patients with confirmed influenza infection.

Additional trials and better access to available data are needed to settle the question of the effectiveness of neuraminidase inhibitors in reducing complications of influenza. Meanwhile, they remain strongly recommended by major health organizations, including the CDC and the WHO, which lists oseltamivir on its “model list of essential medicines.”

VIRAL RESISTANCE TO NEURAMINIDASE INHIBITORS

Viral resistance to neuraminidase inhibitors occurs through multiple mechanisms and may arise without selective pressure from exposure to these drugs.⁵⁵

Oseltamivir possesses a hydrophobic moiety that requires viral neuraminidase to undergo a complex reconfiguration to expose the active site prior to binding. Any mutation affecting its ability to undergo this structural rearrangement can promote resistance by decreased oseltamivir access to the active site.

Zanamivir has a structural homology to the neuraminidase active site and requires no such reconfiguration. Additionally, mutations promoting resistance to zanamivir may actually decrease viral fitness; thus, resistance to zanamivir is significantly less common than to oseltamivir.⁵⁵

About 2,000 influenza virus isolates currently circulating in the United States were tested for resistance; only 1% of the 2009 influenza A H1N1 isolates demonstrated resistance to oseltamivir, and none to zanamivir.⁵⁶

The CDC regularly updates the resistance patterns of circulating influenza strains at www.cdc.gov/flu/weekly/index.htm.

SPECIAL CONSIDERATIONS

Pregnancy

Pregnant women may be at higher risk of severe influenza complications. This was especially true during the 2009 H1N1 pandemic, when pregnant women had a five times higher risk of death from influenza-related complications. Additionally, fever during pregnancy is an independent risk factor for adverse outcomes in the offspring.⁵⁷ Maternal vaccination against influenza effectively protects the infant for the first 6 months of life, when vaccination is not recommended because of a poor immune response.⁵⁸

Live-attenuated influenza vaccine is contraindicated during pregnancy. Given the documented risks to the mother from influenza and no documented harm from preservatives in multiuse vaccine vials, the Advisory Committee on Immunization Practices (ACIP) and ACOG do not state a preference for thimerosal-containing or thimerosal-free vaccine for any group, including pregnant women. Pregnant women should be vaccinated with whatever inactivated influenza vaccine formulation is available at the earliest opportunity in the beginning of the influenza season, regardless of the trimester of pregnancy.

Pregnant women are at high risk of influenza-related complications and should be considered for postexposure antiviral prophylaxis or early treatment with a neuraminidase inhibitor. However, both of the approved neuraminidase inhibitors are in pregnancy safety category C, indicating possible adverse effects in animal studies and a lack of safety data in pregnant humans. As with all category C medications, the risks and benefits must be considered, taking into account maternal comorbidities, vaccination status, effectiveness of the season’s influenza vaccine, and the virulence of circulating influenza strains.

As oseltamivir is associated with nausea and gastrointestinal side effects and as zanamivir has less systemic absorption, it may be reasonable to prescribe zanamivir for women already experiencing severe pregnancy-related nausea.

Immunocompromised people

Inactivated influenza vaccine is recommended and live-attenuated influenza vaccine is contraindicated for all immunocompromised people. Generally speaking, any form of immune compromise will decrease the immunogenicity of the vaccine. Additional considerations vary depending on the cause and severity of the immunocompromised status.

HIV-infected patients have higher seroconversion rates when vaccinated with the high-dose vaccine than with the standard-dose vaccine; however, as in adults over age 65, the clinical benefit has yet to be evaluated.⁵⁹ The efficacy of vaccination is predictably related to the CD4 cell count, as T cells are necessary to mount a response.⁶⁰ No documented benefit is gained from booster influenza vaccination in this group of patients.

Cancer patients should receive inactivated influenza vaccine every year. Postexposure chemoprophylaxis should be considered, and early treatment with a neuraminidase inhibitor is recommended in patients undergoing chemotherapy.

Solid-organ transplant recipients face a risk of organ rejection if they contract influenza infection, in addition to a higher risk of influenza-related complications.⁶¹ Transplant recipients should receive inactivated influenza vaccine as soon as it becomes available at the beginning of every influenza season. Additional research is necessary to evaluate the safety and effectiveness of the high-dose influenza vaccine in this patient group.

MORE OPTIONS, GREAT BENEFIT

Influenza remains a significant source of morbidity and mortality in the United States, and emerging pandemic strains as well as the aging population pose the risk of increased disease burden. New vaccine options offer hope of greater safety, improved efficacy, and higher vaccination rates though broader appeal to individuals. The actual differences in protection between various vaccine options are insignificant relative to the overall benefit of vaccination.

Health care providers should inquire about patients’ understanding and address their concerns about vaccination. Giving an available influenza vaccine within approved indications should not be delayed if alternative vaccine options are not readily available.

In addition to vaccination, patients at high risk of complications should be advised early in the influenza season to inform their doctors about potential exposure to influenza or the development of flu-like symptoms for consideration of early treatment or postexposure prophylaxis with a neuraminidase inhibitor.

Every year, 5% to 20% of US residents contract the flu, 200,000 are hospitalized for it, and 36,000 die of influenza-related complications. The economic impact, including direct medical costs and lost earnings, exceeds $87 billion.¹ Despite this, less than half of eligible US residents were vaccinated in the 2012–2013 season, with uninsured people more than twice as likely to forgo vaccination.^2,3

Several studies have shown that influenza vaccination reduces the need for outpatient encounters and hospitalizations and lowers the incidence of death from acute myocardial infarction, the rate of all-cause mortality, and even the incidence of therapies administered by implantable defibrillators.^4–6 In the 2012–2013 influenza season, vaccination prevented an estimated 3.2 million medically attended illnesses and almost 80,000 hospitalizations; 70% of hospitalizations prevented were in children age 6 months to 4 years and in adults over age 65.⁷

After the 2009 H1N1 pandemic, which disproportionately killed previously healthy adults, the US Centers for Disease Control and Prevention (CDC) expanded its vaccination recommendations to include everyone above the age of 6 months, with few contraindications.⁸

In addition, recent years have seen a great expansion in vaccine options, changes in the at-risk demographics, and continued widespread resistance to certain antiviral agents, with implications for practice in primary care.

Here, we review the barriers and the new options for treatment and prevention of influenza.

HEMAGGLUTININ AND NEURAMINIDASE

Influenza infection is caused by one of the circulating strains of influenza virus A or B.

The major viral surface glycoproteins are hemagglutinin and neuraminidase. Hemagglutinin plays an important role in viral attachment to host cells and is the major immunogen in the influenza vaccine. Neuraminidase contains an active enzymatic site that cleaves the newly formed budding influenza viruses from host-cell sialic acid residues and allows them to be released from the cell membrane to infect other respiratory epithelial cells. It is the target of currently recommended antiviral drugs.

VACCINE PRODUCTION

Throughout the year, 130 influenza centers around the world sample circulating strains and share their data with five World Health Organization (WHO) Collaborating Centers for Reference and Research on Influenza. The WHO analyzes the circulation patterns, predicts the strains most likely to be circulating in the next influenza season, and shares these strains with manufacturers of the vaccine.

Pharmaceutical companies then begin an elaborate process of producing and distributing hundreds of millions of doses of vaccine worldwide. The production traditionally uses millions of fertilized chicken eggs to produce strain-specific influenza hemagglutinin. Individual vaccine strains are combined into the final product after being inactivated by chemical or physical splitting of the viral envelope with or without subsequent purification of the hemagglutinin particles.

Before 2013, the WHO’s yearly recommendations included two strains of influenza A and a single strain of influenza B. In 2013, new quadrivalent vaccines that include protection against a second strain of influenza B were approved.

The WHO strain-selection process allows manufacturers about 6 months to produce the vaccine. In a typical year, the worldwide demand is about 400 million doses. The theoretical maximal annual worldwide capacity, given current techniques, is fewer than 1 billion doses, which is well short of the 10 billion doses necessary to allow for the double vaccination needed in a pandemic.⁹ Newly approved recombinant manufacturing techniques offer greater production efficiency, while novel methods of intradermal administration increase vaccine immunogenicity, decreasing the amount of viral antigens used per dose.

INACTIVATED VS LIVE-ATTENUATED

In addition to intramuscular inactivated influenza vaccine, a live-attenuated vaccine in the form of an intranasal spray (FluMist) became available in 2003. This form is generally favored in children, as it avoids the discomfort of an injection. It contains live, weakened, cold-adapted influenza strains that reproduce in the relatively colder temperatures of the exterior nares but cannot survive in the warmer temperatures of the lung and proximal airways. It is approved for healthy people 2 to 49 years of age, and some evidence suggests that it may be more effective than inactivated influenza vaccine in children,¹⁰ although its utility is limited by multiple contraindications (see below).

INFLUENZA VACCINE INDICATIONS AND CONTRAINDICATIONS

Vaccination for influenza is recommended for all persons 6 months of age and older, an expansion from pre-2009 guidelines that did not recommend vaccination for healthy adults age 19 to 49 who were not in contact with people at high risk of influenza-related complications.⁸ Many new vaccine formulations have become available in recent years, each with specific benefits, risks, and target populations (Table 1).

Contraindications to inactivated vaccine

The only firm contraindication to inactivated influenza vaccine is previous severe allergic reaction to influenza vaccine or any of its components. Those with moderate to severe acute illness are advised to wait until their condition improves before being vaccinated. People who have had Guillain-Barré syndrome and those with egg allergy are discussed in MISAPPREHENSIONS THAT POSE BARRIERS TO VACCINATION, below. There is no risk of influenza infection from inactivated influenza vaccine.

Contraindications to live-attenuated influenza vaccine

Unlike inactivated influenza vaccine, the live-attenuated vaccine does result in shedding of vaccine-strain virus from the vaccinated host, with the theoretical potential for transmission of the virus from the vaccine recipient to other people, as well as the potential for influenza-like illness in vaccine recipients.^11,12 Based on reported events, the former is estimated to occur in 10 to 20 per 1 million vaccinations, although these cases have never been proven to be caused by a cold-adapted vaccine-strain rather than by coincidental transmission of circulating wild-type viral strains.¹³

Despite this exceedingly small risk of viral transmission, live-attenuated influenza vaccine has multiple contraindications, including age less than 2 years and more than 49 years, disease- or drug-related compromised immune status, pregnancy, egg allergy, and history of allergic reaction to the formulation. These limit its use and are important to review in detail before prescribing.¹⁴

Use of neuraminidase inhibitors within 2 days before or 2 weeks after receiving live-attenuated influenza vaccine may interfere with replication of the cold-adapted strain and decrease the vaccine’s effectiveness.¹⁴

EFFECTIVENESS OF INFLUENZA VACCINATION IN OLDER ADULTS

The effectiveness of influenza vaccination depends on the age and health status of the person being vaccinated, as well as on the quality of the match between the vaccine and the circulating influenza viruses.

In the 2012–2013 season, the adjusted vaccine effectiveness was 56% overall, 47% for influenza A H3N2, and 67% for influenza B. However, in people age 65 and older, the overall adjusted vaccine effectiveness was 27%, and only 9% for influenza A H3N2.¹⁵ Thus, even though the vaccine-virus match was considered good, the vaccine was suboptimally effective in the older group. This may be an argument for using the recently approved high-dose vaccine in that age group. Although the high-dose vaccine has been shown to be significantly more immunogenic in older adults, it is too early to know if it is clinically more effective in preventing influenza in this age group.

Despite the lower-than-expected effectiveness in preventing influenza in the 2012–2013 season in people age 65 and older, several well-designed studies found that influenza vaccination prevented severe disease, including one study that found vaccination to be 89% effective in reducing influenza-associated hospitalizations in the 2010–2011 flu season.^4,16

The limited effectiveness of vaccination in the older age group reminds us of the importance of early recognition and treatment of patients at high risk of influenza-related complications (see Table 2). It is also a call for greater compliance with vaccination in younger people, with a goal of achieving the 80% vaccination rate that has been calculated as adequate to achieve herd immunity.¹⁷

MISAPPREHENSIONS THAT POSE BARRIERS TO VACCINATION

Concern about potential adverse effects is the most common reason for refusing influenza vaccination, even among health care workers.¹⁸ However, the only commonly encountered adverse effect of the intramuscular inactivated influenza vaccine is injection-site pain.

‘Catching the flu from a flu shot’

Many people think that they can “catch the flu from a flu shot” (or think that they actually did), but vaccine-acquired influenza is not possible with the inactivated influenza vaccine,¹⁹ and it is only a theoretical, undocumented consideration with the live-attenuated vaccine.

Various respiratory viruses other than influenza also cause viral upper-respiratory infections during the influenza season. These infections may coincide with influenza vaccination and are frequently misconstrued as a side effect of the influenza vaccine or as evidence of vaccine ineffectiveness.

Unnecessary concerns about simultaneous vaccinations

Patients and doctors are often concerned about simultaneous administration of multiple vaccines and choose to spread out indicated vaccinations over multiple visits. This practice increases patients’ risk of illness from vaccine-preventable diseases. Research shows that simultaneous administration does not alter the safety or effectiveness of vaccination.^20–22 The CDC recommends simultaneous administration of all indicated live and inactivated vaccinations in order to reduce barriers to vaccination.²⁰

Fear of Guillain-Barré syndrome

Guillain-Barré syndrome, an acute ascending polyneuropathy, has been blamed on influenza vaccination in cases that developed after the 1976 influenza A (H1N1) epidemic.

Most cases are self-limiting but require intensive treatment and supportive care. Full recovery occurs in 60% of cases, though some people experience persistent symptoms. The mortality rate is less than 5%.²³

After the 1976 influenza pandemic, approximately 400 cases of Guillain-Barré syndrome arose in 45 million vaccine recipients, or about 1 case per 100,000 people.²⁴ Multiple subsequent population analyses concluded that the actual incidence of Guillain-Barré syndrome attributable to influenza vaccination is negligible, at less than 1 case in 1 million vaccinations. Against this, we should compare the real risk of illness and death from influenza infection, which itself is a risk factor for Guillain-Barré syndrome.²⁵

Should a person with a history of Guillain-Barré syndrome be revaccinated against influenza? The risk was evaluated in a large retrospective analysis of cases identified in the Kaiser Permanente Northern California Database from 1995 to 2006.²⁶ Five hundred fifty cases of Guillain-Barré syndrome were identified, of which 18 had arisen within 6 weeks of the patient receiving a flu shot. Four hundred five doses of inactivated influenza vaccine were subsequently given to 105 patients who had a history of Guillain-Barré syndrome, two of whom had developed the syndrome within 6 weeks of receiving the shot. There were no documented episodes of recurrent Guillain-Barré syndrome in any of these patients. Only 6 of 550 patients with a history of the disease developed it again; none of these 6 had received the influenza vaccine in the preceding 2 months, and only 1 had been exposed to the measles-mumps-rubella vaccine in the 4 months before vaccination.

Nevertheless, expert opinion recommends lifelong avoidance of any immunization that had been given within 6 weeks before the onset of symptoms of Guillain-Barré syndrome.²⁷

Overstated concern about egg allergy

Anaphylactic reactions can occur after influenza vaccination in people who have severe egg allergy, and concern about these reactions unfortunately prevents many otherwise eligible people with mild allergy from being vaccinated.

These reactions are much less common than feared. In a well-designed prospective cohort study of 367 patients with a history of egg allergy and positive skin-prick tests, including 132 with a history of severe allergy and 4 with a history of mild allergic symptoms arising in response to previous influenza vaccinations, none developed anaphylaxis.²⁸

The same authors reviewed 26 studies in more than 4,000 egg-allergic patients, of whom more than 500 had a history of severe egg-associated reactions, and likewise found no cases of influenza vaccine-associated anaphylaxis. They concluded that the inactivated influenza vaccine is safer than the egg-derived mumps-measles-rubella vaccine, for which precautions for egg allergy no longer exist.²⁸

People with a history of more serious reactions, ranging from stomach upset to anaphylaxis, can be safely vaccinated with a recombinant vaccine or referred to an allergist for further testing. People who experience hives as their only reaction to egg exposure should receive full-dose vaccination but then be observed for a half hour afterward.

The recombinant trivalent influenza vaccine Flublok was approved in 2013 for people age 18 to 49. It is the first commercially available influenza vaccine produced in a continuous insect cell line using a baculovirus vector. No eggs are used in its production, and it is approved for use in patients with egg allergy of any severity.

People who have a history of more serious reactions, including abdominal pain, nausea, vomiting, dizziness, or wheezing can be vaccinated with the recombinant vaccine or referred to an allergy specialist.

Despite this new option, understanding of alternative immunization guidelines for people with egg allergies, available on the CDC website²⁹ remains important, as the availability of the recombinant trivalent influenza vaccine remains limited in the 2013–2014 influenza season.

Misconception about mercury toxicity

Thimerosal is an ethylmercury-containing preservative used in multidose antiviral vaccines, including some influenza vaccines.³⁰ It is designed to prevent bacterial and fungal colonization of the vaccine vial while not reducing vaccine effectiveness or causing toxicity.

Contemporary understanding of mercury neurotoxicity is based largely on studies of methylmercury, including long-term, low-dose exposure in remote communities in the Faroe Islands and the Seychelles through regular consumption of fish and whale meat.^31,32 These exposure studies had conflicting results: those in the Faroe Islands demonstrated toxicity, but the Seychelles studies actually showed better neurologic test scores at higher mercury levels, a trend the authors attributed to the beneficial effects of maternal fish consumption.

The results of the methylmercury studies have been extrapolated to ethylmercury (contained in thimerosal), although the two chemicals have vastly different pharmacologic properties. For example, methylmercury has a longer half-life and greater transport across the blood-brain barrier.³³ A direct comparison found that ethylmercury is less toxic than methylmercury, although an increase in ethylmercury concentration of only 20% resulted in similar toxicity profiles.³⁴ These studies were performed at concentrations of mercury thousands of times higher than those resulting from vaccination: nearly 150,000 times greater than those in an average adult or 15,000 times greater than those in a 1-year-old child from the typical 25-μg thimerosal dose allowed in contemporary influenza vaccines.

Despite much negative publicity, no link has been shown between thimerosal and autism.³⁰ Multiple regulatory, scientific, and medical organizations including the US Food and Drug Administration (FDA), the WHO, the National Institutes of Health, the CDC, the American Academy of Pediatrics, and the American Congress of Obstetricians and Gynecologists (ACOG) have evaluated the data on the safety of thimerosal in vaccines and have agreed that it is safe. However, most of them urged vaccine manufacturers to eliminate mercury from vaccines as a precaution.^30,35 Thimerosal has subsequently been eliminated from all childhood vaccines except for influenza vaccine, with no resulting decrease in childhood autism diagnoses.³⁶

Considering that no harm from thimerosal at FDA-approved doses has been documented, and considering the real risk of influenza-related complications, particularly in young children and pregnant women, we recommend vaccination using whatever vaccine formulation is locally available for all patients, including children age 6 months and older and pregnant women. Nevertheless, given that mercury is being eliminated from childhood vaccines and that preservative-free single-dose vials are increasingly available in the United States, it seems reasonable to use thimerosal-free formulations for children, expectant mothers, and patients concerned about exposure if these formulations are readily available. Influenza vaccination should not be delayed if a thimerosal-free formulation is not readily available.

NEW VACCINE FORMULATIONS

Recent years have seen a dramatic expansion in influenza vaccine options (Table 1).

Quadrivalent vaccines

Quadrivalent vaccines protect against two strains of influenza A and two strains of influenza B, whereas earlier formulations included only one influenza B strain. Vaccination against either influenza B strain offers only limited cross-protection against the other B strain, and previous formulations involved assumptions about which strain would predominate in any given year. The CDC estimates that switching to quadrivalent vaccines will prevent up to 970,000 cases of influenza, 8,200 hospitalizations, and 485 deaths per year.³⁷

Intradermal vaccine

The newly available Fluzone Intradermal vaccine contains smaller doses of hemagglutinin but is still effective because antigen-presenting dendritic cells in the skin reduce the required amount of vaccine antigen necessary for inducing protection.³⁸ This may provide an advantage in the event of vaccine shortage. Also, since it is given in needles only 1.5 mm long, it may appeal to people who are afraid of needles.

The stronger immune reaction with intradermal administration causes more redness, induration, and tenderness at the injection site than with intramuscular administration.³⁹ Patients should not be surprised by this reaction and can be advised to apply ice packs for symptomatic relief.

High-dose vaccine

A high-dose vaccine was approved in 2009 for use in adults age 65 and older. It contains 60 μg of hemagglutinin, compared with 15 μg in standard-dose vaccines, and has been shown to improve seroconversion rates. It remains to be seen if this translates into better clinical outcomes in older adults.⁴⁰ Further studies will be necessary before we can recommend high-dose vaccines to other people with weakened immune response, such as those undergoing chemotherapy or those infected with human immunodeficiency virus (HIV).

Cell-based vaccines

Flucelvax was the first cell-based influenza vaccine. However, unlike the recombinant trivalent influenza vaccine, which uses no eggs in its manufacturing process, Flucelvax production starts with egg-derived influenza strains that are subsequently propagated in liquid culture of animal cells. It may therefore contain traces of egg protein, and it has not been studied in people with egg allergy.⁴¹

An advantage of the cell-based production technique is the use of fewer or no eggs at all, which may result in greater manufacturing efficiency. Also, it is a closed process that reduces the risk of bacterial contamination as well as reliance on antibiotics or preservatives, such as thimerosal, in the manufacturing process.⁴²

CHEMOPROPHYLAXIS WITH NEURAMINIDASE INHIBITORS

The mainstays of influenza prevention are seasonal vaccination and appropriate infection-prevention practices. In addition, in patients at high risk of influenza-related complications (Table 2),⁴³ postexposure chemoprophylaxis with a neuraminidase inhibitor, ie, oseltamivir (Tamiflu) or zanamivir (Relenza), is an effective preventive strategy, especially in years when the match between vaccine and circulating virus strains is suboptimal.^44,45

Neuraminidase inhibitors are competitive inhibitors of the active site of the influenza glycoprotein neuraminidase, responsible for viral release from infected respiratory epithelial cells. Rates of resistance to neuraminidase inhibitors have been less than 1% in the United States in recent years, while resistance to the adamantanes amantadine (Symmetrel) and rimantadine (Flumadine) can be as high as 92%, depending on the virus isolate. Thus, their use for treatment or prophylaxis of influenza is not currently recommended by the CDC.⁴⁶

Chemoprophylaxis with any agent may promote emergence of resistant strains, can cause adverse reactions, and should never be considered a substitute for vaccination.

ANTI-INFLUENZA AGENTS

Two neuraminidase inhibitors, oseltamivir and zanamivir, are approved by the FDA for preventing and treating uncomplicated influenza. Treatment must be instituted within 2 days of onset of symptoms to be effective.

Oseltamivir is available as an oral capsule or powder for liquid suspension. Its most common adverse effects are gastrointestinal upset including diarrhea, nausea, and vomiting.⁴⁴

Zanamivir is only available in the form of a dry powder inhaler because of the drug’s poor oral bioavailability, and only 4% to 17% of the inhaled dose is systemically absorbed.⁴⁵ There is a theoretical benefit in targeted delivery of zanamivir to the primary organ affected by influenza, and gastrointestinal side effects are less common with this drug.^44,45 Unfortunately, the zanamivir inhaler requires complicated assembly and dexterity for administration (see the video on YouTube⁴⁷), which may make it unreliable in certain patient groups, especially handicapped and elderly patients. Administration has been associated with bronchospasm, resulting in a more than 20% reduction in the forced expiratory volume in 1 second, and it is contraindicated in patients with underlying reactive airway disease such as chronic obstructive pulmonary disease or asthma.⁴⁵

Table 3 lists the doses and duration of therapy for oseltamivir and zanamivir in adults with normal renal function, as well as approximate costs. No generic formulations of neuraminidase inhibitors are currently available, and outpatient use may not be covered by medical insurance. Several other neuraminidase inhibitors are either under development or at various stages in the FDA approval process.

EFFECTIVENESS OF ANTI-INFLUENZA DRUGS

Treatment with oseltamivir has been shown to reduce the duration of symptoms by approximately 1 day if initiated within 36 hours of onset of illness and 1.5 to 2 days if initiated within 24 hours.^48,49 Trials and meta-analyses of zanamivir show similar effectiveness, though some suggest that symptoms were alleviated as much as 3 days sooner than in controls in a subgroup of patients who were febrile at presentation.^50,51 Dual neuraminidase inhibitor therapy in an attempt to prevent emergence of resistance seems logical but was actually found to be less effective than monotherapy, according to a 2010 study.⁵²

The effectiveness of neuraminidase inhibitors in reducing influenza-related complications and mortality rates has been controversial in recent years, as these outcomes were not addressed in initial studies that secured FDA approval. Several meta-analyses differ in their assessments of available data quality and conclusions. A 2009 Cochrane review questioned the completeness and the veracity of the data from manufacturer-funded trial data, much of which was unpublished and not made available to reviewers, and it concluded that a reduction of complications could not be supported by the available data.⁵³ Hernán and Lipsitch,⁵⁴ in a 2011 review, calculated that oseltamivir reduces the risk of lower respiratory tract complications by 28% in patients with influenza-like symptoms and by 37% in patients with confirmed influenza infection.

Additional trials and better access to available data are needed to settle the question of the effectiveness of neuraminidase inhibitors in reducing complications of influenza. Meanwhile, they remain strongly recommended by major health organizations, including the CDC and the WHO, which lists oseltamivir on its “model list of essential medicines.”

VIRAL RESISTANCE TO NEURAMINIDASE INHIBITORS

Viral resistance to neuraminidase inhibitors occurs through multiple mechanisms and may arise without selective pressure from exposure to these drugs.⁵⁵

Oseltamivir possesses a hydrophobic moiety that requires viral neuraminidase to undergo a complex reconfiguration to expose the active site prior to binding. Any mutation affecting its ability to undergo this structural rearrangement can promote resistance by decreased oseltamivir access to the active site.

Zanamivir has a structural homology to the neuraminidase active site and requires no such reconfiguration. Additionally, mutations promoting resistance to zanamivir may actually decrease viral fitness; thus, resistance to zanamivir is significantly less common than to oseltamivir.⁵⁵

About 2,000 influenza virus isolates currently circulating in the United States were tested for resistance; only 1% of the 2009 influenza A H1N1 isolates demonstrated resistance to oseltamivir, and none to zanamivir.⁵⁶

The CDC regularly updates the resistance patterns of circulating influenza strains at www.cdc.gov/flu/weekly/index.htm.

SPECIAL CONSIDERATIONS

Pregnancy

Pregnant women may be at higher risk of severe influenza complications. This was especially true during the 2009 H1N1 pandemic, when pregnant women had a five times higher risk of death from influenza-related complications. Additionally, fever during pregnancy is an independent risk factor for adverse outcomes in the offspring.⁵⁷ Maternal vaccination against influenza effectively protects the infant for the first 6 months of life, when vaccination is not recommended because of a poor immune response.⁵⁸

Live-attenuated influenza vaccine is contraindicated during pregnancy. Given the documented risks to the mother from influenza and no documented harm from preservatives in multiuse vaccine vials, the Advisory Committee on Immunization Practices (ACIP) and ACOG do not state a preference for thimerosal-containing or thimerosal-free vaccine for any group, including pregnant women. Pregnant women should be vaccinated with whatever inactivated influenza vaccine formulation is available at the earliest opportunity in the beginning of the influenza season, regardless of the trimester of pregnancy.

Pregnant women are at high risk of influenza-related complications and should be considered for postexposure antiviral prophylaxis or early treatment with a neuraminidase inhibitor. However, both of the approved neuraminidase inhibitors are in pregnancy safety category C, indicating possible adverse effects in animal studies and a lack of safety data in pregnant humans. As with all category C medications, the risks and benefits must be considered, taking into account maternal comorbidities, vaccination status, effectiveness of the season’s influenza vaccine, and the virulence of circulating influenza strains.

As oseltamivir is associated with nausea and gastrointestinal side effects and as zanamivir has less systemic absorption, it may be reasonable to prescribe zanamivir for women already experiencing severe pregnancy-related nausea.

Immunocompromised people

Inactivated influenza vaccine is recommended and live-attenuated influenza vaccine is contraindicated for all immunocompromised people. Generally speaking, any form of immune compromise will decrease the immunogenicity of the vaccine. Additional considerations vary depending on the cause and severity of the immunocompromised status.

HIV-infected patients have higher seroconversion rates when vaccinated with the high-dose vaccine than with the standard-dose vaccine; however, as in adults over age 65, the clinical benefit has yet to be evaluated.⁵⁹ The efficacy of vaccination is predictably related to the CD4 cell count, as T cells are necessary to mount a response.⁶⁰ No documented benefit is gained from booster influenza vaccination in this group of patients.

Cancer patients should receive inactivated influenza vaccine every year. Postexposure chemoprophylaxis should be considered, and early treatment with a neuraminidase inhibitor is recommended in patients undergoing chemotherapy.

Solid-organ transplant recipients face a risk of organ rejection if they contract influenza infection, in addition to a higher risk of influenza-related complications.⁶¹ Transplant recipients should receive inactivated influenza vaccine as soon as it becomes available at the beginning of every influenza season. Additional research is necessary to evaluate the safety and effectiveness of the high-dose influenza vaccine in this patient group.

MORE OPTIONS, GREAT BENEFIT

Influenza remains a significant source of morbidity and mortality in the United States, and emerging pandemic strains as well as the aging population pose the risk of increased disease burden. New vaccine options offer hope of greater safety, improved efficacy, and higher vaccination rates though broader appeal to individuals. The actual differences in protection between various vaccine options are insignificant relative to the overall benefit of vaccination.

Health care providers should inquire about patients’ understanding and address their concerns about vaccination. Giving an available influenza vaccine within approved indications should not be delayed if alternative vaccine options are not readily available.

In addition to vaccination, patients at high risk of complications should be advised early in the influenza season to inform their doctors about potential exposure to influenza or the development of flu-like symptoms for consideration of early treatment or postexposure prophylaxis with a neuraminidase inhibitor.

ANSWER

The radiograph shows moderate soft-tissue swelling with dislocation of the proximal interphalangeal joint. No definite fracture is seen. In addition, there are some metallic-appearing foreign bodies.

The patient was treated with closed ­reduction and splinting. He also received a referral to outpatient orthopedics for ­follow-up.

ANSWER

The radiograph shows moderate soft-tissue swelling with dislocation of the proximal interphalangeal joint. No definite fracture is seen. In addition, there are some metallic-appearing foreign bodies.

The patient was treated with closed ­reduction and splinting. He also received a referral to outpatient orthopedics for ­follow-up.

ANSWER

The radiograph shows moderate soft-tissue swelling with dislocation of the proximal interphalangeal joint. No definite fracture is seen. In addition, there are some metallic-appearing foreign bodies.

The patient was treated with closed ­reduction and splinting. He also received a referral to outpatient orthopedics for ­follow-up.

ANSWER

The correct interpretation is an atrial tachycardia with 2:1 ventricular conduction. The ventricular rate is 87 beats/min (690 ms), and the atrial rate is 174 beats/min (345 ms). Two P waves are present for each QRS, which excludes a first-degree atrioventricular block. The less obvious P wave is found in the terminal portion of the QRS complex. (You may convince yourself of this by using calipers to measure the R-R interval, dividing that measurement in half, and then applying it to the ECG. You will see the P waves march through without changing the ventricular response.)

A nonspecific intraventricular conduction delay is also present. The QRS duration is > 100 ms; however, the criteria for right or left bundle branch block are absent.

A thorough investigation revealed that the clerk formulating the herbs for the tea was using, among other things, dried foxglove. Foxglove has been used as a remedy for lethargy in the elderly, presumably because it inadvertently treats symptoms of congestive heart failure. It was the tea consumption that accounted for the presence of digoxin in the patient’s blood. (Recall that there is a substantial overlap between therapeutic and toxic serum concentrations of digoxin.) When the patient stopped consuming the tea, his atrial tachycardia resolved, as did his symptoms.

ANSWER

The correct interpretation is an atrial tachycardia with 2:1 ventricular conduction. The ventricular rate is 87 beats/min (690 ms), and the atrial rate is 174 beats/min (345 ms). Two P waves are present for each QRS, which excludes a first-degree atrioventricular block. The less obvious P wave is found in the terminal portion of the QRS complex. (You may convince yourself of this by using calipers to measure the R-R interval, dividing that measurement in half, and then applying it to the ECG. You will see the P waves march through without changing the ventricular response.)

A nonspecific intraventricular conduction delay is also present. The QRS duration is > 100 ms; however, the criteria for right or left bundle branch block are absent.

A thorough investigation revealed that the clerk formulating the herbs for the tea was using, among other things, dried foxglove. Foxglove has been used as a remedy for lethargy in the elderly, presumably because it inadvertently treats symptoms of congestive heart failure. It was the tea consumption that accounted for the presence of digoxin in the patient’s blood. (Recall that there is a substantial overlap between therapeutic and toxic serum concentrations of digoxin.) When the patient stopped consuming the tea, his atrial tachycardia resolved, as did his symptoms.

ANSWER

The correct interpretation is an atrial tachycardia with 2:1 ventricular conduction. The ventricular rate is 87 beats/min (690 ms), and the atrial rate is 174 beats/min (345 ms). Two P waves are present for each QRS, which excludes a first-degree atrioventricular block. The less obvious P wave is found in the terminal portion of the QRS complex. (You may convince yourself of this by using calipers to measure the R-R interval, dividing that measurement in half, and then applying it to the ECG. You will see the P waves march through without changing the ventricular response.)

A nonspecific intraventricular conduction delay is also present. The QRS duration is > 100 ms; however, the criteria for right or left bundle branch block are absent.

A thorough investigation revealed that the clerk formulating the herbs for the tea was using, among other things, dried foxglove. Foxglove has been used as a remedy for lethargy in the elderly, presumably because it inadvertently treats symptoms of congestive heart failure. It was the tea consumption that accounted for the presence of digoxin in the patient’s blood. (Recall that there is a substantial overlap between therapeutic and toxic serum concentrations of digoxin.) When the patient stopped consuming the tea, his atrial tachycardia resolved, as did his symptoms.

ANSWER

The correct answer is disseminated superficial actinic porokeratosis (DSAP; choice “a”). This condition, caused by an inherited defect of the SART3 gene, is seen mostly on the sun-exposed skin of middle-aged women.

Stasis dermatitis (choice “b”) can cause a number of skin changes, but not the discrete annular lesions seen with DSAP.

Seborrheic keratoses (choice “c”) are common on the legs. However, they don’t display this same morphology.

Nummular eczema (choice “d”) presents with annular papulosquamous lesions (as opposed to the fixed lesions seen with DSAP), often on the legs and lower trunk, but without the thready circumferential scaly border.

Continue reading for Joe Monroe's discussion... 

DISCUSSION

Leg skin is prey to an astonishing array of problems; many have to do with increased hydrostatic pressure (eg, venous stasis disease), with the almost complete lack of sebaceous glands (eg, nummular eczema), or with the simple fact of being “in harm’s way.” And there is no law that says a given patient can’t have more than one problem at a time, co-existing and serving to confuse the examiner. Such is the case with this patient.

Her concern about possible blood clots is misplaced but understandable. Deep vein thromboses would not present in multiples, would not be on the surface or scaly, and would almost certainly be painful.

The fixed nature of this patient’s scaly lesions is extremely significant—but only if you know about DSAP, which typically manifests in the third decade of life and slowly worsens. The lesions’ highly palpable and unique scaly border makes them hard to leave alone. This might not be a problem except for the warfarin, which makes otherwise minor trauma visible as purpuric macules. Chronic sun damage tends to accentuate them as well. The positive family history is nicely corroborative and quite common.

The brown macules on the patient’s legs are solar lentigines (sun-caused freckles), which many patients (and even younger providers) erroneously call “age spots.” When these individuals become “aged,” they’ll understand that there is no such thing as an age spot.

This patient could easily have had nummular eczema, but not for 30 years! Those lesions, treated or not, will come and go. But not DSAP, about which many questions remain: If they’re caused by sun exposure, why don’t we see them more often on the face and arms? And why don’t we see them on the sun-damaged skin of older men?

If needed, a biopsy could have been performed. It would have been confirmatory of the diagnosis and effectively would have ruled out the other items in the differential, including wart, squamous cell carcinoma, and actinic or seborrheic keratosis. 

ANSWER

The correct answer is disseminated superficial actinic porokeratosis (DSAP; choice “a”). This condition, caused by an inherited defect of the SART3 gene, is seen mostly on the sun-exposed skin of middle-aged women.

Stasis dermatitis (choice “b”) can cause a number of skin changes, but not the discrete annular lesions seen with DSAP.

Seborrheic keratoses (choice “c”) are common on the legs. However, they don’t display this same morphology.

Nummular eczema (choice “d”) presents with annular papulosquamous lesions (as opposed to the fixed lesions seen with DSAP), often on the legs and lower trunk, but without the thready circumferential scaly border.

Continue reading for Joe Monroe's discussion... 

DISCUSSION

Leg skin is prey to an astonishing array of problems; many have to do with increased hydrostatic pressure (eg, venous stasis disease), with the almost complete lack of sebaceous glands (eg, nummular eczema), or with the simple fact of being “in harm’s way.” And there is no law that says a given patient can’t have more than one problem at a time, co-existing and serving to confuse the examiner. Such is the case with this patient.

Her concern about possible blood clots is misplaced but understandable. Deep vein thromboses would not present in multiples, would not be on the surface or scaly, and would almost certainly be painful.

The fixed nature of this patient’s scaly lesions is extremely significant—but only if you know about DSAP, which typically manifests in the third decade of life and slowly worsens. The lesions’ highly palpable and unique scaly border makes them hard to leave alone. This might not be a problem except for the warfarin, which makes otherwise minor trauma visible as purpuric macules. Chronic sun damage tends to accentuate them as well. The positive family history is nicely corroborative and quite common.

The brown macules on the patient’s legs are solar lentigines (sun-caused freckles), which many patients (and even younger providers) erroneously call “age spots.” When these individuals become “aged,” they’ll understand that there is no such thing as an age spot.

This patient could easily have had nummular eczema, but not for 30 years! Those lesions, treated or not, will come and go. But not DSAP, about which many questions remain: If they’re caused by sun exposure, why don’t we see them more often on the face and arms? And why don’t we see them on the sun-damaged skin of older men?

If needed, a biopsy could have been performed. It would have been confirmatory of the diagnosis and effectively would have ruled out the other items in the differential, including wart, squamous cell carcinoma, and actinic or seborrheic keratosis. 

ANSWER

The correct answer is disseminated superficial actinic porokeratosis (DSAP; choice “a”). This condition, caused by an inherited defect of the SART3 gene, is seen mostly on the sun-exposed skin of middle-aged women.

Stasis dermatitis (choice “b”) can cause a number of skin changes, but not the discrete annular lesions seen with DSAP.

Seborrheic keratoses (choice “c”) are common on the legs. However, they don’t display this same morphology.

Nummular eczema (choice “d”) presents with annular papulosquamous lesions (as opposed to the fixed lesions seen with DSAP), often on the legs and lower trunk, but without the thready circumferential scaly border.

Continue reading for Joe Monroe's discussion... 

DISCUSSION

Leg skin is prey to an astonishing array of problems; many have to do with increased hydrostatic pressure (eg, venous stasis disease), with the almost complete lack of sebaceous glands (eg, nummular eczema), or with the simple fact of being “in harm’s way.” And there is no law that says a given patient can’t have more than one problem at a time, co-existing and serving to confuse the examiner. Such is the case with this patient.

Her concern about possible blood clots is misplaced but understandable. Deep vein thromboses would not present in multiples, would not be on the surface or scaly, and would almost certainly be painful.

The fixed nature of this patient’s scaly lesions is extremely significant—but only if you know about DSAP, which typically manifests in the third decade of life and slowly worsens. The lesions’ highly palpable and unique scaly border makes them hard to leave alone. This might not be a problem except for the warfarin, which makes otherwise minor trauma visible as purpuric macules. Chronic sun damage tends to accentuate them as well. The positive family history is nicely corroborative and quite common.

The brown macules on the patient’s legs are solar lentigines (sun-caused freckles), which many patients (and even younger providers) erroneously call “age spots.” When these individuals become “aged,” they’ll understand that there is no such thing as an age spot.

This patient could easily have had nummular eczema, but not for 30 years! Those lesions, treated or not, will come and go. But not DSAP, about which many questions remain: If they’re caused by sun exposure, why don’t we see them more often on the face and arms? And why don’t we see them on the sun-damaged skin of older men?

If needed, a biopsy could have been performed. It would have been confirmatory of the diagnosis and effectively would have ruled out the other items in the differential, including wart, squamous cell carcinoma, and actinic or seborrheic keratosis. 

The traditional clinical trial, designed to test whether a new treatment is better than a placebo or another active treatment, is known as a “superiority” trial—although rarely labeled as such. In contrast, the goal of a noninferiority trial is simply to demonstrate that a new treatment is not substantially less effective than the standard therapy.

Such trials are useful when a new therapy is thought to be safer, easier to administer, or less costly than the existing treatment, but not necessarily more effective. And, because it would be unethical to randomize patients with a serious condition for which there already is an effective treatment to placebo, a noninferiority trial is another means of determining if the new treatment is effective.

Noninferiority trials have unique design features and methodology and require a different analysis than traditional superiority trials. Yet many physicians know far less about them; many investigators appear to be less than proficient, as well. A review of 116 noninferiority trials and 46 equivalence trials found that only 20% fulfilled generally accepted quality criteria.¹ To improve the quality of noninferiority trials, the CONSORT (Consolidated Standards of Reporting Trials) Group has published a checklist for trial design and reporting standards.^2,3 Based on this checklist, we came up with 7 key questions to consider when evaluating a noninferiority trial. In the pages that follow, you’ll also find an at-a-glance guide (TABLE) and a methodology review using a hypothetical case (page E7).

1. Is a noninferiority trial appropriate?

The introduction to a noninferiority trial should provide the rationale for this design and the absence of a placebo control group. Look for a review of the evidence of the efficacy of the reference treatment that placebo-controlled trials have revealed, along with the effect size. The advantages of the new treatment over the standard treatment—eg, fewer adverse effects, easier administration, or lower cost—should be discussed, as well.

In the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY)—a prominent noninferiority trial—investigators compared the standard anticoagulant (warfarin) for patients with atrial fibrillation (AF) at risk of stroke with a new agent, dabigatran.⁴ In the methods section of the abstract and the statistical analysis section of the main body, the authors clearly indicated that this was a noninferiority trial. They began by referring to the existing evidence of warfarin’s effectiveness, then detailed the qualities that make warfarin cumbersome to use, including the need for frequent laboratory monitoring. This was followed by evidence that many patients stop taking warfarin and that even for those who persist with treatment, adequate anticoagulation is difficult to maintain.

The authors went on to state that because dabigatran requires no long-term monitoring, it is easier to use. Therefore, if dabigatran could be shown to be no worse than warfarin in preventing strokes, it would be a reasonable alternative, leaving no doubt that this was an appropriate noninferiority trial.

2. Is the noninferiority margin based on clinical judgment and statistical reasoning?

The noninferiority margin should be based on clinical judgment as to how effective a new treatment must be in order to be declared not clinically inferior to the standard treatment. This can be based on several factors, including the severity of the outcome and the expected advantages of the new treatment. The margin should also take into account the size of the standard treatment’s effect vs placebo. In RELY, for example, the authors noted that the noninferiority margin was based on the desire to preserve at least 50% of the lower limit of the confidence interval (CI) of warfarin’s estimated effect; this was done using data from a previously published meta-analysis of 6 trials comparing warfarin with placebo for stroke prevention in patients with AF.^4-6

3. Are the hypothesis and statistical analysis formulated correctly?

The clinical hypothesis in a noninferiority trial is that the new treatment is not worse than the standard treatment by a prespecified margin; therefore, the statistical null hypothesis to be tested is that the new treatment is worse than the reference treatment by more than that margin. Rejecting a true null hypothesis (for example, because the P value is <.05) is known as a type l error. In this setting, making a type I error would mean accepting a new treatment that is truly worse than the standard by at least the specified margin. Failure to reject a false null hypothesis is known as a type II error, which in this case would mean failing to identify a new treatment that is truly noninferior to the standard.⁷

In RE-LY, the authors stated that the upper limit of the one-sided 97.5% CI for the relative risk of a stroke with dabigatran vs warfarin had to fall below 1.46.⁴ (This is the same as testing the null hypothesis that the hazard ratio is ≥1.46.) Thus, the hypothesis was formulated correctly.

4. Is the sample size appropriate and justified?

The sample size in a noninferiority trial should provide high power to reject the null hypothesis that the difference (or relative risk) between groups is equal to or greater than the noninferiority margin under some clinically meaningful assumption about the true difference (or absolute risk reduction) between groups. A true difference of 0 (or a relative risk of 1) is typically assumed for sample size calculation. However, assuming that the new treatment is truly slightly better or slightly worse than the standard may be clinically appropriate in some cases. This would indicate a need for a smaller or larger sample size, respectively, than that required under the usual assumption of no difference.

When the justification for the sample size in a noninferiority trial is not provided or the number of participants is based on an inappropriate approach (eg, using superiority trial calculations for a noninferiority trial), questions about the quality of the trial arise. The primary concern is whether the noninferiority margin was actually selected before the trial began, as it should have been. And if the researchers used overly optimistic assumptions about the efficacy of the new treatment relative to the standard therapy, the failure to rule out the margin could be misleading. (As with superiority trials that fail to reject the null hypothesis, post hoc power calculations should be avoided.) After the study has ended, the resulting CIs should be used to evaluate whether the study was large enough to adequately assess the relative effectiveness of the treatments.

The RE-LY trial calculated the sample size that was expected to provide 84% power to rule out the prespecified hazard ratio of 1.46, assuming a true event rate of 1.6% per year (presumably for both groups), a recruitment period of 2 years, and at least one year of follow-up. The sample size was subsequently increased from 15,000 to 18,000 to maintain power in case of a low event rate.^4,5

5. Is the noninferiority trial as similar as possible to the trial(s) comparing the standard treatment with placebo?

Characteristics of participants, setting, reference treatment, and outcomes used in a noninferiority trial should be as close as possible to those in the trial(s) comparing the treatment with placebo. This is known as the constancy assumption, and it is key to researchers’ ability to draw a conclusion about noninferiority.

The trials used to calculate the noninferiority margin and the RE-LY trial itself involved similar populations of patients with AF, and the outcome (stroke) was similar.

6. Is a per protocol analysis reported in the results?

In randomized controlled superiority trials, the participants should be analyzed in the groups to which they were originally allocated, regardless of whether they adhered to treatment during the entire follow-up period. Such intention-to-treat (ITT) analysis is important because it provides a more conservative estimate of treatment effect—taking into account that some people who are offered treatment will not accept it and others will discontinue treatment. An ITT analysis therefore tends to minimize treatment effects compared with a “per protocol” analysis, in which participants are analyzed according to the treatment they actually received and are often removed from the analysis if they discontinue or do not adhere to treatment.

Intention-to-treat analysis is important because it provides a more conservative estimate of treatment effect.In noninferiority trials, if patients in the intervention group cross over to the standard treatment group or those in the standard treatment group have poor adherence, an ITT analysis can increase the risk of wrongly claiming noninferiority.⁷ Therefore, a per protocol analysis should be included—and indeed may be preferable.

In RE-LY, ITT analyses were reported, and complete follow-up data were available for 99.9% of patients. However, the rates of treatment discontinuation at one year were about 15% for those on dabigatran and 10% for the warfarin group, and 21% and 17%, respectively, at 2 years.^4,5 If the new treatment were truly less efficacious than the standard treatment, these moderate discontinuation rates could lead to more similar rates of stroke in the 2 groups than would be expected with higher continuation rates, biasing results towards the alternative of noninferiority. Although the original publication of trial results did not include a per protocol analysis, the RE-LY authors later reported that a per protocol analysis yielded similar results to the ITT analysis.

7. Are the overall design and execution of the trial high quality?

Because a poor quality noninferiority trial can appear to demonstrate noninferiority, looking at such studies critically is crucial. Appropriate randomization, concealed allocation, masking, and careful attention to participant flow must all be assessed.^2,3

To continue with our example, the RE-LY trial was well conducted. Randomization was performed centrally via an automated telephone system and 2 doses of dabigatran were administered in a masked fashion, while warfarin was open-label. Remarkably, follow-up was achieved for 99.9% of participants over a median of 2 years, and independent adjudicators masked to treatment group assessed outcomes.^4,5

CORRESPONDENCE
Anne Mounsey, MD, UNC Chapel Hill Department of Family Medicine, 590 Manning Drive, CB 7595, Chapel Hill, NC 27590; [email protected]

The traditional clinical trial, designed to test whether a new treatment is better than a placebo or another active treatment, is known as a “superiority” trial—although rarely labeled as such. In contrast, the goal of a noninferiority trial is simply to demonstrate that a new treatment is not substantially less effective than the standard therapy.

Such trials are useful when a new therapy is thought to be safer, easier to administer, or less costly than the existing treatment, but not necessarily more effective. And, because it would be unethical to randomize patients with a serious condition for which there already is an effective treatment to placebo, a noninferiority trial is another means of determining if the new treatment is effective.

Noninferiority trials have unique design features and methodology and require a different analysis than traditional superiority trials. Yet many physicians know far less about them; many investigators appear to be less than proficient, as well. A review of 116 noninferiority trials and 46 equivalence trials found that only 20% fulfilled generally accepted quality criteria.¹ To improve the quality of noninferiority trials, the CONSORT (Consolidated Standards of Reporting Trials) Group has published a checklist for trial design and reporting standards.^2,3 Based on this checklist, we came up with 7 key questions to consider when evaluating a noninferiority trial. In the pages that follow, you’ll also find an at-a-glance guide (TABLE) and a methodology review using a hypothetical case (page E7).

1. Is a noninferiority trial appropriate?

The introduction to a noninferiority trial should provide the rationale for this design and the absence of a placebo control group. Look for a review of the evidence of the efficacy of the reference treatment that placebo-controlled trials have revealed, along with the effect size. The advantages of the new treatment over the standard treatment—eg, fewer adverse effects, easier administration, or lower cost—should be discussed, as well.

In the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY)—a prominent noninferiority trial—investigators compared the standard anticoagulant (warfarin) for patients with atrial fibrillation (AF) at risk of stroke with a new agent, dabigatran.⁴ In the methods section of the abstract and the statistical analysis section of the main body, the authors clearly indicated that this was a noninferiority trial. They began by referring to the existing evidence of warfarin’s effectiveness, then detailed the qualities that make warfarin cumbersome to use, including the need for frequent laboratory monitoring. This was followed by evidence that many patients stop taking warfarin and that even for those who persist with treatment, adequate anticoagulation is difficult to maintain.

The authors went on to state that because dabigatran requires no long-term monitoring, it is easier to use. Therefore, if dabigatran could be shown to be no worse than warfarin in preventing strokes, it would be a reasonable alternative, leaving no doubt that this was an appropriate noninferiority trial.

2. Is the noninferiority margin based on clinical judgment and statistical reasoning?

The noninferiority margin should be based on clinical judgment as to how effective a new treatment must be in order to be declared not clinically inferior to the standard treatment. This can be based on several factors, including the severity of the outcome and the expected advantages of the new treatment. The margin should also take into account the size of the standard treatment’s effect vs placebo. In RELY, for example, the authors noted that the noninferiority margin was based on the desire to preserve at least 50% of the lower limit of the confidence interval (CI) of warfarin’s estimated effect; this was done using data from a previously published meta-analysis of 6 trials comparing warfarin with placebo for stroke prevention in patients with AF.^4-6

3. Are the hypothesis and statistical analysis formulated correctly?

The clinical hypothesis in a noninferiority trial is that the new treatment is not worse than the standard treatment by a prespecified margin; therefore, the statistical null hypothesis to be tested is that the new treatment is worse than the reference treatment by more than that margin. Rejecting a true null hypothesis (for example, because the P value is <.05) is known as a type l error. In this setting, making a type I error would mean accepting a new treatment that is truly worse than the standard by at least the specified margin. Failure to reject a false null hypothesis is known as a type II error, which in this case would mean failing to identify a new treatment that is truly noninferior to the standard.⁷

In RE-LY, the authors stated that the upper limit of the one-sided 97.5% CI for the relative risk of a stroke with dabigatran vs warfarin had to fall below 1.46.⁴ (This is the same as testing the null hypothesis that the hazard ratio is ≥1.46.) Thus, the hypothesis was formulated correctly.

4. Is the sample size appropriate and justified?

The sample size in a noninferiority trial should provide high power to reject the null hypothesis that the difference (or relative risk) between groups is equal to or greater than the noninferiority margin under some clinically meaningful assumption about the true difference (or absolute risk reduction) between groups. A true difference of 0 (or a relative risk of 1) is typically assumed for sample size calculation. However, assuming that the new treatment is truly slightly better or slightly worse than the standard may be clinically appropriate in some cases. This would indicate a need for a smaller or larger sample size, respectively, than that required under the usual assumption of no difference.

When the justification for the sample size in a noninferiority trial is not provided or the number of participants is based on an inappropriate approach (eg, using superiority trial calculations for a noninferiority trial), questions about the quality of the trial arise. The primary concern is whether the noninferiority margin was actually selected before the trial began, as it should have been. And if the researchers used overly optimistic assumptions about the efficacy of the new treatment relative to the standard therapy, the failure to rule out the margin could be misleading. (As with superiority trials that fail to reject the null hypothesis, post hoc power calculations should be avoided.) After the study has ended, the resulting CIs should be used to evaluate whether the study was large enough to adequately assess the relative effectiveness of the treatments.

The RE-LY trial calculated the sample size that was expected to provide 84% power to rule out the prespecified hazard ratio of 1.46, assuming a true event rate of 1.6% per year (presumably for both groups), a recruitment period of 2 years, and at least one year of follow-up. The sample size was subsequently increased from 15,000 to 18,000 to maintain power in case of a low event rate.^4,5

5. Is the noninferiority trial as similar as possible to the trial(s) comparing the standard treatment with placebo?

Characteristics of participants, setting, reference treatment, and outcomes used in a noninferiority trial should be as close as possible to those in the trial(s) comparing the treatment with placebo. This is known as the constancy assumption, and it is key to researchers’ ability to draw a conclusion about noninferiority.

The trials used to calculate the noninferiority margin and the RE-LY trial itself involved similar populations of patients with AF, and the outcome (stroke) was similar.

6. Is a per protocol analysis reported in the results?

In randomized controlled superiority trials, the participants should be analyzed in the groups to which they were originally allocated, regardless of whether they adhered to treatment during the entire follow-up period. Such intention-to-treat (ITT) analysis is important because it provides a more conservative estimate of treatment effect—taking into account that some people who are offered treatment will not accept it and others will discontinue treatment. An ITT analysis therefore tends to minimize treatment effects compared with a “per protocol” analysis, in which participants are analyzed according to the treatment they actually received and are often removed from the analysis if they discontinue or do not adhere to treatment.

Intention-to-treat analysis is important because it provides a more conservative estimate of treatment effect.In noninferiority trials, if patients in the intervention group cross over to the standard treatment group or those in the standard treatment group have poor adherence, an ITT analysis can increase the risk of wrongly claiming noninferiority.⁷ Therefore, a per protocol analysis should be included—and indeed may be preferable.

In RE-LY, ITT analyses were reported, and complete follow-up data were available for 99.9% of patients. However, the rates of treatment discontinuation at one year were about 15% for those on dabigatran and 10% for the warfarin group, and 21% and 17%, respectively, at 2 years.^4,5 If the new treatment were truly less efficacious than the standard treatment, these moderate discontinuation rates could lead to more similar rates of stroke in the 2 groups than would be expected with higher continuation rates, biasing results towards the alternative of noninferiority. Although the original publication of trial results did not include a per protocol analysis, the RE-LY authors later reported that a per protocol analysis yielded similar results to the ITT analysis.

7. Are the overall design and execution of the trial high quality?

Because a poor quality noninferiority trial can appear to demonstrate noninferiority, looking at such studies critically is crucial. Appropriate randomization, concealed allocation, masking, and careful attention to participant flow must all be assessed.^2,3

To continue with our example, the RE-LY trial was well conducted. Randomization was performed centrally via an automated telephone system and 2 doses of dabigatran were administered in a masked fashion, while warfarin was open-label. Remarkably, follow-up was achieved for 99.9% of participants over a median of 2 years, and independent adjudicators masked to treatment group assessed outcomes.^4,5

CORRESPONDENCE
Anne Mounsey, MD, UNC Chapel Hill Department of Family Medicine, 590 Manning Drive, CB 7595, Chapel Hill, NC 27590; [email protected]

The traditional clinical trial, designed to test whether a new treatment is better than a placebo or another active treatment, is known as a “superiority” trial—although rarely labeled as such. In contrast, the goal of a noninferiority trial is simply to demonstrate that a new treatment is not substantially less effective than the standard therapy.

Such trials are useful when a new therapy is thought to be safer, easier to administer, or less costly than the existing treatment, but not necessarily more effective. And, because it would be unethical to randomize patients with a serious condition for which there already is an effective treatment to placebo, a noninferiority trial is another means of determining if the new treatment is effective.

Noninferiority trials have unique design features and methodology and require a different analysis than traditional superiority trials. Yet many physicians know far less about them; many investigators appear to be less than proficient, as well. A review of 116 noninferiority trials and 46 equivalence trials found that only 20% fulfilled generally accepted quality criteria.¹ To improve the quality of noninferiority trials, the CONSORT (Consolidated Standards of Reporting Trials) Group has published a checklist for trial design and reporting standards.^2,3 Based on this checklist, we came up with 7 key questions to consider when evaluating a noninferiority trial. In the pages that follow, you’ll also find an at-a-glance guide (TABLE) and a methodology review using a hypothetical case (page E7).

1. Is a noninferiority trial appropriate?

The introduction to a noninferiority trial should provide the rationale for this design and the absence of a placebo control group. Look for a review of the evidence of the efficacy of the reference treatment that placebo-controlled trials have revealed, along with the effect size. The advantages of the new treatment over the standard treatment—eg, fewer adverse effects, easier administration, or lower cost—should be discussed, as well.

In the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY)—a prominent noninferiority trial—investigators compared the standard anticoagulant (warfarin) for patients with atrial fibrillation (AF) at risk of stroke with a new agent, dabigatran.⁴ In the methods section of the abstract and the statistical analysis section of the main body, the authors clearly indicated that this was a noninferiority trial. They began by referring to the existing evidence of warfarin’s effectiveness, then detailed the qualities that make warfarin cumbersome to use, including the need for frequent laboratory monitoring. This was followed by evidence that many patients stop taking warfarin and that even for those who persist with treatment, adequate anticoagulation is difficult to maintain.

The authors went on to state that because dabigatran requires no long-term monitoring, it is easier to use. Therefore, if dabigatran could be shown to be no worse than warfarin in preventing strokes, it would be a reasonable alternative, leaving no doubt that this was an appropriate noninferiority trial.

2. Is the noninferiority margin based on clinical judgment and statistical reasoning?

The noninferiority margin should be based on clinical judgment as to how effective a new treatment must be in order to be declared not clinically inferior to the standard treatment. This can be based on several factors, including the severity of the outcome and the expected advantages of the new treatment. The margin should also take into account the size of the standard treatment’s effect vs placebo. In RELY, for example, the authors noted that the noninferiority margin was based on the desire to preserve at least 50% of the lower limit of the confidence interval (CI) of warfarin’s estimated effect; this was done using data from a previously published meta-analysis of 6 trials comparing warfarin with placebo for stroke prevention in patients with AF.^4-6

3. Are the hypothesis and statistical analysis formulated correctly?

The clinical hypothesis in a noninferiority trial is that the new treatment is not worse than the standard treatment by a prespecified margin; therefore, the statistical null hypothesis to be tested is that the new treatment is worse than the reference treatment by more than that margin. Rejecting a true null hypothesis (for example, because the P value is <.05) is known as a type l error. In this setting, making a type I error would mean accepting a new treatment that is truly worse than the standard by at least the specified margin. Failure to reject a false null hypothesis is known as a type II error, which in this case would mean failing to identify a new treatment that is truly noninferior to the standard.⁷

In RE-LY, the authors stated that the upper limit of the one-sided 97.5% CI for the relative risk of a stroke with dabigatran vs warfarin had to fall below 1.46.⁴ (This is the same as testing the null hypothesis that the hazard ratio is ≥1.46.) Thus, the hypothesis was formulated correctly.

4. Is the sample size appropriate and justified?

The sample size in a noninferiority trial should provide high power to reject the null hypothesis that the difference (or relative risk) between groups is equal to or greater than the noninferiority margin under some clinically meaningful assumption about the true difference (or absolute risk reduction) between groups. A true difference of 0 (or a relative risk of 1) is typically assumed for sample size calculation. However, assuming that the new treatment is truly slightly better or slightly worse than the standard may be clinically appropriate in some cases. This would indicate a need for a smaller or larger sample size, respectively, than that required under the usual assumption of no difference.

When the justification for the sample size in a noninferiority trial is not provided or the number of participants is based on an inappropriate approach (eg, using superiority trial calculations for a noninferiority trial), questions about the quality of the trial arise. The primary concern is whether the noninferiority margin was actually selected before the trial began, as it should have been. And if the researchers used overly optimistic assumptions about the efficacy of the new treatment relative to the standard therapy, the failure to rule out the margin could be misleading. (As with superiority trials that fail to reject the null hypothesis, post hoc power calculations should be avoided.) After the study has ended, the resulting CIs should be used to evaluate whether the study was large enough to adequately assess the relative effectiveness of the treatments.

The RE-LY trial calculated the sample size that was expected to provide 84% power to rule out the prespecified hazard ratio of 1.46, assuming a true event rate of 1.6% per year (presumably for both groups), a recruitment period of 2 years, and at least one year of follow-up. The sample size was subsequently increased from 15,000 to 18,000 to maintain power in case of a low event rate.^4,5

5. Is the noninferiority trial as similar as possible to the trial(s) comparing the standard treatment with placebo?

Characteristics of participants, setting, reference treatment, and outcomes used in a noninferiority trial should be as close as possible to those in the trial(s) comparing the treatment with placebo. This is known as the constancy assumption, and it is key to researchers’ ability to draw a conclusion about noninferiority.

The trials used to calculate the noninferiority margin and the RE-LY trial itself involved similar populations of patients with AF, and the outcome (stroke) was similar.

6. Is a per protocol analysis reported in the results?

In randomized controlled superiority trials, the participants should be analyzed in the groups to which they were originally allocated, regardless of whether they adhered to treatment during the entire follow-up period. Such intention-to-treat (ITT) analysis is important because it provides a more conservative estimate of treatment effect—taking into account that some people who are offered treatment will not accept it and others will discontinue treatment. An ITT analysis therefore tends to minimize treatment effects compared with a “per protocol” analysis, in which participants are analyzed according to the treatment they actually received and are often removed from the analysis if they discontinue or do not adhere to treatment.

Intention-to-treat analysis is important because it provides a more conservative estimate of treatment effect.In noninferiority trials, if patients in the intervention group cross over to the standard treatment group or those in the standard treatment group have poor adherence, an ITT analysis can increase the risk of wrongly claiming noninferiority.⁷ Therefore, a per protocol analysis should be included—and indeed may be preferable.

In RE-LY, ITT analyses were reported, and complete follow-up data were available for 99.9% of patients. However, the rates of treatment discontinuation at one year were about 15% for those on dabigatran and 10% for the warfarin group, and 21% and 17%, respectively, at 2 years.^4,5 If the new treatment were truly less efficacious than the standard treatment, these moderate discontinuation rates could lead to more similar rates of stroke in the 2 groups than would be expected with higher continuation rates, biasing results towards the alternative of noninferiority. Although the original publication of trial results did not include a per protocol analysis, the RE-LY authors later reported that a per protocol analysis yielded similar results to the ITT analysis.

7. Are the overall design and execution of the trial high quality?

Because a poor quality noninferiority trial can appear to demonstrate noninferiority, looking at such studies critically is crucial. Appropriate randomization, concealed allocation, masking, and careful attention to participant flow must all be assessed.^2,3

To continue with our example, the RE-LY trial was well conducted. Randomization was performed centrally via an automated telephone system and 2 doses of dabigatran were administered in a masked fashion, while warfarin was open-label. Remarkably, follow-up was achieved for 99.9% of participants over a median of 2 years, and independent adjudicators masked to treatment group assessed outcomes.^4,5

CORRESPONDENCE
Anne Mounsey, MD, UNC Chapel Hill Department of Family Medicine, 590 Manning Drive, CB 7595, Chapel Hill, NC 27590; [email protected]

Drop of blood

Credit: Максим Кукушкин

Researchers have developed an optical device that requires only a few drops of blood and a few minutes to measure coagulation parameters that can guide blood transfusions and anticoagulant therapy.

The team described their device in Biomedical Optics Express.

“Currently, the most comprehensive measures of coagulation are a battery of lab tests that are expensive and can take hours to perform,” said study author Seemantini Nadkarni, PhD, of Massachusetts General Hospital in Boston.

She noted that other systems have been developed that provide clotting measurements at the point of care, but the systems can be big and expensive or have other limitations, such as requiring significant amounts of blood or only measuring clotting time.

“Our goal is to provide as much information as a lab test, but to provide it quickly and cheaply at a patient’s bedside,” Dr Nadkarni said.

To reach this goal, she and her colleagues turned to an optical technique they pioneered called laser speckle rheology. The technique involves shining a laser into a sample and monitoring the patterns of light that bounce back.

The researchers had previously used the technique to measure the mechanical properties of a range of different tissue types and found that it was extremely sensitive to the coagulation of blood.

When light hits a blood sample, blood cells and platelets scatter the light. In unclotted blood, these light-scattering particles move easily about, making the pattern of scattered light, a speckle pattern, fluctuate rapidly.

“It’s almost like looking at a starry night sky, with twinkling stars,” Dr Nadkarni said. “But as the blood starts to coagulate, blood cells and platelets come together within a fibrin network to form a clot. The motion is restricted as the sample gets stiffer, and the ‘twinkling’ of the speckle pattern is reduced significantly.”

Dr Nadkarni and her colleagues used a miniature high-speed camera to record the fluctuating speckle pattern and then correlated the intensity of changes in the pattern with 2 blood sample measurements: clotting time and fibrinogen concentration.

The team noted that physicians could use the measurements to make decisions about how much blood to give a bleeding patient and what type of blood product is needed most.

“The timely detection of clotting defects followed by the appropriate blood product transfusion is critical in managing bleeding patients,” Dr Nadkarni said. “If you transfuse too much, there could be further coagulation defects that occur, but if you don’t transfuse enough, bleeding continues.”

On the other end of the spectrum, the device could help patients on anticoagulant therapy. Having a small device that can analyze their blood in a doctor’s office or at home could reduce the cost and inconvenience of blood tests, while increasing the safety of anticoagulation treatment, Dr Nadkarni said.

At present, her team’s device is about the size of a tissue box and is connected to a computer. The researchers are working to further miniaturize the system and aim to perform clinical studies with a  version smaller than a cell phone within the next year.

Drop of blood

Credit: Максим Кукушкин

Researchers have developed an optical device that requires only a few drops of blood and a few minutes to measure coagulation parameters that can guide blood transfusions and anticoagulant therapy.

The team described their device in Biomedical Optics Express.

“Currently, the most comprehensive measures of coagulation are a battery of lab tests that are expensive and can take hours to perform,” said study author Seemantini Nadkarni, PhD, of Massachusetts General Hospital in Boston.

She noted that other systems have been developed that provide clotting measurements at the point of care, but the systems can be big and expensive or have other limitations, such as requiring significant amounts of blood or only measuring clotting time.

“Our goal is to provide as much information as a lab test, but to provide it quickly and cheaply at a patient’s bedside,” Dr Nadkarni said.

To reach this goal, she and her colleagues turned to an optical technique they pioneered called laser speckle rheology. The technique involves shining a laser into a sample and monitoring the patterns of light that bounce back.

The researchers had previously used the technique to measure the mechanical properties of a range of different tissue types and found that it was extremely sensitive to the coagulation of blood.

When light hits a blood sample, blood cells and platelets scatter the light. In unclotted blood, these light-scattering particles move easily about, making the pattern of scattered light, a speckle pattern, fluctuate rapidly.

“It’s almost like looking at a starry night sky, with twinkling stars,” Dr Nadkarni said. “But as the blood starts to coagulate, blood cells and platelets come together within a fibrin network to form a clot. The motion is restricted as the sample gets stiffer, and the ‘twinkling’ of the speckle pattern is reduced significantly.”

Dr Nadkarni and her colleagues used a miniature high-speed camera to record the fluctuating speckle pattern and then correlated the intensity of changes in the pattern with 2 blood sample measurements: clotting time and fibrinogen concentration.

The team noted that physicians could use the measurements to make decisions about how much blood to give a bleeding patient and what type of blood product is needed most.

“The timely detection of clotting defects followed by the appropriate blood product transfusion is critical in managing bleeding patients,” Dr Nadkarni said. “If you transfuse too much, there could be further coagulation defects that occur, but if you don’t transfuse enough, bleeding continues.”

On the other end of the spectrum, the device could help patients on anticoagulant therapy. Having a small device that can analyze their blood in a doctor’s office or at home could reduce the cost and inconvenience of blood tests, while increasing the safety of anticoagulation treatment, Dr Nadkarni said.

At present, her team’s device is about the size of a tissue box and is connected to a computer. The researchers are working to further miniaturize the system and aim to perform clinical studies with a  version smaller than a cell phone within the next year.

Drop of blood

Credit: Максим Кукушкин

Researchers have developed an optical device that requires only a few drops of blood and a few minutes to measure coagulation parameters that can guide blood transfusions and anticoagulant therapy.

The team described their device in Biomedical Optics Express.

“Currently, the most comprehensive measures of coagulation are a battery of lab tests that are expensive and can take hours to perform,” said study author Seemantini Nadkarni, PhD, of Massachusetts General Hospital in Boston.

She noted that other systems have been developed that provide clotting measurements at the point of care, but the systems can be big and expensive or have other limitations, such as requiring significant amounts of blood or only measuring clotting time.

“Our goal is to provide as much information as a lab test, but to provide it quickly and cheaply at a patient’s bedside,” Dr Nadkarni said.

To reach this goal, she and her colleagues turned to an optical technique they pioneered called laser speckle rheology. The technique involves shining a laser into a sample and monitoring the patterns of light that bounce back.

The researchers had previously used the technique to measure the mechanical properties of a range of different tissue types and found that it was extremely sensitive to the coagulation of blood.

When light hits a blood sample, blood cells and platelets scatter the light. In unclotted blood, these light-scattering particles move easily about, making the pattern of scattered light, a speckle pattern, fluctuate rapidly.

“It’s almost like looking at a starry night sky, with twinkling stars,” Dr Nadkarni said. “But as the blood starts to coagulate, blood cells and platelets come together within a fibrin network to form a clot. The motion is restricted as the sample gets stiffer, and the ‘twinkling’ of the speckle pattern is reduced significantly.”

Dr Nadkarni and her colleagues used a miniature high-speed camera to record the fluctuating speckle pattern and then correlated the intensity of changes in the pattern with 2 blood sample measurements: clotting time and fibrinogen concentration.

The team noted that physicians could use the measurements to make decisions about how much blood to give a bleeding patient and what type of blood product is needed most.

“The timely detection of clotting defects followed by the appropriate blood product transfusion is critical in managing bleeding patients,” Dr Nadkarni said. “If you transfuse too much, there could be further coagulation defects that occur, but if you don’t transfuse enough, bleeding continues.”

On the other end of the spectrum, the device could help patients on anticoagulant therapy. Having a small device that can analyze their blood in a doctor’s office or at home could reduce the cost and inconvenience of blood tests, while increasing the safety of anticoagulation treatment, Dr Nadkarni said.

At present, her team’s device is about the size of a tissue box and is connected to a computer. The researchers are working to further miniaturize the system and aim to perform clinical studies with a  version smaller than a cell phone within the next year.

Man loading a pump to

spray insecticide

Credit: Morgana Wingard

A single genetic mutation can cause resistance to the main insecticides used to combat malaria, according to a study published in Genome Biology.

Researchers identified a mutation in the gene GSTe2 that allows mosquitoes to break down the insecticide DDT into non-toxic substances.

The mutation also makes mosquitoes resistant to pyrethroids, an insecticide class used in mosquito nets.

“We found a population of mosquitoes fully resistant to DDT but also to pyrethroids,” said study author Charles Wondji, PhD, of the Liverpool School of Tropical Medicine in the UK.

“So we wanted to elucidate the molecular basis of that resistance in the population and design a field-applicable diagnostic assay for its monitoring.”

To that end, the researchers did a genome-wide comparison on mosquitoes that were fully susceptible to insecticides and Anopheles funestus mosquitoes from the Republic of Benin in Africa, which were resistant to DDT and the pyrethroid permethrin.

The team found the GSTe2 gene was upregulated in the resistant mosquitoes. And a single mutation (L119F) changed a non-resistant version of the gene to an insecticide-resistant version.

The researchers then designed a DNA-based diagnostic test for this metabolic resistance and confirmed that this mutation was found in mosquitoes from other areas of the world with DDT resistance, but it was completely absent in regions without resistance.

X-ray crystallography of the protein coded by the gene illustrated exactly how the mutation conferred resistance—by opening up the active site where DDT molecules bind to the protein so that more can be broken down. In other words, the mosquito can survive by breaking down the poison into non-toxic substances.

The researchers also introduced the gene into Drosophila melanogaster and found the flies became resistant to DDT and pyrethroids, whereas control flies did not. The team said this confirms that a single mutation is enough to make insects resistant to both DDT and pyrethroids.

“For the first time, we have been able to identify a molecular marker for metabolic resistance in a mosquito population and to design a DNA-based diagnostic assay,” Dr Wondji said.

“Such tools will allow control programs to detect and track resistance at an early stage in the field, which is an essential requirement to successfully tackle the growing problem of insecticide resistance in vector control. This significant progress opens the door for us to do this with other forms of resistance as well and in other vector species.”

Man loading a pump to

spray insecticide

Credit: Morgana Wingard

A single genetic mutation can cause resistance to the main insecticides used to combat malaria, according to a study published in Genome Biology.

Researchers identified a mutation in the gene GSTe2 that allows mosquitoes to break down the insecticide DDT into non-toxic substances.

The mutation also makes mosquitoes resistant to pyrethroids, an insecticide class used in mosquito nets.

“We found a population of mosquitoes fully resistant to DDT but also to pyrethroids,” said study author Charles Wondji, PhD, of the Liverpool School of Tropical Medicine in the UK.

“So we wanted to elucidate the molecular basis of that resistance in the population and design a field-applicable diagnostic assay for its monitoring.”

To that end, the researchers did a genome-wide comparison on mosquitoes that were fully susceptible to insecticides and Anopheles funestus mosquitoes from the Republic of Benin in Africa, which were resistant to DDT and the pyrethroid permethrin.

The team found the GSTe2 gene was upregulated in the resistant mosquitoes. And a single mutation (L119F) changed a non-resistant version of the gene to an insecticide-resistant version.

The researchers then designed a DNA-based diagnostic test for this metabolic resistance and confirmed that this mutation was found in mosquitoes from other areas of the world with DDT resistance, but it was completely absent in regions without resistance.

X-ray crystallography of the protein coded by the gene illustrated exactly how the mutation conferred resistance—by opening up the active site where DDT molecules bind to the protein so that more can be broken down. In other words, the mosquito can survive by breaking down the poison into non-toxic substances.

The researchers also introduced the gene into Drosophila melanogaster and found the flies became resistant to DDT and pyrethroids, whereas control flies did not. The team said this confirms that a single mutation is enough to make insects resistant to both DDT and pyrethroids.

“For the first time, we have been able to identify a molecular marker for metabolic resistance in a mosquito population and to design a DNA-based diagnostic assay,” Dr Wondji said.

“Such tools will allow control programs to detect and track resistance at an early stage in the field, which is an essential requirement to successfully tackle the growing problem of insecticide resistance in vector control. This significant progress opens the door for us to do this with other forms of resistance as well and in other vector species.”

Man loading a pump to

spray insecticide

Credit: Morgana Wingard

A single genetic mutation can cause resistance to the main insecticides used to combat malaria, according to a study published in Genome Biology.

Researchers identified a mutation in the gene GSTe2 that allows mosquitoes to break down the insecticide DDT into non-toxic substances.

The mutation also makes mosquitoes resistant to pyrethroids, an insecticide class used in mosquito nets.

“We found a population of mosquitoes fully resistant to DDT but also to pyrethroids,” said study author Charles Wondji, PhD, of the Liverpool School of Tropical Medicine in the UK.

“So we wanted to elucidate the molecular basis of that resistance in the population and design a field-applicable diagnostic assay for its monitoring.”

To that end, the researchers did a genome-wide comparison on mosquitoes that were fully susceptible to insecticides and Anopheles funestus mosquitoes from the Republic of Benin in Africa, which were resistant to DDT and the pyrethroid permethrin.

The team found the GSTe2 gene was upregulated in the resistant mosquitoes. And a single mutation (L119F) changed a non-resistant version of the gene to an insecticide-resistant version.

The researchers then designed a DNA-based diagnostic test for this metabolic resistance and confirmed that this mutation was found in mosquitoes from other areas of the world with DDT resistance, but it was completely absent in regions without resistance.

X-ray crystallography of the protein coded by the gene illustrated exactly how the mutation conferred resistance—by opening up the active site where DDT molecules bind to the protein so that more can be broken down. In other words, the mosquito can survive by breaking down the poison into non-toxic substances.

The researchers also introduced the gene into Drosophila melanogaster and found the flies became resistant to DDT and pyrethroids, whereas control flies did not. The team said this confirms that a single mutation is enough to make insects resistant to both DDT and pyrethroids.

“For the first time, we have been able to identify a molecular marker for metabolic resistance in a mosquito population and to design a DNA-based diagnostic assay,” Dr Wondji said.

“Such tools will allow control programs to detect and track resistance at an early stage in the field, which is an essential requirement to successfully tackle the growing problem of insecticide resistance in vector control. This significant progress opens the door for us to do this with other forms of resistance as well and in other vector species.”

Bone marrow aspirate

showing multiple myeloma

Blacks may be twice as likely as whites to develop multiple myeloma (MM) because they are more likely to have monoclonal gammopathy of undetermined significance (MGUS), according to research published in Leukemia.

In a US-wide study, researchers found that MGUS is more common in blacks than in whites or Hispanics.

And the type of MGUS seen in the black population is more apt to have features associated with a higher risk of progression to full-blown MM.

The study also revealed different rates of MGUS in different parts of the country, which suggests there may be an environmental component to the racial disparities.

“We have known for a long time that there is a marked racial disparity in multiple myeloma, but the big question has been why that disparity exists,” said study author Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota.

“We suspected it may be genetic or it may be environmental. We also thought that the predisposing factor is more common, or it may be that the predisposing factor progresses to cancer much more quickly. We found that the answer is all of the above.”

A number of studies have investigated the prevalence of MGUS in various populations. The most prominent took place in the predominantly white community of Olmsted County, Minnesota. There, researchers estimated that MGUS occurred in approximately 3.2% of individuals aged 50 and older.

In the current study, Dr Rajkumar and his colleagues set out to determine the prevalence of MGUS in blacks and Hispanics, as well as whites in other parts of the country. They analyzed stored serum samples of 12,482 people older than 50 years of age taken from the National Health and Nutritional Examination Survey.

By examining the M protein present in each sample, the researchers assessed both the prevalence of MGUS and its likelihood for progression. They found that the prevalence of MGUS was significantly higher in blacks (3.7%) compared with whites (2.3%) or Hispanics (1.8%), as were features that posed a higher risk of progression to MM.

The researchers were surprised that the prevalence of MGUS in whites in their national sample was significantly lower than the rates previously reported for Olmsted County. However, when they broke down the national numbers into geographic regions, they found that people living in Northern and Midwestern states have a higher incidence of MGUS than those living in Southern and Western states.

“We would have missed this geographic difference if we hadn’t looked at the whole country,” Dr Rajkumar said. “This is the largest study of its kind and the first to look at MGUS in a sample of the entire US population.”

Dr Rajkumar and his colleagues are now investigating the underlying causes of these geographic variations to see if they can identify the genetic and environmental factors contributing to the risk of MGUS. They are also repeating their experiments in samples from individuals under age 50 in an effort to pinpoint when the risk of MGUS and, ultimately, MM begins.

Bone marrow aspirate

showing multiple myeloma

Blacks may be twice as likely as whites to develop multiple myeloma (MM) because they are more likely to have monoclonal gammopathy of undetermined significance (MGUS), according to research published in Leukemia.

In a US-wide study, researchers found that MGUS is more common in blacks than in whites or Hispanics.

And the type of MGUS seen in the black population is more apt to have features associated with a higher risk of progression to full-blown MM.

The study also revealed different rates of MGUS in different parts of the country, which suggests there may be an environmental component to the racial disparities.

“We have known for a long time that there is a marked racial disparity in multiple myeloma, but the big question has been why that disparity exists,” said study author Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota.

“We suspected it may be genetic or it may be environmental. We also thought that the predisposing factor is more common, or it may be that the predisposing factor progresses to cancer much more quickly. We found that the answer is all of the above.”

A number of studies have investigated the prevalence of MGUS in various populations. The most prominent took place in the predominantly white community of Olmsted County, Minnesota. There, researchers estimated that MGUS occurred in approximately 3.2% of individuals aged 50 and older.

In the current study, Dr Rajkumar and his colleagues set out to determine the prevalence of MGUS in blacks and Hispanics, as well as whites in other parts of the country. They analyzed stored serum samples of 12,482 people older than 50 years of age taken from the National Health and Nutritional Examination Survey.

By examining the M protein present in each sample, the researchers assessed both the prevalence of MGUS and its likelihood for progression. They found that the prevalence of MGUS was significantly higher in blacks (3.7%) compared with whites (2.3%) or Hispanics (1.8%), as were features that posed a higher risk of progression to MM.

The researchers were surprised that the prevalence of MGUS in whites in their national sample was significantly lower than the rates previously reported for Olmsted County. However, when they broke down the national numbers into geographic regions, they found that people living in Northern and Midwestern states have a higher incidence of MGUS than those living in Southern and Western states.

“We would have missed this geographic difference if we hadn’t looked at the whole country,” Dr Rajkumar said. “This is the largest study of its kind and the first to look at MGUS in a sample of the entire US population.”

Dr Rajkumar and his colleagues are now investigating the underlying causes of these geographic variations to see if they can identify the genetic and environmental factors contributing to the risk of MGUS. They are also repeating their experiments in samples from individuals under age 50 in an effort to pinpoint when the risk of MGUS and, ultimately, MM begins.

Bone marrow aspirate

showing multiple myeloma

Blacks may be twice as likely as whites to develop multiple myeloma (MM) because they are more likely to have monoclonal gammopathy of undetermined significance (MGUS), according to research published in Leukemia.

In a US-wide study, researchers found that MGUS is more common in blacks than in whites or Hispanics.

And the type of MGUS seen in the black population is more apt to have features associated with a higher risk of progression to full-blown MM.

The study also revealed different rates of MGUS in different parts of the country, which suggests there may be an environmental component to the racial disparities.

“We have known for a long time that there is a marked racial disparity in multiple myeloma, but the big question has been why that disparity exists,” said study author Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota.

“We suspected it may be genetic or it may be environmental. We also thought that the predisposing factor is more common, or it may be that the predisposing factor progresses to cancer much more quickly. We found that the answer is all of the above.”

A number of studies have investigated the prevalence of MGUS in various populations. The most prominent took place in the predominantly white community of Olmsted County, Minnesota. There, researchers estimated that MGUS occurred in approximately 3.2% of individuals aged 50 and older.

In the current study, Dr Rajkumar and his colleagues set out to determine the prevalence of MGUS in blacks and Hispanics, as well as whites in other parts of the country. They analyzed stored serum samples of 12,482 people older than 50 years of age taken from the National Health and Nutritional Examination Survey.

By examining the M protein present in each sample, the researchers assessed both the prevalence of MGUS and its likelihood for progression. They found that the prevalence of MGUS was significantly higher in blacks (3.7%) compared with whites (2.3%) or Hispanics (1.8%), as were features that posed a higher risk of progression to MM.

The researchers were surprised that the prevalence of MGUS in whites in their national sample was significantly lower than the rates previously reported for Olmsted County. However, when they broke down the national numbers into geographic regions, they found that people living in Northern and Midwestern states have a higher incidence of MGUS than those living in Southern and Western states.

“We would have missed this geographic difference if we hadn’t looked at the whole country,” Dr Rajkumar said. “This is the largest study of its kind and the first to look at MGUS in a sample of the entire US population.”

Dr Rajkumar and his colleagues are now investigating the underlying causes of these geographic variations to see if they can identify the genetic and environmental factors contributing to the risk of MGUS. They are also repeating their experiments in samples from individuals under age 50 in an effort to pinpoint when the risk of MGUS and, ultimately, MM begins.

Thrombus

Credit: Kevin MacKenzie

Updated guidelines from the American Academy of Neurology provide a comparison of oral anticoagulants as stroke prophylaxis in patients with nonvalvular atrial fibrillation (NVAF).

The guidelines suggest that newer anticoagulants, such as dabigatran, rivaroxaban, and apixaban, are at least as effective, if not more effective, than warfarin at preventing stroke in patients with NVAF. But bleeding risks vary.

Clopidogrel plus aspirin appears to be less effective than warfarin and its derivatives but more effective than aspirin alone.

Apixaban also appears to be more effective than aspirin, with a similar bleeding risk.  And triflusal plus acenocoumarol is likely more effective than acenocoumarol alone.

“Of course, doctors will need to consider the individual patient’s situation in making a decision whether or not to use anticoagulants and which one to use, as the risks and benefits can vary for each person,”  said guideline author Antonio Culebras, MD, of SUNY Upstate Medical University in Syracuse, New York.

Comparing therapies

The authors noted that several new anticoagulants have been developed since the American Academy of Neurology’s last published guidelines on this topic, in 1998.

For the current guidelines, the authors evaluated the results of 6 studies comparing antithrombotics to warfarin and its derivatives, as well as 2 studies comparing antithrombotics to aspirin.

One study suggested that dabigatran is probably more effective than warfarin for reducing the risk of stroke or systemic embolism. Hemorrhage risks were similar with the 2 drugs. But intracranial hemorrhage was less frequent with dabigatran, and gastrointestinal bleeding was higher with dabigatran.

Another study indicated that rivaroxaban is likely as effective as warfarin for preventing cerebral and systemic embolism. Patients who received rivaroxaban had an increased risk of gastrointestinal bleeding but a decreased risk of intracranial hemorrhage and fatal bleeding.

Apixaban seemed to be more effective than warfarin in patients with NVAF who were at moderate risk of embolism. However, this superiority appeared to be the result of a decreased risk in bleeding and reduced mortality. Apixaban was no more effective than warfarin in reducing the risk of cerebral and systemic embolism.

Yet another study suggested that vitamin K antagonists (VKAs) are likely more effective than clopidogrel plus aspirin as stroke prevention in NVAF patients. However, intracranial bleeding was more common with VKAs.

In NVAF patients at moderate risk of stroke, treatment with triflusal plus acenocoumarol and moderate-intensity anticoagulation (INR target 1.25–2.0) appeared to be more effective than treatment with acenocoumarol alone and conventional-intensity anticoagulation (INR target 2.0–3.0).

Low-dose aspirin plus dose-adjusted VKA (fluindione) appeared to increase the risk of hemorrhagic complications compared to VKA therapy alone. However, there was not enough evidence to determine whether aspirin plus VKA decreases the risk of ischemic stroke or other thromboembolic events.

Apixaban appeared to be more effective than aspirin for decreasing the risk of stroke or systemic embolism in patients with NVAF who have a moderate risk of embolism and are not candidates for warfarin treatment. And the bleeding risks were similar with apixaban and aspirin.

In patients with NVAF who were ineligible for VKA therapy, clopidogrel plus aspirin reduced the risk of major vascular events, especially stroke, when compared to aspirin alone. However, the combination also increased the risk of major hemorrhage, including intracranial bleeding.

Recommendations

The authors noted that determining stroke risk in NVAF patients is difficult. So they recommend that clinicians weigh the risks and benefits of stroke prophylaxis in each patient. The authors also recommend informing patients about the potential risk of stroke and taking the patient’s preferences into account.

Clinicians should routinely offer anticoagulant therapy to patients with NVAF and a history of transient ischemic attack or stroke. On the other hand, anticoagulants might not be necessary in NVAF patients who lack additional risk factors for stroke.

Clinicians should use a risk-stratification scheme to help them identify patients at a higher risk for stroke and those with no clinically significant risk. However, anticoagulation thresholds are not necessarily  definitive indicators of the need for anticoagulant therapy.

When choosing among anticoagulants, clinicians should consider the individual patient’s needs and take into account the aforementioned efficacy and safety data.

For more details, see the guidelines in Neurology.

Thrombus

Credit: Kevin MacKenzie

Updated guidelines from the American Academy of Neurology provide a comparison of oral anticoagulants as stroke prophylaxis in patients with nonvalvular atrial fibrillation (NVAF).

The guidelines suggest that newer anticoagulants, such as dabigatran, rivaroxaban, and apixaban, are at least as effective, if not more effective, than warfarin at preventing stroke in patients with NVAF. But bleeding risks vary.

Clopidogrel plus aspirin appears to be less effective than warfarin and its derivatives but more effective than aspirin alone.

Apixaban also appears to be more effective than aspirin, with a similar bleeding risk.  And triflusal plus acenocoumarol is likely more effective than acenocoumarol alone.

“Of course, doctors will need to consider the individual patient’s situation in making a decision whether or not to use anticoagulants and which one to use, as the risks and benefits can vary for each person,”  said guideline author Antonio Culebras, MD, of SUNY Upstate Medical University in Syracuse, New York.

Comparing therapies

The authors noted that several new anticoagulants have been developed since the American Academy of Neurology’s last published guidelines on this topic, in 1998.

For the current guidelines, the authors evaluated the results of 6 studies comparing antithrombotics to warfarin and its derivatives, as well as 2 studies comparing antithrombotics to aspirin.

One study suggested that dabigatran is probably more effective than warfarin for reducing the risk of stroke or systemic embolism. Hemorrhage risks were similar with the 2 drugs. But intracranial hemorrhage was less frequent with dabigatran, and gastrointestinal bleeding was higher with dabigatran.

Another study indicated that rivaroxaban is likely as effective as warfarin for preventing cerebral and systemic embolism. Patients who received rivaroxaban had an increased risk of gastrointestinal bleeding but a decreased risk of intracranial hemorrhage and fatal bleeding.

Apixaban seemed to be more effective than warfarin in patients with NVAF who were at moderate risk of embolism. However, this superiority appeared to be the result of a decreased risk in bleeding and reduced mortality. Apixaban was no more effective than warfarin in reducing the risk of cerebral and systemic embolism.

Yet another study suggested that vitamin K antagonists (VKAs) are likely more effective than clopidogrel plus aspirin as stroke prevention in NVAF patients. However, intracranial bleeding was more common with VKAs.

In NVAF patients at moderate risk of stroke, treatment with triflusal plus acenocoumarol and moderate-intensity anticoagulation (INR target 1.25–2.0) appeared to be more effective than treatment with acenocoumarol alone and conventional-intensity anticoagulation (INR target 2.0–3.0).

Low-dose aspirin plus dose-adjusted VKA (fluindione) appeared to increase the risk of hemorrhagic complications compared to VKA therapy alone. However, there was not enough evidence to determine whether aspirin plus VKA decreases the risk of ischemic stroke or other thromboembolic events.

Apixaban appeared to be more effective than aspirin for decreasing the risk of stroke or systemic embolism in patients with NVAF who have a moderate risk of embolism and are not candidates for warfarin treatment. And the bleeding risks were similar with apixaban and aspirin.

In patients with NVAF who were ineligible for VKA therapy, clopidogrel plus aspirin reduced the risk of major vascular events, especially stroke, when compared to aspirin alone. However, the combination also increased the risk of major hemorrhage, including intracranial bleeding.

Recommendations

The authors noted that determining stroke risk in NVAF patients is difficult. So they recommend that clinicians weigh the risks and benefits of stroke prophylaxis in each patient. The authors also recommend informing patients about the potential risk of stroke and taking the patient’s preferences into account.

Clinicians should routinely offer anticoagulant therapy to patients with NVAF and a history of transient ischemic attack or stroke. On the other hand, anticoagulants might not be necessary in NVAF patients who lack additional risk factors for stroke.

Clinicians should use a risk-stratification scheme to help them identify patients at a higher risk for stroke and those with no clinically significant risk. However, anticoagulation thresholds are not necessarily  definitive indicators of the need for anticoagulant therapy.

When choosing among anticoagulants, clinicians should consider the individual patient’s needs and take into account the aforementioned efficacy and safety data.

For more details, see the guidelines in Neurology.

Thrombus

Credit: Kevin MacKenzie

Updated guidelines from the American Academy of Neurology provide a comparison of oral anticoagulants as stroke prophylaxis in patients with nonvalvular atrial fibrillation (NVAF).

The guidelines suggest that newer anticoagulants, such as dabigatran, rivaroxaban, and apixaban, are at least as effective, if not more effective, than warfarin at preventing stroke in patients with NVAF. But bleeding risks vary.

Clopidogrel plus aspirin appears to be less effective than warfarin and its derivatives but more effective than aspirin alone.

Apixaban also appears to be more effective than aspirin, with a similar bleeding risk.  And triflusal plus acenocoumarol is likely more effective than acenocoumarol alone.

“Of course, doctors will need to consider the individual patient’s situation in making a decision whether or not to use anticoagulants and which one to use, as the risks and benefits can vary for each person,”  said guideline author Antonio Culebras, MD, of SUNY Upstate Medical University in Syracuse, New York.

Comparing therapies

The authors noted that several new anticoagulants have been developed since the American Academy of Neurology’s last published guidelines on this topic, in 1998.

For the current guidelines, the authors evaluated the results of 6 studies comparing antithrombotics to warfarin and its derivatives, as well as 2 studies comparing antithrombotics to aspirin.

One study suggested that dabigatran is probably more effective than warfarin for reducing the risk of stroke or systemic embolism. Hemorrhage risks were similar with the 2 drugs. But intracranial hemorrhage was less frequent with dabigatran, and gastrointestinal bleeding was higher with dabigatran.

Another study indicated that rivaroxaban is likely as effective as warfarin for preventing cerebral and systemic embolism. Patients who received rivaroxaban had an increased risk of gastrointestinal bleeding but a decreased risk of intracranial hemorrhage and fatal bleeding.

Apixaban seemed to be more effective than warfarin in patients with NVAF who were at moderate risk of embolism. However, this superiority appeared to be the result of a decreased risk in bleeding and reduced mortality. Apixaban was no more effective than warfarin in reducing the risk of cerebral and systemic embolism.

Yet another study suggested that vitamin K antagonists (VKAs) are likely more effective than clopidogrel plus aspirin as stroke prevention in NVAF patients. However, intracranial bleeding was more common with VKAs.

In NVAF patients at moderate risk of stroke, treatment with triflusal plus acenocoumarol and moderate-intensity anticoagulation (INR target 1.25–2.0) appeared to be more effective than treatment with acenocoumarol alone and conventional-intensity anticoagulation (INR target 2.0–3.0).

Low-dose aspirin plus dose-adjusted VKA (fluindione) appeared to increase the risk of hemorrhagic complications compared to VKA therapy alone. However, there was not enough evidence to determine whether aspirin plus VKA decreases the risk of ischemic stroke or other thromboembolic events.

Apixaban appeared to be more effective than aspirin for decreasing the risk of stroke or systemic embolism in patients with NVAF who have a moderate risk of embolism and are not candidates for warfarin treatment. And the bleeding risks were similar with apixaban and aspirin.

In patients with NVAF who were ineligible for VKA therapy, clopidogrel plus aspirin reduced the risk of major vascular events, especially stroke, when compared to aspirin alone. However, the combination also increased the risk of major hemorrhage, including intracranial bleeding.

Recommendations

The authors noted that determining stroke risk in NVAF patients is difficult. So they recommend that clinicians weigh the risks and benefits of stroke prophylaxis in each patient. The authors also recommend informing patients about the potential risk of stroke and taking the patient’s preferences into account.

Clinicians should routinely offer anticoagulant therapy to patients with NVAF and a history of transient ischemic attack or stroke. On the other hand, anticoagulants might not be necessary in NVAF patients who lack additional risk factors for stroke.

Clinicians should use a risk-stratification scheme to help them identify patients at a higher risk for stroke and those with no clinically significant risk. However, anticoagulation thresholds are not necessarily  definitive indicators of the need for anticoagulant therapy.

When choosing among anticoagulants, clinicians should consider the individual patient’s needs and take into account the aforementioned efficacy and safety data.

For more details, see the guidelines in Neurology.