Cleveland Clinic Journal of Medicine

A 69-year-old ohio man with leukemia was treated in another state in late June. During the car trip back to Ohio, he developed a sore throat, fever, cough, and nasal congestion. He was admitted to Cleveland Clinic with a presumed diagnosis of neutropenic fever; his absolute neutrophil count was 0.4 × 10⁹/L (reference range 1.8–7.7). His chest radiograph was normal. He was treated with empiric broad-spectrum antimicrobials. On his second day in the hospital, he was tested for influenza by a polymerase chain reaction (PCR) test, which was positive for influenza A. He was moved to a private room and started on oseltamivir (Tamiflu) and rimantadine (Flumadine). The patient’s previous roommate subsequently tested positive for influenza A, as did two health care workers working on the ward. All patients on the floor received prophylactic oseltamivir.

The patient’s condition worsened, and he subsequently went into respiratory distress with diffuse pulmonary infiltrates. He was transferred to the intensive care unit, where he was intubated. Influenza A was isolated from a bronchoscopic specimen. He subsequently recovered after a prolonged course and was discharged on hospital day 50. Testing by the Ohio Department of Health confirmed that this was the 2009 pandemic influenza A (H1N1) virus.

THE CHALLENGES WE FACE

We are now in the midst of an influenza pandemic of the 2009 influenza A (H1N1) virus, with pandemic defined as “worldwide sustained community transmission.” The circulation of seasonal and 2009 pandemic influenza A (H1N1) strains will make this flu season both interesting and challenging.

The approaches to vaccination, prophylaxis, and treatment will be more complex. As of this writing (mid-September 2009), it is clear that we will be giving two influenza vaccines this season: a trivalent vaccine for seasonal influenza, and a monovalent vaccine for pandemic H1N1. It appears the monovalent vaccine may require only one dose to provide protective immunity.¹ Fortunately, the vast majority of cases of pandemic H1N1 are relatively mild and uncomplicated. Still, some people are at higher risk of complications, including young patients, pregnant women, and people with immune deficiency or concomitant health conditions that put them at higher risk of flu-associated complications. Thus, clinicians will need to be educated about whom to test, who needs prophylaxis, and who should not be treated.

As our case demonstrates, unsuspected cases of influenza in hospitalized patients or health care workers working with influenza pose the greatest threat for transmission of influenza within the hospital. Adults hospitalized with influenza tend to present late (more than 48 hours after the onset of symptoms) and tend to have prolonged illness.² Ambulatory adults shed virus for 3 to 6 days; virus shedding is more prolonged for hospitalized patients. Antiviral agents started within 4 days of illness enhance viral clearance and are associated with a shorter stay.³ Therefore, we should have a low threshold for testing for influenza and for isolating all suspected cases.

This is also creating a paradigm shift for health care workers, who are notorious for working through an illness. If you are sick, stay home! This applies whether you have pandemic H1N1 or something else.

EPIDEMIOLOGY OF PANDEMIC 2009 INFLUENZA A (H1N1) VIRUS

The location of cases can now be found on Google Maps; the US Centers for Disease Control and Prevention (CDC) provides weekly influenza reports at www.cdc.gov/flu/weekly/fluactivity.htm.

Pandemic H1N1 appeared in the spring of 2009, and cases continued to mount all summer in the United States (when influenza is normally absent) and around the world. In Mexico in March and April 2009, 2,155 cases of pneumonia, 821 hospitalizations, and 100 deaths were reported.⁴

In contrast with seasonal influenza, children and younger adults were hit the hardest in Mexico. The age group 5 through 59 years accounted for 87% of the deaths (usually, they account for about 17%) and 71% of the cases of severe pneumonia (usually, they account for 32%). These observations may be explained in part by the possibility that people who were alive during the 1957 pandemic (which was an H1N1 strain) have some immunity to the new virus. However, the case-fatality rate was highest in people age 65 and older.⁴

As of July 2009, there were more than 43,000 confirmed cases of pandemic H1N1 in the United States, and actual cases probably exceed 1 million, with more than 400 deaths. An underlying risk factor was identified in more than half of the fatal cases.⁵ Ten percent of the women who died were pregnant.

Pandemic H1N1 has several distinctive epidemiologic features:

• The distribution of cases is similar across multiple geographic areas.
• The distribution of cases by age group is markedly different than that of seasonal influenza, with more cases in school children and fewer cases in older adults.
• Fewer cases have been reported in older adults, but this group has the highest case-fatality rate.

2009 PANDEMIC H1N1 IS A MONGREL

There are three types of influenza viruses, designated A, B, and C. Type A undergoes antigenic shift (rapid changes) and antigenic drift (gradual changes) from year to year, and so it is the type associated with pandemics. In contrast, type B undergoes antigenic drift only, and type C is relatively stable.

Influenza virus is subtyped on the basis of surface glycoproteins: 16 hemagglutinins and nine neuraminidases. The circulating subtypes change every year; the current circulating human subtypes are a seasonal subtype of H1N1 that is different than the pandemic H1N1 subtype, and H3N2.

The 2009 pandemic H1N1 is a new virus never seen before in North America.⁶ Genetically, it is a mongrel, coming from three recognized sources (pigs, birds, and humans) which were combined in pigs.⁷ It is similar to subtypes that circulated in the 1920s through the 1940s.

Most influenza in the Western world comes from Asia every fall, and its arrival is probably facilitated by air travel. The spread is usually unidirectional and is unlikely to contribute to long-term viral evolution.⁸ It appears that 2009 H1N1 virus is the predominant strain circulating in the current influenza season in the Southern Hemisphere. Virologic studies indicate that the H1N1 virus strain has remained antigenically stable since it appeared in April 2009. Thus, it appears likely that the strain selected by the United States for vaccine manufacturing will match the currently circulating seasonal and pandemic H1N1 strains.

VACCINATION IS THE FIRST LINE OF DEFENSE

In addition to the trivalent vaccine against seasonal influenza, a monovalent vaccine for pandemic H1N1 virus is being produced. The CDC has indicated that 45 million doses of pandemic influenza vaccine are expected in October 2009, with an average of 20 million doses each week thereafter. It is anticipated that half of these will be in multidose vials, that 20% will be in prefilled syringes for children over 5 years old and for pregnant women, and that 20% will be in the form of live-attenuated influenza vaccine (nasal spray). The inhaled vaccine should not be given to children under 2 years old, to children under 5 years old who have recurrent wheezing, or to anyone with severe asthma. Neither vaccine should be given to people allergic to hen eggs, from which the vaccine is produced.

An ample supply of the seasonal trivalent vaccine should be available. Once the CDC has more information about specific product availability of the pandemic H1N1 vaccine, that vaccine will be distributed. It can be given concurrently with seasonal influenza vaccine.

Several definitions should be kept in mind when discussing vaccination strategies. Supply is the number of vaccine doses available for distribution. Availability is the ability of a person recommended to be vaccinated to do so in a local venue. Prioritization is the recommendation to vaccination venues to selectively use vaccine for certain population groups first. Targeting is the recommendation that immunization programs encourage and promote vaccination for certain population groups.

The Advisory Committee on Immunization Practices and the CDC recommend both seasonal and H1N1 vaccinations for anyone 6 months of age or older who is at risk of becoming ill or of transmitting the viruses to others. Based on a review of epidemiologic data, the recommendation is for targeting the following five groups for H1N1 vaccination: children and young adults aged 6 months through 24 years; pregnant women; health care workers and emergency medical service workers; people ages 25 through 64 years who have certain health conditions (eg, diabetes, heart disease, lung disease); and people who live with or care for children younger than 6 months of age. This represents approximately 159 million people in the United States.

If the estimates for the vaccine supply are met, and if pandemic H1N1 vaccine requires only a single injection, there should be no need for prioritization of vaccine. If the supply of pandemic H1N1 vaccine is inadequate, then those groups who are targeted would also receive the first doses of the pandemic H1N1 vaccine. It should be used only with caution after consideration of potential benefits and risks in people who have had Guillain-Barré syndrome during the previous 6 weeks, in people with altered immunocompetence, or in people with medical conditions predisposing to influenza complications.

A mass vaccination campaign involving two separate flu vaccines can pose challenges in execution and messaging for public health officials and politicians. In 1976, an aggressive vaccination program turned into a disaster, as there was no pandemic and the vaccine was associated with adverse effects such as Guillain-Barré syndrome. The government and the medical profession need to prepare for a vaccine controversy and to communicate and continue to explain the plan to the public. As pointed out in a recent op-ed piece,⁹ we would hope that all expectant women in the fall flu season will get the flu vaccines. We also know that, normally, one in seven pregnancies would be expected to miscarry. The challenge for public health officials and physicians will be to explain to these patients that there may be an association rather than a causal relationship.

In health care workers, the average vaccination rate is only 37%. We should be doing much better. Cleveland Clinic previously increased the rate of vaccination among its employees via a program in which all workers must either be vaccinated or formally declare (on an internal Web site) that they decline to be vaccinated.¹⁰ This season, even more resources are being directed at decreasing the barriers to flu vaccinations for our health care workers with the support from hospital leadership.

INFECTION CONTROL IN THE HOSPITAL AND IN THE COMMUNITY

Influenza is very contagious and is spread in droplets via sneezing and coughing (within a 3-foot radius), or via unwashed hands—thus the infection-control campaigns urging you to cover your cough and wash your hands.

As noted, for patients being admitted or transferred to the hospital, we need to have a low threshold for testing for influenza and for isolating patients suspected of having influenza. For patients with suspected or proven seasonal influenza, transmission precautions are those recommended by the CDC for droplet precautions (www.cdc.gov/ncidod/dhqp/gl_isolation_droplet.html). A face mask is deemed adequate to protect transmission when coming within 3 feet of an infected person. CDC guidelines for pandemic H1N1 recommends airborne-transmission-based precautions for health care workers who are in close contact with patients with proven or possible H1N1 (www.cdc.gov/ncidod/dhqp/gl_isolation_airborne.html). This recommendation implies the use of fit-tested N95 respirators and negative air pressure rooms (if available).

The recent Institute of Medicine report, Respiratory Protection for Healthcare Workers in the Workplace Against Novel H1N1 Influenza A (www.iom.edu/CMS/3740/71769/72967/72970.aspx) endorses the current CDC guidelines and recommends following these guidelines until we have evidence that other forms of protection or guidelines are equally or more effective.

Personally, I am against this requirement because it creates a terrible administrative burden with no proven benefit. Requiring a respirator means requiring fit-testing, and this will negatively affect our ability to deliver patient care. Recent studies have shown that surgical masks may not be as effective¹¹ but are probably sufficient. Lim et al¹² reported that 79 (37%) of 212 workers who responded to a survey experienced headaches while wearing N95 masks. This remains a controversial issue.

Besides getting the flu shot, what can one do to avoid getting influenza or transmitting to others?

• Cover your cough (cough etiquette) and sneeze.
• Practice good hand hygiene.
• Avoid close contact with people who are sick.
• Do not go to school or work if sick.

A recent study of influenza in households suggested that having the person with flu and household contacts wear face masks and practice hand hygiene within the first 36 hours decreased transmission of flu within the household.¹³

The United States does have a national influenza pandemic plan that outlines specific roles in the event of a pandemic, and I urge you to peruse it at www.hhs.gov/pandemicflu/plan/.

RECOGNIZING AND DIAGNOSING INFLUENZA

The familiar signs and symptoms of influenza—fever, cough, muscle aches, and headache—are nonspecific. Call et al¹⁴ analyzed the diagnostic accuracy of symptoms and signs of influenza and found that fever and cough during an epidemic suggest but do not confirm influenza, and that sneezing in those over age 60 argues against influenza. They concluded that signs and symptoms can tell us whether a patient has an influenza-like illness, but do not confirm or exclude the diagnosis of influenza: “Clinicians need to consider whether influenza is circulating in their communities, and then either treat patients with influenza-like illness empirically or obtain a rapid influenza test.”¹⁴

The signs and symptoms of pandemic 2009 H1N1 are the same as for seasonal flu, except that about 25% of patients with pandemic flu develop gastrointestinal symptoms. It has not been more virulent than seasonal influenza to date.

Should you order a test for influenza?

Most people with influenza are neither tested nor treated. Before ordering a test for influenza, ask, “Does this patient actually have influenza?” Patients diagnosed with “influenza” may have a range of infectious and noninfectious causes, such as vasculitis, endocarditis, or any other condition that can cause a fever and cough.

If I truly suspect influenza, I would still only order a test if the results would change how I manage the patient—for example, a patient being admitted to the hospital where isolation would be required.

Pandemic H1N1 will be detected only as influenza A in our current PCR screen for human influenza. The test does not differentiate between seasonal strains of influenza A (which is resistant to oseltamivir) and pandemic H1N1 (which is susceptible to oseltamivir). This means if you intend to treat, you will have to address further complexity.

Testing for influenza

The clinician should be familiar with the types of tests available. Each test has advantages and disadvantages¹⁵:

Rapid antigen assay is a point-of-care test that can give results in 15 minutes but unfortunately is only 20% to 30% sensitive, so a negative result does not exclude the diagnosis. The positive predictive value is high, meaning a positive test means the patient does have the flu.

Direct fluorescent antibody testing takes about 2.5 hours to complete and requires special training for technicians. It has a sensitivity of 47%, a positive predictive value of 95%, and a negative predictive value of 92%.

PCR testing takes about 6 hours and has a sensitivity of 98%, a positive predictive value of 100%, and a negative predictive value of 98%. This is probably the best test, in view of its all-around performance, but it is not a point-of-care test.

Culture takes 2 to 3 days, has a sensitivity of 89%, a positive predictive value of 100%, and a negative predictive value of 88%.

These tests can determine that the patient has influenza A, but a confirmatory test is always required to confirm pandemic H1N1. This confirmatory testing can be done by the CDC, by state public health laboratories, and by commercial reference laboratories.

ANTIVIRAL TREATMENT

Since influenza test results do not specify whether the patient has seasonal or pandemic influenza, treatment decisions are a sticky wicket. Most patients with pandemic H1N1 do not need to be tested or treated.

Several drugs are approved for treating influenza and shorten the duration of symptoms by about 1 day. The earlier the treatment is started, the better: the time of antiviral initiation affects influenza viral load and the duration of viral shedding.³

The neuraminidase inhibitors oseltamivir and zanamivir (Relenza) block release of virus from the cell. Resistance to oseltamivir is emerging in seasonal influenza A, while most pandemic H1N1 strains are susceptible.

Oseltamivir resistance in pandemic H1N1

A total of 11 cases of oseltamivir-resistant pandemic H1N1 have been confirmed worldwide, including 3 in the United States (2 in immunosuppressed patients in Seattle, WA). Ten of the 11 cases occurred with oseltamivir exposure. All involved a histidine-to-tyrosine substitution at position 275 (H275Y) of the neuraminidase gene. Most were susceptible to zanamivir.

Supplies of oseltamivir and zanamivir are limited, so they should be used only in those who will benefit the most, ie, those at higher risk of influenza complications. These include children under 5 years old, adults age 65 and older, children and adolescents on long-term aspirin therapy, pregnant women, patients who have chronic conditions or who are immunosuppressed, and residents of long-term care facilities.

A 69-year-old ohio man with leukemia was treated in another state in late June. During the car trip back to Ohio, he developed a sore throat, fever, cough, and nasal congestion. He was admitted to Cleveland Clinic with a presumed diagnosis of neutropenic fever; his absolute neutrophil count was 0.4 × 10⁹/L (reference range 1.8–7.7). His chest radiograph was normal. He was treated with empiric broad-spectrum antimicrobials. On his second day in the hospital, he was tested for influenza by a polymerase chain reaction (PCR) test, which was positive for influenza A. He was moved to a private room and started on oseltamivir (Tamiflu) and rimantadine (Flumadine). The patient’s previous roommate subsequently tested positive for influenza A, as did two health care workers working on the ward. All patients on the floor received prophylactic oseltamivir.

The patient’s condition worsened, and he subsequently went into respiratory distress with diffuse pulmonary infiltrates. He was transferred to the intensive care unit, where he was intubated. Influenza A was isolated from a bronchoscopic specimen. He subsequently recovered after a prolonged course and was discharged on hospital day 50. Testing by the Ohio Department of Health confirmed that this was the 2009 pandemic influenza A (H1N1) virus.

THE CHALLENGES WE FACE

We are now in the midst of an influenza pandemic of the 2009 influenza A (H1N1) virus, with pandemic defined as “worldwide sustained community transmission.” The circulation of seasonal and 2009 pandemic influenza A (H1N1) strains will make this flu season both interesting and challenging.

The approaches to vaccination, prophylaxis, and treatment will be more complex. As of this writing (mid-September 2009), it is clear that we will be giving two influenza vaccines this season: a trivalent vaccine for seasonal influenza, and a monovalent vaccine for pandemic H1N1. It appears the monovalent vaccine may require only one dose to provide protective immunity.¹ Fortunately, the vast majority of cases of pandemic H1N1 are relatively mild and uncomplicated. Still, some people are at higher risk of complications, including young patients, pregnant women, and people with immune deficiency or concomitant health conditions that put them at higher risk of flu-associated complications. Thus, clinicians will need to be educated about whom to test, who needs prophylaxis, and who should not be treated.

As our case demonstrates, unsuspected cases of influenza in hospitalized patients or health care workers working with influenza pose the greatest threat for transmission of influenza within the hospital. Adults hospitalized with influenza tend to present late (more than 48 hours after the onset of symptoms) and tend to have prolonged illness.² Ambulatory adults shed virus for 3 to 6 days; virus shedding is more prolonged for hospitalized patients. Antiviral agents started within 4 days of illness enhance viral clearance and are associated with a shorter stay.³ Therefore, we should have a low threshold for testing for influenza and for isolating all suspected cases.

This is also creating a paradigm shift for health care workers, who are notorious for working through an illness. If you are sick, stay home! This applies whether you have pandemic H1N1 or something else.

EPIDEMIOLOGY OF PANDEMIC 2009 INFLUENZA A (H1N1) VIRUS

The location of cases can now be found on Google Maps; the US Centers for Disease Control and Prevention (CDC) provides weekly influenza reports at www.cdc.gov/flu/weekly/fluactivity.htm.

Pandemic H1N1 appeared in the spring of 2009, and cases continued to mount all summer in the United States (when influenza is normally absent) and around the world. In Mexico in March and April 2009, 2,155 cases of pneumonia, 821 hospitalizations, and 100 deaths were reported.⁴

In contrast with seasonal influenza, children and younger adults were hit the hardest in Mexico. The age group 5 through 59 years accounted for 87% of the deaths (usually, they account for about 17%) and 71% of the cases of severe pneumonia (usually, they account for 32%). These observations may be explained in part by the possibility that people who were alive during the 1957 pandemic (which was an H1N1 strain) have some immunity to the new virus. However, the case-fatality rate was highest in people age 65 and older.⁴

As of July 2009, there were more than 43,000 confirmed cases of pandemic H1N1 in the United States, and actual cases probably exceed 1 million, with more than 400 deaths. An underlying risk factor was identified in more than half of the fatal cases.⁵ Ten percent of the women who died were pregnant.

Pandemic H1N1 has several distinctive epidemiologic features:

• The distribution of cases is similar across multiple geographic areas.
• The distribution of cases by age group is markedly different than that of seasonal influenza, with more cases in school children and fewer cases in older adults.
• Fewer cases have been reported in older adults, but this group has the highest case-fatality rate.

2009 PANDEMIC H1N1 IS A MONGREL

There are three types of influenza viruses, designated A, B, and C. Type A undergoes antigenic shift (rapid changes) and antigenic drift (gradual changes) from year to year, and so it is the type associated with pandemics. In contrast, type B undergoes antigenic drift only, and type C is relatively stable.

Influenza virus is subtyped on the basis of surface glycoproteins: 16 hemagglutinins and nine neuraminidases. The circulating subtypes change every year; the current circulating human subtypes are a seasonal subtype of H1N1 that is different than the pandemic H1N1 subtype, and H3N2.

The 2009 pandemic H1N1 is a new virus never seen before in North America.⁶ Genetically, it is a mongrel, coming from three recognized sources (pigs, birds, and humans) which were combined in pigs.⁷ It is similar to subtypes that circulated in the 1920s through the 1940s.

Most influenza in the Western world comes from Asia every fall, and its arrival is probably facilitated by air travel. The spread is usually unidirectional and is unlikely to contribute to long-term viral evolution.⁸ It appears that 2009 H1N1 virus is the predominant strain circulating in the current influenza season in the Southern Hemisphere. Virologic studies indicate that the H1N1 virus strain has remained antigenically stable since it appeared in April 2009. Thus, it appears likely that the strain selected by the United States for vaccine manufacturing will match the currently circulating seasonal and pandemic H1N1 strains.

VACCINATION IS THE FIRST LINE OF DEFENSE

In addition to the trivalent vaccine against seasonal influenza, a monovalent vaccine for pandemic H1N1 virus is being produced. The CDC has indicated that 45 million doses of pandemic influenza vaccine are expected in October 2009, with an average of 20 million doses each week thereafter. It is anticipated that half of these will be in multidose vials, that 20% will be in prefilled syringes for children over 5 years old and for pregnant women, and that 20% will be in the form of live-attenuated influenza vaccine (nasal spray). The inhaled vaccine should not be given to children under 2 years old, to children under 5 years old who have recurrent wheezing, or to anyone with severe asthma. Neither vaccine should be given to people allergic to hen eggs, from which the vaccine is produced.

An ample supply of the seasonal trivalent vaccine should be available. Once the CDC has more information about specific product availability of the pandemic H1N1 vaccine, that vaccine will be distributed. It can be given concurrently with seasonal influenza vaccine.

Several definitions should be kept in mind when discussing vaccination strategies. Supply is the number of vaccine doses available for distribution. Availability is the ability of a person recommended to be vaccinated to do so in a local venue. Prioritization is the recommendation to vaccination venues to selectively use vaccine for certain population groups first. Targeting is the recommendation that immunization programs encourage and promote vaccination for certain population groups.

The Advisory Committee on Immunization Practices and the CDC recommend both seasonal and H1N1 vaccinations for anyone 6 months of age or older who is at risk of becoming ill or of transmitting the viruses to others. Based on a review of epidemiologic data, the recommendation is for targeting the following five groups for H1N1 vaccination: children and young adults aged 6 months through 24 years; pregnant women; health care workers and emergency medical service workers; people ages 25 through 64 years who have certain health conditions (eg, diabetes, heart disease, lung disease); and people who live with or care for children younger than 6 months of age. This represents approximately 159 million people in the United States.

If the estimates for the vaccine supply are met, and if pandemic H1N1 vaccine requires only a single injection, there should be no need for prioritization of vaccine. If the supply of pandemic H1N1 vaccine is inadequate, then those groups who are targeted would also receive the first doses of the pandemic H1N1 vaccine. It should be used only with caution after consideration of potential benefits and risks in people who have had Guillain-Barré syndrome during the previous 6 weeks, in people with altered immunocompetence, or in people with medical conditions predisposing to influenza complications.

A mass vaccination campaign involving two separate flu vaccines can pose challenges in execution and messaging for public health officials and politicians. In 1976, an aggressive vaccination program turned into a disaster, as there was no pandemic and the vaccine was associated with adverse effects such as Guillain-Barré syndrome. The government and the medical profession need to prepare for a vaccine controversy and to communicate and continue to explain the plan to the public. As pointed out in a recent op-ed piece,⁹ we would hope that all expectant women in the fall flu season will get the flu vaccines. We also know that, normally, one in seven pregnancies would be expected to miscarry. The challenge for public health officials and physicians will be to explain to these patients that there may be an association rather than a causal relationship.

In health care workers, the average vaccination rate is only 37%. We should be doing much better. Cleveland Clinic previously increased the rate of vaccination among its employees via a program in which all workers must either be vaccinated or formally declare (on an internal Web site) that they decline to be vaccinated.¹⁰ This season, even more resources are being directed at decreasing the barriers to flu vaccinations for our health care workers with the support from hospital leadership.

INFECTION CONTROL IN THE HOSPITAL AND IN THE COMMUNITY

Influenza is very contagious and is spread in droplets via sneezing and coughing (within a 3-foot radius), or via unwashed hands—thus the infection-control campaigns urging you to cover your cough and wash your hands.

As noted, for patients being admitted or transferred to the hospital, we need to have a low threshold for testing for influenza and for isolating patients suspected of having influenza. For patients with suspected or proven seasonal influenza, transmission precautions are those recommended by the CDC for droplet precautions (www.cdc.gov/ncidod/dhqp/gl_isolation_droplet.html). A face mask is deemed adequate to protect transmission when coming within 3 feet of an infected person. CDC guidelines for pandemic H1N1 recommends airborne-transmission-based precautions for health care workers who are in close contact with patients with proven or possible H1N1 (www.cdc.gov/ncidod/dhqp/gl_isolation_airborne.html). This recommendation implies the use of fit-tested N95 respirators and negative air pressure rooms (if available).

The recent Institute of Medicine report, Respiratory Protection for Healthcare Workers in the Workplace Against Novel H1N1 Influenza A (www.iom.edu/CMS/3740/71769/72967/72970.aspx) endorses the current CDC guidelines and recommends following these guidelines until we have evidence that other forms of protection or guidelines are equally or more effective.

Personally, I am against this requirement because it creates a terrible administrative burden with no proven benefit. Requiring a respirator means requiring fit-testing, and this will negatively affect our ability to deliver patient care. Recent studies have shown that surgical masks may not be as effective¹¹ but are probably sufficient. Lim et al¹² reported that 79 (37%) of 212 workers who responded to a survey experienced headaches while wearing N95 masks. This remains a controversial issue.

Besides getting the flu shot, what can one do to avoid getting influenza or transmitting to others?

• Cover your cough (cough etiquette) and sneeze.
• Practice good hand hygiene.
• Avoid close contact with people who are sick.
• Do not go to school or work if sick.

A recent study of influenza in households suggested that having the person with flu and household contacts wear face masks and practice hand hygiene within the first 36 hours decreased transmission of flu within the household.¹³

The United States does have a national influenza pandemic plan that outlines specific roles in the event of a pandemic, and I urge you to peruse it at www.hhs.gov/pandemicflu/plan/.

RECOGNIZING AND DIAGNOSING INFLUENZA

The familiar signs and symptoms of influenza—fever, cough, muscle aches, and headache—are nonspecific. Call et al¹⁴ analyzed the diagnostic accuracy of symptoms and signs of influenza and found that fever and cough during an epidemic suggest but do not confirm influenza, and that sneezing in those over age 60 argues against influenza. They concluded that signs and symptoms can tell us whether a patient has an influenza-like illness, but do not confirm or exclude the diagnosis of influenza: “Clinicians need to consider whether influenza is circulating in their communities, and then either treat patients with influenza-like illness empirically or obtain a rapid influenza test.”¹⁴

The signs and symptoms of pandemic 2009 H1N1 are the same as for seasonal flu, except that about 25% of patients with pandemic flu develop gastrointestinal symptoms. It has not been more virulent than seasonal influenza to date.

Should you order a test for influenza?

Most people with influenza are neither tested nor treated. Before ordering a test for influenza, ask, “Does this patient actually have influenza?” Patients diagnosed with “influenza” may have a range of infectious and noninfectious causes, such as vasculitis, endocarditis, or any other condition that can cause a fever and cough.

If I truly suspect influenza, I would still only order a test if the results would change how I manage the patient—for example, a patient being admitted to the hospital where isolation would be required.

Pandemic H1N1 will be detected only as influenza A in our current PCR screen for human influenza. The test does not differentiate between seasonal strains of influenza A (which is resistant to oseltamivir) and pandemic H1N1 (which is susceptible to oseltamivir). This means if you intend to treat, you will have to address further complexity.

Testing for influenza

The clinician should be familiar with the types of tests available. Each test has advantages and disadvantages¹⁵:

Rapid antigen assay is a point-of-care test that can give results in 15 minutes but unfortunately is only 20% to 30% sensitive, so a negative result does not exclude the diagnosis. The positive predictive value is high, meaning a positive test means the patient does have the flu.

Direct fluorescent antibody testing takes about 2.5 hours to complete and requires special training for technicians. It has a sensitivity of 47%, a positive predictive value of 95%, and a negative predictive value of 92%.

PCR testing takes about 6 hours and has a sensitivity of 98%, a positive predictive value of 100%, and a negative predictive value of 98%. This is probably the best test, in view of its all-around performance, but it is not a point-of-care test.

Culture takes 2 to 3 days, has a sensitivity of 89%, a positive predictive value of 100%, and a negative predictive value of 88%.

These tests can determine that the patient has influenza A, but a confirmatory test is always required to confirm pandemic H1N1. This confirmatory testing can be done by the CDC, by state public health laboratories, and by commercial reference laboratories.

ANTIVIRAL TREATMENT

Since influenza test results do not specify whether the patient has seasonal or pandemic influenza, treatment decisions are a sticky wicket. Most patients with pandemic H1N1 do not need to be tested or treated.

Several drugs are approved for treating influenza and shorten the duration of symptoms by about 1 day. The earlier the treatment is started, the better: the time of antiviral initiation affects influenza viral load and the duration of viral shedding.³

The neuraminidase inhibitors oseltamivir and zanamivir (Relenza) block release of virus from the cell. Resistance to oseltamivir is emerging in seasonal influenza A, while most pandemic H1N1 strains are susceptible.

Oseltamivir resistance in pandemic H1N1

A total of 11 cases of oseltamivir-resistant pandemic H1N1 have been confirmed worldwide, including 3 in the United States (2 in immunosuppressed patients in Seattle, WA). Ten of the 11 cases occurred with oseltamivir exposure. All involved a histidine-to-tyrosine substitution at position 275 (H275Y) of the neuraminidase gene. Most were susceptible to zanamivir.

Supplies of oseltamivir and zanamivir are limited, so they should be used only in those who will benefit the most, ie, those at higher risk of influenza complications. These include children under 5 years old, adults age 65 and older, children and adolescents on long-term aspirin therapy, pregnant women, patients who have chronic conditions or who are immunosuppressed, and residents of long-term care facilities.

A 69-year-old ohio man with leukemia was treated in another state in late June. During the car trip back to Ohio, he developed a sore throat, fever, cough, and nasal congestion. He was admitted to Cleveland Clinic with a presumed diagnosis of neutropenic fever; his absolute neutrophil count was 0.4 × 10⁹/L (reference range 1.8–7.7). His chest radiograph was normal. He was treated with empiric broad-spectrum antimicrobials. On his second day in the hospital, he was tested for influenza by a polymerase chain reaction (PCR) test, which was positive for influenza A. He was moved to a private room and started on oseltamivir (Tamiflu) and rimantadine (Flumadine). The patient’s previous roommate subsequently tested positive for influenza A, as did two health care workers working on the ward. All patients on the floor received prophylactic oseltamivir.

The patient’s condition worsened, and he subsequently went into respiratory distress with diffuse pulmonary infiltrates. He was transferred to the intensive care unit, where he was intubated. Influenza A was isolated from a bronchoscopic specimen. He subsequently recovered after a prolonged course and was discharged on hospital day 50. Testing by the Ohio Department of Health confirmed that this was the 2009 pandemic influenza A (H1N1) virus.

THE CHALLENGES WE FACE

We are now in the midst of an influenza pandemic of the 2009 influenza A (H1N1) virus, with pandemic defined as “worldwide sustained community transmission.” The circulation of seasonal and 2009 pandemic influenza A (H1N1) strains will make this flu season both interesting and challenging.

The approaches to vaccination, prophylaxis, and treatment will be more complex. As of this writing (mid-September 2009), it is clear that we will be giving two influenza vaccines this season: a trivalent vaccine for seasonal influenza, and a monovalent vaccine for pandemic H1N1. It appears the monovalent vaccine may require only one dose to provide protective immunity.¹ Fortunately, the vast majority of cases of pandemic H1N1 are relatively mild and uncomplicated. Still, some people are at higher risk of complications, including young patients, pregnant women, and people with immune deficiency or concomitant health conditions that put them at higher risk of flu-associated complications. Thus, clinicians will need to be educated about whom to test, who needs prophylaxis, and who should not be treated.

As our case demonstrates, unsuspected cases of influenza in hospitalized patients or health care workers working with influenza pose the greatest threat for transmission of influenza within the hospital. Adults hospitalized with influenza tend to present late (more than 48 hours after the onset of symptoms) and tend to have prolonged illness.² Ambulatory adults shed virus for 3 to 6 days; virus shedding is more prolonged for hospitalized patients. Antiviral agents started within 4 days of illness enhance viral clearance and are associated with a shorter stay.³ Therefore, we should have a low threshold for testing for influenza and for isolating all suspected cases.

This is also creating a paradigm shift for health care workers, who are notorious for working through an illness. If you are sick, stay home! This applies whether you have pandemic H1N1 or something else.

EPIDEMIOLOGY OF PANDEMIC 2009 INFLUENZA A (H1N1) VIRUS

The location of cases can now be found on Google Maps; the US Centers for Disease Control and Prevention (CDC) provides weekly influenza reports at www.cdc.gov/flu/weekly/fluactivity.htm.

Pandemic H1N1 appeared in the spring of 2009, and cases continued to mount all summer in the United States (when influenza is normally absent) and around the world. In Mexico in March and April 2009, 2,155 cases of pneumonia, 821 hospitalizations, and 100 deaths were reported.⁴

In contrast with seasonal influenza, children and younger adults were hit the hardest in Mexico. The age group 5 through 59 years accounted for 87% of the deaths (usually, they account for about 17%) and 71% of the cases of severe pneumonia (usually, they account for 32%). These observations may be explained in part by the possibility that people who were alive during the 1957 pandemic (which was an H1N1 strain) have some immunity to the new virus. However, the case-fatality rate was highest in people age 65 and older.⁴

As of July 2009, there were more than 43,000 confirmed cases of pandemic H1N1 in the United States, and actual cases probably exceed 1 million, with more than 400 deaths. An underlying risk factor was identified in more than half of the fatal cases.⁵ Ten percent of the women who died were pregnant.

Pandemic H1N1 has several distinctive epidemiologic features:

• The distribution of cases is similar across multiple geographic areas.
• The distribution of cases by age group is markedly different than that of seasonal influenza, with more cases in school children and fewer cases in older adults.
• Fewer cases have been reported in older adults, but this group has the highest case-fatality rate.

2009 PANDEMIC H1N1 IS A MONGREL

There are three types of influenza viruses, designated A, B, and C. Type A undergoes antigenic shift (rapid changes) and antigenic drift (gradual changes) from year to year, and so it is the type associated with pandemics. In contrast, type B undergoes antigenic drift only, and type C is relatively stable.

Influenza virus is subtyped on the basis of surface glycoproteins: 16 hemagglutinins and nine neuraminidases. The circulating subtypes change every year; the current circulating human subtypes are a seasonal subtype of H1N1 that is different than the pandemic H1N1 subtype, and H3N2.

The 2009 pandemic H1N1 is a new virus never seen before in North America.⁶ Genetically, it is a mongrel, coming from three recognized sources (pigs, birds, and humans) which were combined in pigs.⁷ It is similar to subtypes that circulated in the 1920s through the 1940s.

Most influenza in the Western world comes from Asia every fall, and its arrival is probably facilitated by air travel. The spread is usually unidirectional and is unlikely to contribute to long-term viral evolution.⁸ It appears that 2009 H1N1 virus is the predominant strain circulating in the current influenza season in the Southern Hemisphere. Virologic studies indicate that the H1N1 virus strain has remained antigenically stable since it appeared in April 2009. Thus, it appears likely that the strain selected by the United States for vaccine manufacturing will match the currently circulating seasonal and pandemic H1N1 strains.

VACCINATION IS THE FIRST LINE OF DEFENSE

In addition to the trivalent vaccine against seasonal influenza, a monovalent vaccine for pandemic H1N1 virus is being produced. The CDC has indicated that 45 million doses of pandemic influenza vaccine are expected in October 2009, with an average of 20 million doses each week thereafter. It is anticipated that half of these will be in multidose vials, that 20% will be in prefilled syringes for children over 5 years old and for pregnant women, and that 20% will be in the form of live-attenuated influenza vaccine (nasal spray). The inhaled vaccine should not be given to children under 2 years old, to children under 5 years old who have recurrent wheezing, or to anyone with severe asthma. Neither vaccine should be given to people allergic to hen eggs, from which the vaccine is produced.

An ample supply of the seasonal trivalent vaccine should be available. Once the CDC has more information about specific product availability of the pandemic H1N1 vaccine, that vaccine will be distributed. It can be given concurrently with seasonal influenza vaccine.

Several definitions should be kept in mind when discussing vaccination strategies. Supply is the number of vaccine doses available for distribution. Availability is the ability of a person recommended to be vaccinated to do so in a local venue. Prioritization is the recommendation to vaccination venues to selectively use vaccine for certain population groups first. Targeting is the recommendation that immunization programs encourage and promote vaccination for certain population groups.

The Advisory Committee on Immunization Practices and the CDC recommend both seasonal and H1N1 vaccinations for anyone 6 months of age or older who is at risk of becoming ill or of transmitting the viruses to others. Based on a review of epidemiologic data, the recommendation is for targeting the following five groups for H1N1 vaccination: children and young adults aged 6 months through 24 years; pregnant women; health care workers and emergency medical service workers; people ages 25 through 64 years who have certain health conditions (eg, diabetes, heart disease, lung disease); and people who live with or care for children younger than 6 months of age. This represents approximately 159 million people in the United States.

If the estimates for the vaccine supply are met, and if pandemic H1N1 vaccine requires only a single injection, there should be no need for prioritization of vaccine. If the supply of pandemic H1N1 vaccine is inadequate, then those groups who are targeted would also receive the first doses of the pandemic H1N1 vaccine. It should be used only with caution after consideration of potential benefits and risks in people who have had Guillain-Barré syndrome during the previous 6 weeks, in people with altered immunocompetence, or in people with medical conditions predisposing to influenza complications.

A mass vaccination campaign involving two separate flu vaccines can pose challenges in execution and messaging for public health officials and politicians. In 1976, an aggressive vaccination program turned into a disaster, as there was no pandemic and the vaccine was associated with adverse effects such as Guillain-Barré syndrome. The government and the medical profession need to prepare for a vaccine controversy and to communicate and continue to explain the plan to the public. As pointed out in a recent op-ed piece,⁹ we would hope that all expectant women in the fall flu season will get the flu vaccines. We also know that, normally, one in seven pregnancies would be expected to miscarry. The challenge for public health officials and physicians will be to explain to these patients that there may be an association rather than a causal relationship.

In health care workers, the average vaccination rate is only 37%. We should be doing much better. Cleveland Clinic previously increased the rate of vaccination among its employees via a program in which all workers must either be vaccinated or formally declare (on an internal Web site) that they decline to be vaccinated.¹⁰ This season, even more resources are being directed at decreasing the barriers to flu vaccinations for our health care workers with the support from hospital leadership.

INFECTION CONTROL IN THE HOSPITAL AND IN THE COMMUNITY

Influenza is very contagious and is spread in droplets via sneezing and coughing (within a 3-foot radius), or via unwashed hands—thus the infection-control campaigns urging you to cover your cough and wash your hands.

As noted, for patients being admitted or transferred to the hospital, we need to have a low threshold for testing for influenza and for isolating patients suspected of having influenza. For patients with suspected or proven seasonal influenza, transmission precautions are those recommended by the CDC for droplet precautions (www.cdc.gov/ncidod/dhqp/gl_isolation_droplet.html). A face mask is deemed adequate to protect transmission when coming within 3 feet of an infected person. CDC guidelines for pandemic H1N1 recommends airborne-transmission-based precautions for health care workers who are in close contact with patients with proven or possible H1N1 (www.cdc.gov/ncidod/dhqp/gl_isolation_airborne.html). This recommendation implies the use of fit-tested N95 respirators and negative air pressure rooms (if available).

The recent Institute of Medicine report, Respiratory Protection for Healthcare Workers in the Workplace Against Novel H1N1 Influenza A (www.iom.edu/CMS/3740/71769/72967/72970.aspx) endorses the current CDC guidelines and recommends following these guidelines until we have evidence that other forms of protection or guidelines are equally or more effective.

Personally, I am against this requirement because it creates a terrible administrative burden with no proven benefit. Requiring a respirator means requiring fit-testing, and this will negatively affect our ability to deliver patient care. Recent studies have shown that surgical masks may not be as effective¹¹ but are probably sufficient. Lim et al¹² reported that 79 (37%) of 212 workers who responded to a survey experienced headaches while wearing N95 masks. This remains a controversial issue.

Besides getting the flu shot, what can one do to avoid getting influenza or transmitting to others?

• Cover your cough (cough etiquette) and sneeze.
• Practice good hand hygiene.
• Avoid close contact with people who are sick.
• Do not go to school or work if sick.

A recent study of influenza in households suggested that having the person with flu and household contacts wear face masks and practice hand hygiene within the first 36 hours decreased transmission of flu within the household.¹³

The United States does have a national influenza pandemic plan that outlines specific roles in the event of a pandemic, and I urge you to peruse it at www.hhs.gov/pandemicflu/plan/.

RECOGNIZING AND DIAGNOSING INFLUENZA

The familiar signs and symptoms of influenza—fever, cough, muscle aches, and headache—are nonspecific. Call et al¹⁴ analyzed the diagnostic accuracy of symptoms and signs of influenza and found that fever and cough during an epidemic suggest but do not confirm influenza, and that sneezing in those over age 60 argues against influenza. They concluded that signs and symptoms can tell us whether a patient has an influenza-like illness, but do not confirm or exclude the diagnosis of influenza: “Clinicians need to consider whether influenza is circulating in their communities, and then either treat patients with influenza-like illness empirically or obtain a rapid influenza test.”¹⁴

The signs and symptoms of pandemic 2009 H1N1 are the same as for seasonal flu, except that about 25% of patients with pandemic flu develop gastrointestinal symptoms. It has not been more virulent than seasonal influenza to date.

Should you order a test for influenza?

Most people with influenza are neither tested nor treated. Before ordering a test for influenza, ask, “Does this patient actually have influenza?” Patients diagnosed with “influenza” may have a range of infectious and noninfectious causes, such as vasculitis, endocarditis, or any other condition that can cause a fever and cough.

If I truly suspect influenza, I would still only order a test if the results would change how I manage the patient—for example, a patient being admitted to the hospital where isolation would be required.

Pandemic H1N1 will be detected only as influenza A in our current PCR screen for human influenza. The test does not differentiate between seasonal strains of influenza A (which is resistant to oseltamivir) and pandemic H1N1 (which is susceptible to oseltamivir). This means if you intend to treat, you will have to address further complexity.

Testing for influenza

The clinician should be familiar with the types of tests available. Each test has advantages and disadvantages¹⁵:

Rapid antigen assay is a point-of-care test that can give results in 15 minutes but unfortunately is only 20% to 30% sensitive, so a negative result does not exclude the diagnosis. The positive predictive value is high, meaning a positive test means the patient does have the flu.

Direct fluorescent antibody testing takes about 2.5 hours to complete and requires special training for technicians. It has a sensitivity of 47%, a positive predictive value of 95%, and a negative predictive value of 92%.

PCR testing takes about 6 hours and has a sensitivity of 98%, a positive predictive value of 100%, and a negative predictive value of 98%. This is probably the best test, in view of its all-around performance, but it is not a point-of-care test.

Culture takes 2 to 3 days, has a sensitivity of 89%, a positive predictive value of 100%, and a negative predictive value of 88%.

These tests can determine that the patient has influenza A, but a confirmatory test is always required to confirm pandemic H1N1. This confirmatory testing can be done by the CDC, by state public health laboratories, and by commercial reference laboratories.

ANTIVIRAL TREATMENT

Since influenza test results do not specify whether the patient has seasonal or pandemic influenza, treatment decisions are a sticky wicket. Most patients with pandemic H1N1 do not need to be tested or treated.

Several drugs are approved for treating influenza and shorten the duration of symptoms by about 1 day. The earlier the treatment is started, the better: the time of antiviral initiation affects influenza viral load and the duration of viral shedding.³

The neuraminidase inhibitors oseltamivir and zanamivir (Relenza) block release of virus from the cell. Resistance to oseltamivir is emerging in seasonal influenza A, while most pandemic H1N1 strains are susceptible.

Oseltamivir resistance in pandemic H1N1

A total of 11 cases of oseltamivir-resistant pandemic H1N1 have been confirmed worldwide, including 3 in the United States (2 in immunosuppressed patients in Seattle, WA). Ten of the 11 cases occurred with oseltamivir exposure. All involved a histidine-to-tyrosine substitution at position 275 (H275Y) of the neuraminidase gene. Most were susceptible to zanamivir.

Supplies of oseltamivir and zanamivir are limited, so they should be used only in those who will benefit the most, ie, those at higher risk of influenza complications. These include children under 5 years old, adults age 65 and older, children and adolescents on long-term aspirin therapy, pregnant women, patients who have chronic conditions or who are immunosuppressed, and residents of long-term care facilities.

In recent years the role of beta-blockers as a primary tool to treat hypertension has come under question. These drugs have shown disappointing results when used as antihypertensive therapy in patients without heart disease, ie, when used as primary prevention. At the same time, beta-blockers clearly reduce the risk of future cardiovascular events in patients who already have heart disease, eg, who already have had a myocardial infarction or who have congestive heart failure.

Several meta-analyses and a few clinical trials have shown that beta-blockers may have no advantage over other antihypertensive drugs, and in fact may not reduce the risk of stroke as effectively as other classes of blood pressure medications.

Why should this be? Is it that the patients in the antihypertensive trials were mostly older, and that beta-blockers do not work as well in older patients as in younger ones? Or does it have to do with the fact that atenolol (Tenormin) was the drug most often used in the trials? Would newer, different beta-blockers be better?

Hypertension experts currently disagree on how to interpret the available data, and this has led to conflict and confusion among clinicians as to the role of beta-blockers in managing hypertension. Current evidence suggests that older beta-blockers may not be the preferred first-line antihypertensive drugs for hypertensive patients who have no compelling indications for them (eg, heart failure, myocardial infarction, diabetes, high risk of coronary heart disease). However, newer beta-blockers with vasodilatory properties should be considered in cases of uncontrolled or resistant hypertension, especially in younger patients.

Further, while controversy and debate continue over the benefits and adverse effects of one class of antihypertensive drugs vs another, it is indisputable that controlling arterial blood pressure to the recommended goal offers major protection against cardiovascular and renal events in patients with hypertension.^1,2

MECHANISM OF ACTION OF BETA-BLOCKERS

Beta-blockers effectively reduce blood pressure in both systolic-diastolic hypertension and isolated systolic hypertension.^3–5 Exactly how is not known, but it has been proposed that they may do so by:

Reducing the heart rate and cardiac output. When catecholamines activate beta-1 receptors in the heart, the heart rate and myocardial contractility increase. By blocking beta-1 receptors, beta-blockers reduce the heart rate and myocardial contractility, thus lowering cardiac output and arterial blood pressure.⁶

Inhibiting renin release. Activation of the renin-angiotensin system is another major pathway that can lead to elevated arterial blood pressure. Renin release is mediated through the sympathetic nervous system via beta-1 receptors on the juxtaglomerular cells of the kidney. Beta-blockers can therefore lower blood pressure by inhibiting renin release.⁷

Inhibiting central nervous sympathetic outflow, thereby inducing presynaptic blockade, which in turn reduces the release of catecholamines.

Reducing venous return and plasma volume.

Generating nitric oxide, thus reducing peripheral vascular resistance (some agents).⁸

Reducing vasomotor tone.

Reducing vascular tone.

Improving vascular compliance.

Resetting baroreceptor levels.

Attenuating the pressor response to catecholamines with exercise and stress.

HETEROGENEITY OF BETA-BLOCKERS

Selectivity

Beta-blockers are not all the same. They can be classified into three categories.

Nonselective beta-blockers block both beta-1 and beta-2 adrenergic receptors. It is generally accepted that beta-blockers exert their primary antihypertensive effect by blocking beta-1 adrenergic receptors.⁶ Of interest, nonselective beta-blockers inhibit beta-2 receptors on arteries and thus cause an unopposed alpha-adrenergic effect, leading to increased peripheral vascular resistance.⁹ Examples of this category:

• Nadolol (Corgard)
• Pindolol (Visken)
• Propranolol (Inderal)
• Timolol (Blocadren).

Selective beta-blockers specifically block beta-1 receptors alone, although they are known to be nonselective at higher doses. Examples:

• Atenolol (Tenormin)
• Betaxolol (Kerlone)
• Bisoprolol (Zebeta)
• Esmolol (Brevibloc)
• Metoprolol (Lopressor, Toprol).

Beta-blockers with peripheral vasodilatatory effects act either via antagonism of the alpha-1 receptor, as with labetolol (Normodyne) and carvedilol (Coreg),¹⁰ or via enhanced release of nitric oxide, as with nebivolol (Bystolic).⁸

Lipid and water solubility

The lipid solubility and water solubility of each beta-blocker determine its bioavailability and side-effect profile.

Lipid solubility determines the degree to which a beta-blocker penetrates the blood-brain barrier and thereby leads to central nervous system side effects such as lethargy, nightmares, confusion, and depression. Propranolol is highly lipid-soluble; metoprolol and labetalol are moderately so.

Water-soluble beta-blockers such as atenolol have less tissue permeation, have a longer half-life, and cause fewer central nervous system effects and symptoms.¹¹

Routes of elimination

Beta-blockers also differ in their route of elimination.

Atenolol and nadolol are eliminated by the kidney and require dose adjustment in patients with impaired renal function.^12,13

On the other hand, propranolol, metoprolol, labetalol, carvedilol, and nebivolol are excreted primarily via hepatic metabolism.¹³

BETA-BLOCKERS IN THE MANAGEMENT OF HYPERTENSION

Beta-blockers were initially used to treat arrhythmias, but by the early 1970s they were also widely accepted for managing hypertension. ¹⁴ Their initial acceptance as one of the first-line classes of drugs for hypertension was based on their better side-effect profile compared with other antihypertensive drugs available at that time.

In the 1980s and 1990s, beta-blockers were listed as preferred first-line antihypertensive drugs along with diuretics in national hypertension guidelines.¹⁵ Subsequent updates of the guidelines favored diuretics as initial therapy and relegated all other classes of antihypertensive medications to be alternatives to diuretics.¹⁶ Although beta-blockers remain alternative first-line drugs in the latest guidelines (published in 2003; see reference 66), they are the preferred antihypertensive agents for patients with cardiac disease.

The current recommendations reflect the findings from hypertension trials in which patients with myocardial infarction and congestive heart failure had better cardiovascular outcomes if they received these drugs,^17–19 including a lower risk of death.^20,21 It was widely assumed that beta-blockers would also prevent first episodes of cardiovascular events.

However, to date, there is no evidence that beta-blockers are effective as primary prevention. Several large randomized controlled trials showed no benefit with beta-blockers compared with other antihypertensive drugs—in fact, there were more cardiovascular events with beta-blockers (see below).

Beta-blockers are well tolerated in clinical practice, although they can have side effects that include fatigue, depression, impaired exercise tolerance, sexual dysfunction, and asthma attacks.

Wiysonge et al²² analyzed how many patients withdrew from randomized trials of antihypertensive treatment because of drug-related adverse events. There was no significant difference in the incidence of fatigue, depressive symptoms, or sexual dysfunction with beta-blockers compared with placebo, and trial participants on a beta-blocker were not statistically significantly more likely to discontinue treatment than those receiving a placebo in three trials with 22,729 participants (relative risk [RR] 2.34, 95% confidence interval [CI] 0.84–6.52).

THE CONTROVERSY: WHAT THE TRIALS SHOWED

Messerli et al²³ performed a meta-analysis published in 1998 that suggested that beta-blockers may not be as effective as diuretics in preventing cardiovascular events when used as first-line antihypertensive therapy in elderly patients. In 10 randomized controlled trials in 16,164 patients who were treated with either a diuretic or a beta-blocker (atenolol), blood pressure was normalized in two-thirds of diuretic-treated patients but only one-third of patients treated with atenolol as monotherapy. Diuretic therapy was superior with regard to all end points, and beta-blockers were found to be ineffective except in reducing cerebrovascular events.

The LIFE study (Losartan Intervention for Endpoint Reduction in Hypertension)²⁴ compared the angiotensin-receptor blocker losartan (Cozaar) and atenolol in 9,193 patients with hypertension and left ventricular hypertrophy. At 4 years of follow-up, the rate of primary cardiovascular events (death, myocardial infarction, or stroke) was lower in the losartan group than in the atenolol group. The difference was mainly due to a 25% lower incidence of stroke, which was statistically significant. The rates of myocardial infarction and death from cardiovascular causes were not significantly different between the two treatment groups. The systolic blood pressure was 1 mm Hg lower in the losartan group than in the atenolol group, which was statistically significant.

Carlberg et al²⁵ performed another important meta-analysis that questioned whether atenolol reduces rates of cardiovascular morbidity and death in hypertensive patients. The results were surprising: eight randomized controlled trials including more than 6,000 patients and comparing atenolol with placebo or no treatment showed no differences between the treatment groups with regard to the outcomes of all-cause mortality (RR 1.01, 95% CI 0.89–1.15), cardiovascular mortality (RR 0.99, 95% CI 0.83–1.18), or myocardial infarction (RR 0.99, 95% CI 0.83–1.19).

In addition, when atenolol was compared with other antihypertensives in five other randomized controlled trials that included more than 14,000 patients, those treated with atenolol had a higher risk of stroke (RR 1.30, 95% CI 1.12–1.50) and death (RR 1.13, 95% CI 1.02–1.25).

The ASCOT-BPLA trial (Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm)²⁶ had similar results. This trial compared the combination of atenolol plus the diuretic bendroflumethiazide against the combination of the calcium channel blocker amlodipine (Norvasc) plus the angiotensin-converting enzyme (ACE) inhibitor perindopril (Aceon). Although no significant difference was seen in the primary outcome of nonfatal myocardial infarction or fatal coronary heart disease (unadjusted hazard ratio [HR] with amlodipine-perindopril 0.90, 95% CI 0.79–1.02, P = .1052), the amlodipine-plus-perindopril group had significantly fewer strokes (327 vs 422, HR 0.77, 95% CI 0.66–0.89, P = .0003), fewer total cardiovascular events (1,362 vs 1,602, HR 0.84, 95% CI 0.78–0.90, P = .0001), and fewer deaths from any cause (738 vs 820; HR 0.89, 95% CI 0.81–0.99, P = .025).

Lindholm et al²⁷ performed a meta-analysis that included studies of selective beta-blockers (including atenolol) and nonselective beta-blockers, with a follow-up time of more than 2 years. Compared with placebo or no treatment, beta-blockers reduced the risk of stroke by 19% but had no effect on myocardial infarction or all-cause mortality. Compared with other antihypertensive drugs, beta-blockers were less than optimum, and the relative risk of stroke was 16% higher. Atenolol was the beta-blocker used in most of the randomized clinical trials included in this meta-analysis.

The Cochrane group²² found beta-blockers to be inferior to all other antihypertensive drugs with respect to the ability to lower the risk of stroke.

WHY WERE THE RESULTS SO DISAPPOINTING?

Problems with atenolol

Most of the trials in the meta-analyses discussed above used atenolol and other beta-blockers that had no vasodilatory properties.

Further, in most of the trials atenolol was used in a once-daily dosage, whereas ideally it needs to be taken more frequently, based on its pharmacokinetic and pharmacodynamic properties (a half-life of 6–9 hours).³ Neutel et al²⁸ confirmed that atenolol, when taken once daily, leaves the patient unprotected in the last 6 hours of a 24-hour period, as demonstrated by 24-hour ambulatory blood pressure monitoring. It is possible that this short duration of action of atenolol may have contributed to the results observed in clinical trials that used atenolol to treat hypertension.

Differences between older and younger patients

Another possible reason for the disappointing results is that the trials included many elderly patients, in whom beta-blockers may not be as effective. The pathophysiology of hypertension in younger people is different from that in older patients.²⁹ Hemodynamic characteristics of younger hypertensive patients include a high cardiac output and hyperdynamic circulation with a low pulse pressure, while older patients have lower arterial compliance with an elevated vascular resistance.

The notion of choosing antihypertensive medications on the basis of age and age-related pathophysiology is supported by several clinical studies. Randomized controlled trials appear to show that beta-blockers are effective in younger hypertensive patients.³⁰

Conversely, the CAFE (Conduit Artery Function Evaluation) trial,³¹ a substudy of the main ASCOT trial,²⁶ indicated that betablocker-based therapy was less effective in reducing central aortic pressure than were regimens based on an ACE inhibitor or a calcium channel blocker.

The CAFE researchers recruited 2,073 patients from five ASCOT centers and used radial artery applanation tonometry and pulse-wave analysis to derive central aortic pressures and hemodynamic indices during study visits up to a period of 4 years. Although the two treatment groups achieved similar brachial systolic blood pressures, the central aortic systolic pressure was 4.3 mm Hg lower in the amlodipine group (95% CI 3.3–5.4; P < .0001), and the central aortic pulse pressure was 3.0 mm Hg lower (95% CI 2.1–3.9; P < .0001).

Pulse-wave dyssynchrony

Bangalore et al⁴⁷ offer an interesting hypothesis to explain the probable adverse effect of beta-blockers. Their theory concerns the effect of these drugs on the arterial pulse wave.

Normally, with each contraction of the left ventricle during systole, an arterial pulse wave is generated and propagated forward to the peripheral arteries. This wave is then reflected back to the heart from the branching points of peripheral arteries. The final form of the pressure wave at the aortic root is a synchronized summation of the forward-traveling wave and the backward-reflected wave.

In healthy people with normal arteries, the reflected wave merges with the forward-traveling wave in diastole and augments coronary blood flow. In patients whose arteries are stiff due to aging or vascular comorbidities, the reflected wave returns faster and merges with the incident wave in systole, resulting in higher left ventricular afterload and less coronary perfusion.⁴⁸

Bangalore et al⁴⁷ propose that artificially reducing the heart rate with beta-blockers may further dyssynchronize the pulse wave, adversely affecting coronary perfusion and leading to an increased risk of cardiovascular events and death.

Metabolic side effects

Older beta-blockers, and especially atenolol, have well-known metabolic adverse effects, particularly impairment of glycemic control. This adverse effect appears to occur only with beta-blockers that do not possess vasodilatory properties and thus increase peripheral vascular resistance, which results in lower glucose availability and reduced uptake by skeletal muscles.⁴⁹

Bangalore et al⁵⁰ evaluated the effect of beta-blockers in a meta-analysis of 12 studies in 94,492 patients followed up for more than 1 year. Beta-blocker therapy resulted in a 22% higher risk of new-onset diabetes mellitus (RR 1.22, 95% CI 1.12–1.33) than with other nondiuretic antihypertensive agents.

Of note, however, the meta-analysis did not show a significantly higher risk of the onset of diabetes with propranolol or metoprolol than with other nondiuretic antihypertensives when studies of these beta-blockers were separated from atenolol-based studies.

Further, the United Kingdom Prospective Diabetes Study⁴⁰ found that cardiovascular outcomes in patients with good blood pressure control were similar when atenolol-based therapy was compared with therapy with the ACE inhibitor captopril (Capoten).

A meta-analysis conducted by Balamuthusamy et al⁵¹ in 2009 found no higher risk of stroke in patients with hypertension and diabetes mellitus who received beta-blockers than in those who received other antihypertensive medications. However, beta-blockers were associated with a higher risk of death from cardiovascular causes (RR 1.39, 95% CI 1.07–1.804; P < .01) compared with reninangiotensin blockade.

NEWER BETA-BLOCKERS MAY BE BETTER

In the United States, more than 40 million prescriptions for atenolol are written every year, making it by far the most commonly used beta-blocker for the treatment of hypertension. ⁵² It is clear, however, that atenolol is not an ideal representative of this class of antihypertensive medications.

Preliminary data from studies of newer beta-blockers that possess beneficial vasodilatory properties are encouraging. Animal studies and preliminary human studies find that these new-generation beta-blockers cause fewer adverse metabolic effects and improve endothelial function, measures of arterial stiffness, and cardiovascular outcomes.

Carvedilol

Carvedilol is a nonselective beta-blocker with vasodilatory effects that are thought to be due to its ability to concurrently block alpha-1 receptors in addition to beta receptors. ⁵³ In experiments in vitro and in trials in patients with diabetes and hypertension, carvedilol increased endothelial vasodilation and reduced inflammation and platelet aggregation. These effects may be achieved though antioxidant actions, thereby preserving nitric oxide bioactivity.^54,55

In the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial,⁵⁶ carvedilol was associated with better maintenance of glycemic control in diabetic hypertensive patients than was metoprolol. Insulin sensitivity improved with carvedilol but not with metoprolol, and fewer patients on carvedilol progressed to microalbuminuria.

Nebivolol

Nebivolol is a novel selective beta-blocker with a much higher affinity for beta-1 adrenergic receptors than for beta-2 adrenergic receptors. Among all the beta-blockers in clinical use today, nebivolol has the highest selectivity for beta-1 receptors.⁸

Nebivolol causes vasodilation through activation of the l-arginine/nitric oxide pathway.^57–59 Blockade of synthesis of nitric oxide leads to local arterial stiffness. Endothelial dysfunction is characterized by decreased bioavailability of nitric oxide and has been shown to be a strong predictor of cardiovascular outcomes. By generating nitric oxide, nebivolol reduces peripheral vascular resistance, overcoming a significant side effect of earlier beta-blockers that lowered blood pressure but ultimately increased peripheral vascular tone and resistance.⁸

In an experiment in a bovine model,⁶⁰ nebivolol significantly reduced the pulse-wave velocity (a measure of arterial stiffness), while atenolol had no effect. Moreover, evidence for the role of the l-arginine/nitric oxide pathway in the vasodilatory effect of nebivolol was demonstrated by co-infusion of N^G-monomethyl-L-arginine, a specific endothelial nitric oxide synthetase inhibitor that attenuated the reduction of pulse-wave velocity by nebivolol.

In studies in hypertensive patients, nebivolol was associated with a better metabolic profile than atenolol, with none of the adverse effects on insulin sensitivity that atenolol had.⁶¹ In the Study of Effects of Nebivolol Interventions on Outcomes and Rehospitalization in Seniors With Heart Failure (SENIORS) trial, significantly fewer patients receiving nebivolol died or were admitted to the hospital for cardiovascular reasons compared with those receiving placebo.⁶²

Although these findings are encouraging, we do not yet know if these effects will translate into a significant reduction in cardiovascular outcomes in clinical trials. Large, prospective hypertension outcome trials, particularly to evaluate primary prevention of cardiovascular outcomes, are needed for an evidence-based approach to using the newer beta-blockers as preferred first-line therapy for hypertension.

WHAT RECENT GUIDELINES SAY ABOUT BETA-BLOCKERS

The British National Institute for Health and Clinical Excellence and the British Hypertension Society, in their 2004 guidelines, recommended beta-blockers as one of several first-line antihypertensive medications in young, nonblack patients.⁶³ On the other hand, they advised clinicians to be aware of the reported increase in onset of diabetes mellitus in patients treated with these medications. After the LIFE²⁴ and ASCOT²⁶ study results were published, these guidelines were amended to exclude beta-blockers as preferred routine initial therapy for hypertension.⁶⁴

More recently, the 2007 European Society of Hypertension and European Society of Cardiology reconsidered the role of beta-blockers, recommending them as an option in both initial and subsequent antihypertensive treatment strategies.⁶⁵

The current guidelines from the National Heart, Lung, and Blood Institute,⁶⁶ which were published in 2003, were highly influenced by the results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),² and favor diuretics as the first-line therapy. However, they indicate that beta-blockers are a suitable alternative, particularly when a compelling cardiac indication is present.⁵³ We hope that the next update, expected late in 2009, will re-address this issue in the light of more recent data.

In recent years the role of beta-blockers as a primary tool to treat hypertension has come under question. These drugs have shown disappointing results when used as antihypertensive therapy in patients without heart disease, ie, when used as primary prevention. At the same time, beta-blockers clearly reduce the risk of future cardiovascular events in patients who already have heart disease, eg, who already have had a myocardial infarction or who have congestive heart failure.

Several meta-analyses and a few clinical trials have shown that beta-blockers may have no advantage over other antihypertensive drugs, and in fact may not reduce the risk of stroke as effectively as other classes of blood pressure medications.

Why should this be? Is it that the patients in the antihypertensive trials were mostly older, and that beta-blockers do not work as well in older patients as in younger ones? Or does it have to do with the fact that atenolol (Tenormin) was the drug most often used in the trials? Would newer, different beta-blockers be better?

Hypertension experts currently disagree on how to interpret the available data, and this has led to conflict and confusion among clinicians as to the role of beta-blockers in managing hypertension. Current evidence suggests that older beta-blockers may not be the preferred first-line antihypertensive drugs for hypertensive patients who have no compelling indications for them (eg, heart failure, myocardial infarction, diabetes, high risk of coronary heart disease). However, newer beta-blockers with vasodilatory properties should be considered in cases of uncontrolled or resistant hypertension, especially in younger patients.

Further, while controversy and debate continue over the benefits and adverse effects of one class of antihypertensive drugs vs another, it is indisputable that controlling arterial blood pressure to the recommended goal offers major protection against cardiovascular and renal events in patients with hypertension.^1,2

MECHANISM OF ACTION OF BETA-BLOCKERS

Beta-blockers effectively reduce blood pressure in both systolic-diastolic hypertension and isolated systolic hypertension.^3–5 Exactly how is not known, but it has been proposed that they may do so by:

Reducing the heart rate and cardiac output. When catecholamines activate beta-1 receptors in the heart, the heart rate and myocardial contractility increase. By blocking beta-1 receptors, beta-blockers reduce the heart rate and myocardial contractility, thus lowering cardiac output and arterial blood pressure.⁶

Inhibiting renin release. Activation of the renin-angiotensin system is another major pathway that can lead to elevated arterial blood pressure. Renin release is mediated through the sympathetic nervous system via beta-1 receptors on the juxtaglomerular cells of the kidney. Beta-blockers can therefore lower blood pressure by inhibiting renin release.⁷

Inhibiting central nervous sympathetic outflow, thereby inducing presynaptic blockade, which in turn reduces the release of catecholamines.

Reducing venous return and plasma volume.

Generating nitric oxide, thus reducing peripheral vascular resistance (some agents).⁸

Reducing vasomotor tone.

Reducing vascular tone.

Improving vascular compliance.

Resetting baroreceptor levels.

Attenuating the pressor response to catecholamines with exercise and stress.

HETEROGENEITY OF BETA-BLOCKERS

Selectivity

Beta-blockers are not all the same. They can be classified into three categories.

Nonselective beta-blockers block both beta-1 and beta-2 adrenergic receptors. It is generally accepted that beta-blockers exert their primary antihypertensive effect by blocking beta-1 adrenergic receptors.⁶ Of interest, nonselective beta-blockers inhibit beta-2 receptors on arteries and thus cause an unopposed alpha-adrenergic effect, leading to increased peripheral vascular resistance.⁹ Examples of this category:

• Nadolol (Corgard)
• Pindolol (Visken)
• Propranolol (Inderal)
• Timolol (Blocadren).

Selective beta-blockers specifically block beta-1 receptors alone, although they are known to be nonselective at higher doses. Examples:

• Atenolol (Tenormin)
• Betaxolol (Kerlone)
• Bisoprolol (Zebeta)
• Esmolol (Brevibloc)
• Metoprolol (Lopressor, Toprol).

Beta-blockers with peripheral vasodilatatory effects act either via antagonism of the alpha-1 receptor, as with labetolol (Normodyne) and carvedilol (Coreg),¹⁰ or via enhanced release of nitric oxide, as with nebivolol (Bystolic).⁸

Lipid and water solubility

The lipid solubility and water solubility of each beta-blocker determine its bioavailability and side-effect profile.

Lipid solubility determines the degree to which a beta-blocker penetrates the blood-brain barrier and thereby leads to central nervous system side effects such as lethargy, nightmares, confusion, and depression. Propranolol is highly lipid-soluble; metoprolol and labetalol are moderately so.

Water-soluble beta-blockers such as atenolol have less tissue permeation, have a longer half-life, and cause fewer central nervous system effects and symptoms.¹¹

Routes of elimination

Beta-blockers also differ in their route of elimination.

Atenolol and nadolol are eliminated by the kidney and require dose adjustment in patients with impaired renal function.^12,13

On the other hand, propranolol, metoprolol, labetalol, carvedilol, and nebivolol are excreted primarily via hepatic metabolism.¹³

BETA-BLOCKERS IN THE MANAGEMENT OF HYPERTENSION

Beta-blockers were initially used to treat arrhythmias, but by the early 1970s they were also widely accepted for managing hypertension. ¹⁴ Their initial acceptance as one of the first-line classes of drugs for hypertension was based on their better side-effect profile compared with other antihypertensive drugs available at that time.

In the 1980s and 1990s, beta-blockers were listed as preferred first-line antihypertensive drugs along with diuretics in national hypertension guidelines.¹⁵ Subsequent updates of the guidelines favored diuretics as initial therapy and relegated all other classes of antihypertensive medications to be alternatives to diuretics.¹⁶ Although beta-blockers remain alternative first-line drugs in the latest guidelines (published in 2003; see reference 66), they are the preferred antihypertensive agents for patients with cardiac disease.

The current recommendations reflect the findings from hypertension trials in which patients with myocardial infarction and congestive heart failure had better cardiovascular outcomes if they received these drugs,^17–19 including a lower risk of death.^20,21 It was widely assumed that beta-blockers would also prevent first episodes of cardiovascular events.

However, to date, there is no evidence that beta-blockers are effective as primary prevention. Several large randomized controlled trials showed no benefit with beta-blockers compared with other antihypertensive drugs—in fact, there were more cardiovascular events with beta-blockers (see below).

Beta-blockers are well tolerated in clinical practice, although they can have side effects that include fatigue, depression, impaired exercise tolerance, sexual dysfunction, and asthma attacks.

Wiysonge et al²² analyzed how many patients withdrew from randomized trials of antihypertensive treatment because of drug-related adverse events. There was no significant difference in the incidence of fatigue, depressive symptoms, or sexual dysfunction with beta-blockers compared with placebo, and trial participants on a beta-blocker were not statistically significantly more likely to discontinue treatment than those receiving a placebo in three trials with 22,729 participants (relative risk [RR] 2.34, 95% confidence interval [CI] 0.84–6.52).

THE CONTROVERSY: WHAT THE TRIALS SHOWED

Messerli et al²³ performed a meta-analysis published in 1998 that suggested that beta-blockers may not be as effective as diuretics in preventing cardiovascular events when used as first-line antihypertensive therapy in elderly patients. In 10 randomized controlled trials in 16,164 patients who were treated with either a diuretic or a beta-blocker (atenolol), blood pressure was normalized in two-thirds of diuretic-treated patients but only one-third of patients treated with atenolol as monotherapy. Diuretic therapy was superior with regard to all end points, and beta-blockers were found to be ineffective except in reducing cerebrovascular events.

The LIFE study (Losartan Intervention for Endpoint Reduction in Hypertension)²⁴ compared the angiotensin-receptor blocker losartan (Cozaar) and atenolol in 9,193 patients with hypertension and left ventricular hypertrophy. At 4 years of follow-up, the rate of primary cardiovascular events (death, myocardial infarction, or stroke) was lower in the losartan group than in the atenolol group. The difference was mainly due to a 25% lower incidence of stroke, which was statistically significant. The rates of myocardial infarction and death from cardiovascular causes were not significantly different between the two treatment groups. The systolic blood pressure was 1 mm Hg lower in the losartan group than in the atenolol group, which was statistically significant.

Carlberg et al²⁵ performed another important meta-analysis that questioned whether atenolol reduces rates of cardiovascular morbidity and death in hypertensive patients. The results were surprising: eight randomized controlled trials including more than 6,000 patients and comparing atenolol with placebo or no treatment showed no differences between the treatment groups with regard to the outcomes of all-cause mortality (RR 1.01, 95% CI 0.89–1.15), cardiovascular mortality (RR 0.99, 95% CI 0.83–1.18), or myocardial infarction (RR 0.99, 95% CI 0.83–1.19).

In addition, when atenolol was compared with other antihypertensives in five other randomized controlled trials that included more than 14,000 patients, those treated with atenolol had a higher risk of stroke (RR 1.30, 95% CI 1.12–1.50) and death (RR 1.13, 95% CI 1.02–1.25).

The ASCOT-BPLA trial (Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm)²⁶ had similar results. This trial compared the combination of atenolol plus the diuretic bendroflumethiazide against the combination of the calcium channel blocker amlodipine (Norvasc) plus the angiotensin-converting enzyme (ACE) inhibitor perindopril (Aceon). Although no significant difference was seen in the primary outcome of nonfatal myocardial infarction or fatal coronary heart disease (unadjusted hazard ratio [HR] with amlodipine-perindopril 0.90, 95% CI 0.79–1.02, P = .1052), the amlodipine-plus-perindopril group had significantly fewer strokes (327 vs 422, HR 0.77, 95% CI 0.66–0.89, P = .0003), fewer total cardiovascular events (1,362 vs 1,602, HR 0.84, 95% CI 0.78–0.90, P = .0001), and fewer deaths from any cause (738 vs 820; HR 0.89, 95% CI 0.81–0.99, P = .025).

Lindholm et al²⁷ performed a meta-analysis that included studies of selective beta-blockers (including atenolol) and nonselective beta-blockers, with a follow-up time of more than 2 years. Compared with placebo or no treatment, beta-blockers reduced the risk of stroke by 19% but had no effect on myocardial infarction or all-cause mortality. Compared with other antihypertensive drugs, beta-blockers were less than optimum, and the relative risk of stroke was 16% higher. Atenolol was the beta-blocker used in most of the randomized clinical trials included in this meta-analysis.

The Cochrane group²² found beta-blockers to be inferior to all other antihypertensive drugs with respect to the ability to lower the risk of stroke.

WHY WERE THE RESULTS SO DISAPPOINTING?

Problems with atenolol

Most of the trials in the meta-analyses discussed above used atenolol and other beta-blockers that had no vasodilatory properties.

Further, in most of the trials atenolol was used in a once-daily dosage, whereas ideally it needs to be taken more frequently, based on its pharmacokinetic and pharmacodynamic properties (a half-life of 6–9 hours).³ Neutel et al²⁸ confirmed that atenolol, when taken once daily, leaves the patient unprotected in the last 6 hours of a 24-hour period, as demonstrated by 24-hour ambulatory blood pressure monitoring. It is possible that this short duration of action of atenolol may have contributed to the results observed in clinical trials that used atenolol to treat hypertension.

Differences between older and younger patients

Another possible reason for the disappointing results is that the trials included many elderly patients, in whom beta-blockers may not be as effective. The pathophysiology of hypertension in younger people is different from that in older patients.²⁹ Hemodynamic characteristics of younger hypertensive patients include a high cardiac output and hyperdynamic circulation with a low pulse pressure, while older patients have lower arterial compliance with an elevated vascular resistance.

The notion of choosing antihypertensive medications on the basis of age and age-related pathophysiology is supported by several clinical studies. Randomized controlled trials appear to show that beta-blockers are effective in younger hypertensive patients.³⁰

Conversely, the CAFE (Conduit Artery Function Evaluation) trial,³¹ a substudy of the main ASCOT trial,²⁶ indicated that betablocker-based therapy was less effective in reducing central aortic pressure than were regimens based on an ACE inhibitor or a calcium channel blocker.

The CAFE researchers recruited 2,073 patients from five ASCOT centers and used radial artery applanation tonometry and pulse-wave analysis to derive central aortic pressures and hemodynamic indices during study visits up to a period of 4 years. Although the two treatment groups achieved similar brachial systolic blood pressures, the central aortic systolic pressure was 4.3 mm Hg lower in the amlodipine group (95% CI 3.3–5.4; P < .0001), and the central aortic pulse pressure was 3.0 mm Hg lower (95% CI 2.1–3.9; P < .0001).

Pulse-wave dyssynchrony

Bangalore et al⁴⁷ offer an interesting hypothesis to explain the probable adverse effect of beta-blockers. Their theory concerns the effect of these drugs on the arterial pulse wave.

Normally, with each contraction of the left ventricle during systole, an arterial pulse wave is generated and propagated forward to the peripheral arteries. This wave is then reflected back to the heart from the branching points of peripheral arteries. The final form of the pressure wave at the aortic root is a synchronized summation of the forward-traveling wave and the backward-reflected wave.

In healthy people with normal arteries, the reflected wave merges with the forward-traveling wave in diastole and augments coronary blood flow. In patients whose arteries are stiff due to aging or vascular comorbidities, the reflected wave returns faster and merges with the incident wave in systole, resulting in higher left ventricular afterload and less coronary perfusion.⁴⁸

Bangalore et al⁴⁷ propose that artificially reducing the heart rate with beta-blockers may further dyssynchronize the pulse wave, adversely affecting coronary perfusion and leading to an increased risk of cardiovascular events and death.

Metabolic side effects

Older beta-blockers, and especially atenolol, have well-known metabolic adverse effects, particularly impairment of glycemic control. This adverse effect appears to occur only with beta-blockers that do not possess vasodilatory properties and thus increase peripheral vascular resistance, which results in lower glucose availability and reduced uptake by skeletal muscles.⁴⁹

Bangalore et al⁵⁰ evaluated the effect of beta-blockers in a meta-analysis of 12 studies in 94,492 patients followed up for more than 1 year. Beta-blocker therapy resulted in a 22% higher risk of new-onset diabetes mellitus (RR 1.22, 95% CI 1.12–1.33) than with other nondiuretic antihypertensive agents.

Of note, however, the meta-analysis did not show a significantly higher risk of the onset of diabetes with propranolol or metoprolol than with other nondiuretic antihypertensives when studies of these beta-blockers were separated from atenolol-based studies.

Further, the United Kingdom Prospective Diabetes Study⁴⁰ found that cardiovascular outcomes in patients with good blood pressure control were similar when atenolol-based therapy was compared with therapy with the ACE inhibitor captopril (Capoten).

A meta-analysis conducted by Balamuthusamy et al⁵¹ in 2009 found no higher risk of stroke in patients with hypertension and diabetes mellitus who received beta-blockers than in those who received other antihypertensive medications. However, beta-blockers were associated with a higher risk of death from cardiovascular causes (RR 1.39, 95% CI 1.07–1.804; P < .01) compared with reninangiotensin blockade.

NEWER BETA-BLOCKERS MAY BE BETTER

In the United States, more than 40 million prescriptions for atenolol are written every year, making it by far the most commonly used beta-blocker for the treatment of hypertension. ⁵² It is clear, however, that atenolol is not an ideal representative of this class of antihypertensive medications.

Preliminary data from studies of newer beta-blockers that possess beneficial vasodilatory properties are encouraging. Animal studies and preliminary human studies find that these new-generation beta-blockers cause fewer adverse metabolic effects and improve endothelial function, measures of arterial stiffness, and cardiovascular outcomes.

Carvedilol

Carvedilol is a nonselective beta-blocker with vasodilatory effects that are thought to be due to its ability to concurrently block alpha-1 receptors in addition to beta receptors. ⁵³ In experiments in vitro and in trials in patients with diabetes and hypertension, carvedilol increased endothelial vasodilation and reduced inflammation and platelet aggregation. These effects may be achieved though antioxidant actions, thereby preserving nitric oxide bioactivity.^54,55

In the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial,⁵⁶ carvedilol was associated with better maintenance of glycemic control in diabetic hypertensive patients than was metoprolol. Insulin sensitivity improved with carvedilol but not with metoprolol, and fewer patients on carvedilol progressed to microalbuminuria.

Nebivolol

Nebivolol is a novel selective beta-blocker with a much higher affinity for beta-1 adrenergic receptors than for beta-2 adrenergic receptors. Among all the beta-blockers in clinical use today, nebivolol has the highest selectivity for beta-1 receptors.⁸

Nebivolol causes vasodilation through activation of the l-arginine/nitric oxide pathway.^57–59 Blockade of synthesis of nitric oxide leads to local arterial stiffness. Endothelial dysfunction is characterized by decreased bioavailability of nitric oxide and has been shown to be a strong predictor of cardiovascular outcomes. By generating nitric oxide, nebivolol reduces peripheral vascular resistance, overcoming a significant side effect of earlier beta-blockers that lowered blood pressure but ultimately increased peripheral vascular tone and resistance.⁸

In an experiment in a bovine model,⁶⁰ nebivolol significantly reduced the pulse-wave velocity (a measure of arterial stiffness), while atenolol had no effect. Moreover, evidence for the role of the l-arginine/nitric oxide pathway in the vasodilatory effect of nebivolol was demonstrated by co-infusion of N^G-monomethyl-L-arginine, a specific endothelial nitric oxide synthetase inhibitor that attenuated the reduction of pulse-wave velocity by nebivolol.

In studies in hypertensive patients, nebivolol was associated with a better metabolic profile than atenolol, with none of the adverse effects on insulin sensitivity that atenolol had.⁶¹ In the Study of Effects of Nebivolol Interventions on Outcomes and Rehospitalization in Seniors With Heart Failure (SENIORS) trial, significantly fewer patients receiving nebivolol died or were admitted to the hospital for cardiovascular reasons compared with those receiving placebo.⁶²

Although these findings are encouraging, we do not yet know if these effects will translate into a significant reduction in cardiovascular outcomes in clinical trials. Large, prospective hypertension outcome trials, particularly to evaluate primary prevention of cardiovascular outcomes, are needed for an evidence-based approach to using the newer beta-blockers as preferred first-line therapy for hypertension.

WHAT RECENT GUIDELINES SAY ABOUT BETA-BLOCKERS

The British National Institute for Health and Clinical Excellence and the British Hypertension Society, in their 2004 guidelines, recommended beta-blockers as one of several first-line antihypertensive medications in young, nonblack patients.⁶³ On the other hand, they advised clinicians to be aware of the reported increase in onset of diabetes mellitus in patients treated with these medications. After the LIFE²⁴ and ASCOT²⁶ study results were published, these guidelines were amended to exclude beta-blockers as preferred routine initial therapy for hypertension.⁶⁴

More recently, the 2007 European Society of Hypertension and European Society of Cardiology reconsidered the role of beta-blockers, recommending them as an option in both initial and subsequent antihypertensive treatment strategies.⁶⁵

The current guidelines from the National Heart, Lung, and Blood Institute,⁶⁶ which were published in 2003, were highly influenced by the results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),² and favor diuretics as the first-line therapy. However, they indicate that beta-blockers are a suitable alternative, particularly when a compelling cardiac indication is present.⁵³ We hope that the next update, expected late in 2009, will re-address this issue in the light of more recent data.

In recent years the role of beta-blockers as a primary tool to treat hypertension has come under question. These drugs have shown disappointing results when used as antihypertensive therapy in patients without heart disease, ie, when used as primary prevention. At the same time, beta-blockers clearly reduce the risk of future cardiovascular events in patients who already have heart disease, eg, who already have had a myocardial infarction or who have congestive heart failure.

Several meta-analyses and a few clinical trials have shown that beta-blockers may have no advantage over other antihypertensive drugs, and in fact may not reduce the risk of stroke as effectively as other classes of blood pressure medications.

Why should this be? Is it that the patients in the antihypertensive trials were mostly older, and that beta-blockers do not work as well in older patients as in younger ones? Or does it have to do with the fact that atenolol (Tenormin) was the drug most often used in the trials? Would newer, different beta-blockers be better?

Hypertension experts currently disagree on how to interpret the available data, and this has led to conflict and confusion among clinicians as to the role of beta-blockers in managing hypertension. Current evidence suggests that older beta-blockers may not be the preferred first-line antihypertensive drugs for hypertensive patients who have no compelling indications for them (eg, heart failure, myocardial infarction, diabetes, high risk of coronary heart disease). However, newer beta-blockers with vasodilatory properties should be considered in cases of uncontrolled or resistant hypertension, especially in younger patients.

Further, while controversy and debate continue over the benefits and adverse effects of one class of antihypertensive drugs vs another, it is indisputable that controlling arterial blood pressure to the recommended goal offers major protection against cardiovascular and renal events in patients with hypertension.^1,2

MECHANISM OF ACTION OF BETA-BLOCKERS

Beta-blockers effectively reduce blood pressure in both systolic-diastolic hypertension and isolated systolic hypertension.^3–5 Exactly how is not known, but it has been proposed that they may do so by:

Reducing the heart rate and cardiac output. When catecholamines activate beta-1 receptors in the heart, the heart rate and myocardial contractility increase. By blocking beta-1 receptors, beta-blockers reduce the heart rate and myocardial contractility, thus lowering cardiac output and arterial blood pressure.⁶

Inhibiting renin release. Activation of the renin-angiotensin system is another major pathway that can lead to elevated arterial blood pressure. Renin release is mediated through the sympathetic nervous system via beta-1 receptors on the juxtaglomerular cells of the kidney. Beta-blockers can therefore lower blood pressure by inhibiting renin release.⁷

Inhibiting central nervous sympathetic outflow, thereby inducing presynaptic blockade, which in turn reduces the release of catecholamines.

Reducing venous return and plasma volume.

Generating nitric oxide, thus reducing peripheral vascular resistance (some agents).⁸

Reducing vasomotor tone.

Reducing vascular tone.

Improving vascular compliance.

Resetting baroreceptor levels.

Attenuating the pressor response to catecholamines with exercise and stress.

HETEROGENEITY OF BETA-BLOCKERS

Selectivity

Beta-blockers are not all the same. They can be classified into three categories.

Nonselective beta-blockers block both beta-1 and beta-2 adrenergic receptors. It is generally accepted that beta-blockers exert their primary antihypertensive effect by blocking beta-1 adrenergic receptors.⁶ Of interest, nonselective beta-blockers inhibit beta-2 receptors on arteries and thus cause an unopposed alpha-adrenergic effect, leading to increased peripheral vascular resistance.⁹ Examples of this category:

• Nadolol (Corgard)
• Pindolol (Visken)
• Propranolol (Inderal)
• Timolol (Blocadren).

Selective beta-blockers specifically block beta-1 receptors alone, although they are known to be nonselective at higher doses. Examples:

• Atenolol (Tenormin)
• Betaxolol (Kerlone)
• Bisoprolol (Zebeta)
• Esmolol (Brevibloc)
• Metoprolol (Lopressor, Toprol).

Beta-blockers with peripheral vasodilatatory effects act either via antagonism of the alpha-1 receptor, as with labetolol (Normodyne) and carvedilol (Coreg),¹⁰ or via enhanced release of nitric oxide, as with nebivolol (Bystolic).⁸

Lipid and water solubility

The lipid solubility and water solubility of each beta-blocker determine its bioavailability and side-effect profile.

Lipid solubility determines the degree to which a beta-blocker penetrates the blood-brain barrier and thereby leads to central nervous system side effects such as lethargy, nightmares, confusion, and depression. Propranolol is highly lipid-soluble; metoprolol and labetalol are moderately so.

Water-soluble beta-blockers such as atenolol have less tissue permeation, have a longer half-life, and cause fewer central nervous system effects and symptoms.¹¹

Routes of elimination

Beta-blockers also differ in their route of elimination.

Atenolol and nadolol are eliminated by the kidney and require dose adjustment in patients with impaired renal function.^12,13

On the other hand, propranolol, metoprolol, labetalol, carvedilol, and nebivolol are excreted primarily via hepatic metabolism.¹³

BETA-BLOCKERS IN THE MANAGEMENT OF HYPERTENSION

Beta-blockers were initially used to treat arrhythmias, but by the early 1970s they were also widely accepted for managing hypertension. ¹⁴ Their initial acceptance as one of the first-line classes of drugs for hypertension was based on their better side-effect profile compared with other antihypertensive drugs available at that time.

In the 1980s and 1990s, beta-blockers were listed as preferred first-line antihypertensive drugs along with diuretics in national hypertension guidelines.¹⁵ Subsequent updates of the guidelines favored diuretics as initial therapy and relegated all other classes of antihypertensive medications to be alternatives to diuretics.¹⁶ Although beta-blockers remain alternative first-line drugs in the latest guidelines (published in 2003; see reference 66), they are the preferred antihypertensive agents for patients with cardiac disease.

The current recommendations reflect the findings from hypertension trials in which patients with myocardial infarction and congestive heart failure had better cardiovascular outcomes if they received these drugs,^17–19 including a lower risk of death.^20,21 It was widely assumed that beta-blockers would also prevent first episodes of cardiovascular events.

However, to date, there is no evidence that beta-blockers are effective as primary prevention. Several large randomized controlled trials showed no benefit with beta-blockers compared with other antihypertensive drugs—in fact, there were more cardiovascular events with beta-blockers (see below).

Beta-blockers are well tolerated in clinical practice, although they can have side effects that include fatigue, depression, impaired exercise tolerance, sexual dysfunction, and asthma attacks.

Wiysonge et al²² analyzed how many patients withdrew from randomized trials of antihypertensive treatment because of drug-related adverse events. There was no significant difference in the incidence of fatigue, depressive symptoms, or sexual dysfunction with beta-blockers compared with placebo, and trial participants on a beta-blocker were not statistically significantly more likely to discontinue treatment than those receiving a placebo in three trials with 22,729 participants (relative risk [RR] 2.34, 95% confidence interval [CI] 0.84–6.52).

THE CONTROVERSY: WHAT THE TRIALS SHOWED

Messerli et al²³ performed a meta-analysis published in 1998 that suggested that beta-blockers may not be as effective as diuretics in preventing cardiovascular events when used as first-line antihypertensive therapy in elderly patients. In 10 randomized controlled trials in 16,164 patients who were treated with either a diuretic or a beta-blocker (atenolol), blood pressure was normalized in two-thirds of diuretic-treated patients but only one-third of patients treated with atenolol as monotherapy. Diuretic therapy was superior with regard to all end points, and beta-blockers were found to be ineffective except in reducing cerebrovascular events.

The LIFE study (Losartan Intervention for Endpoint Reduction in Hypertension)²⁴ compared the angiotensin-receptor blocker losartan (Cozaar) and atenolol in 9,193 patients with hypertension and left ventricular hypertrophy. At 4 years of follow-up, the rate of primary cardiovascular events (death, myocardial infarction, or stroke) was lower in the losartan group than in the atenolol group. The difference was mainly due to a 25% lower incidence of stroke, which was statistically significant. The rates of myocardial infarction and death from cardiovascular causes were not significantly different between the two treatment groups. The systolic blood pressure was 1 mm Hg lower in the losartan group than in the atenolol group, which was statistically significant.

Carlberg et al²⁵ performed another important meta-analysis that questioned whether atenolol reduces rates of cardiovascular morbidity and death in hypertensive patients. The results were surprising: eight randomized controlled trials including more than 6,000 patients and comparing atenolol with placebo or no treatment showed no differences between the treatment groups with regard to the outcomes of all-cause mortality (RR 1.01, 95% CI 0.89–1.15), cardiovascular mortality (RR 0.99, 95% CI 0.83–1.18), or myocardial infarction (RR 0.99, 95% CI 0.83–1.19).

In addition, when atenolol was compared with other antihypertensives in five other randomized controlled trials that included more than 14,000 patients, those treated with atenolol had a higher risk of stroke (RR 1.30, 95% CI 1.12–1.50) and death (RR 1.13, 95% CI 1.02–1.25).

The ASCOT-BPLA trial (Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm)²⁶ had similar results. This trial compared the combination of atenolol plus the diuretic bendroflumethiazide against the combination of the calcium channel blocker amlodipine (Norvasc) plus the angiotensin-converting enzyme (ACE) inhibitor perindopril (Aceon). Although no significant difference was seen in the primary outcome of nonfatal myocardial infarction or fatal coronary heart disease (unadjusted hazard ratio [HR] with amlodipine-perindopril 0.90, 95% CI 0.79–1.02, P = .1052), the amlodipine-plus-perindopril group had significantly fewer strokes (327 vs 422, HR 0.77, 95% CI 0.66–0.89, P = .0003), fewer total cardiovascular events (1,362 vs 1,602, HR 0.84, 95% CI 0.78–0.90, P = .0001), and fewer deaths from any cause (738 vs 820; HR 0.89, 95% CI 0.81–0.99, P = .025).

Lindholm et al²⁷ performed a meta-analysis that included studies of selective beta-blockers (including atenolol) and nonselective beta-blockers, with a follow-up time of more than 2 years. Compared with placebo or no treatment, beta-blockers reduced the risk of stroke by 19% but had no effect on myocardial infarction or all-cause mortality. Compared with other antihypertensive drugs, beta-blockers were less than optimum, and the relative risk of stroke was 16% higher. Atenolol was the beta-blocker used in most of the randomized clinical trials included in this meta-analysis.

The Cochrane group²² found beta-blockers to be inferior to all other antihypertensive drugs with respect to the ability to lower the risk of stroke.

WHY WERE THE RESULTS SO DISAPPOINTING?

Problems with atenolol

Most of the trials in the meta-analyses discussed above used atenolol and other beta-blockers that had no vasodilatory properties.

Further, in most of the trials atenolol was used in a once-daily dosage, whereas ideally it needs to be taken more frequently, based on its pharmacokinetic and pharmacodynamic properties (a half-life of 6–9 hours).³ Neutel et al²⁸ confirmed that atenolol, when taken once daily, leaves the patient unprotected in the last 6 hours of a 24-hour period, as demonstrated by 24-hour ambulatory blood pressure monitoring. It is possible that this short duration of action of atenolol may have contributed to the results observed in clinical trials that used atenolol to treat hypertension.

Differences between older and younger patients

Another possible reason for the disappointing results is that the trials included many elderly patients, in whom beta-blockers may not be as effective. The pathophysiology of hypertension in younger people is different from that in older patients.²⁹ Hemodynamic characteristics of younger hypertensive patients include a high cardiac output and hyperdynamic circulation with a low pulse pressure, while older patients have lower arterial compliance with an elevated vascular resistance.

The notion of choosing antihypertensive medications on the basis of age and age-related pathophysiology is supported by several clinical studies. Randomized controlled trials appear to show that beta-blockers are effective in younger hypertensive patients.³⁰

Conversely, the CAFE (Conduit Artery Function Evaluation) trial,³¹ a substudy of the main ASCOT trial,²⁶ indicated that betablocker-based therapy was less effective in reducing central aortic pressure than were regimens based on an ACE inhibitor or a calcium channel blocker.

The CAFE researchers recruited 2,073 patients from five ASCOT centers and used radial artery applanation tonometry and pulse-wave analysis to derive central aortic pressures and hemodynamic indices during study visits up to a period of 4 years. Although the two treatment groups achieved similar brachial systolic blood pressures, the central aortic systolic pressure was 4.3 mm Hg lower in the amlodipine group (95% CI 3.3–5.4; P < .0001), and the central aortic pulse pressure was 3.0 mm Hg lower (95% CI 2.1–3.9; P < .0001).

Pulse-wave dyssynchrony

Bangalore et al⁴⁷ offer an interesting hypothesis to explain the probable adverse effect of beta-blockers. Their theory concerns the effect of these drugs on the arterial pulse wave.

Normally, with each contraction of the left ventricle during systole, an arterial pulse wave is generated and propagated forward to the peripheral arteries. This wave is then reflected back to the heart from the branching points of peripheral arteries. The final form of the pressure wave at the aortic root is a synchronized summation of the forward-traveling wave and the backward-reflected wave.

In healthy people with normal arteries, the reflected wave merges with the forward-traveling wave in diastole and augments coronary blood flow. In patients whose arteries are stiff due to aging or vascular comorbidities, the reflected wave returns faster and merges with the incident wave in systole, resulting in higher left ventricular afterload and less coronary perfusion.⁴⁸

Bangalore et al⁴⁷ propose that artificially reducing the heart rate with beta-blockers may further dyssynchronize the pulse wave, adversely affecting coronary perfusion and leading to an increased risk of cardiovascular events and death.

Metabolic side effects

Older beta-blockers, and especially atenolol, have well-known metabolic adverse effects, particularly impairment of glycemic control. This adverse effect appears to occur only with beta-blockers that do not possess vasodilatory properties and thus increase peripheral vascular resistance, which results in lower glucose availability and reduced uptake by skeletal muscles.⁴⁹

Bangalore et al⁵⁰ evaluated the effect of beta-blockers in a meta-analysis of 12 studies in 94,492 patients followed up for more than 1 year. Beta-blocker therapy resulted in a 22% higher risk of new-onset diabetes mellitus (RR 1.22, 95% CI 1.12–1.33) than with other nondiuretic antihypertensive agents.

Of note, however, the meta-analysis did not show a significantly higher risk of the onset of diabetes with propranolol or metoprolol than with other nondiuretic antihypertensives when studies of these beta-blockers were separated from atenolol-based studies.

Further, the United Kingdom Prospective Diabetes Study⁴⁰ found that cardiovascular outcomes in patients with good blood pressure control were similar when atenolol-based therapy was compared with therapy with the ACE inhibitor captopril (Capoten).

A meta-analysis conducted by Balamuthusamy et al⁵¹ in 2009 found no higher risk of stroke in patients with hypertension and diabetes mellitus who received beta-blockers than in those who received other antihypertensive medications. However, beta-blockers were associated with a higher risk of death from cardiovascular causes (RR 1.39, 95% CI 1.07–1.804; P < .01) compared with reninangiotensin blockade.

NEWER BETA-BLOCKERS MAY BE BETTER

In the United States, more than 40 million prescriptions for atenolol are written every year, making it by far the most commonly used beta-blocker for the treatment of hypertension. ⁵² It is clear, however, that atenolol is not an ideal representative of this class of antihypertensive medications.

Preliminary data from studies of newer beta-blockers that possess beneficial vasodilatory properties are encouraging. Animal studies and preliminary human studies find that these new-generation beta-blockers cause fewer adverse metabolic effects and improve endothelial function, measures of arterial stiffness, and cardiovascular outcomes.

Carvedilol

Carvedilol is a nonselective beta-blocker with vasodilatory effects that are thought to be due to its ability to concurrently block alpha-1 receptors in addition to beta receptors. ⁵³ In experiments in vitro and in trials in patients with diabetes and hypertension, carvedilol increased endothelial vasodilation and reduced inflammation and platelet aggregation. These effects may be achieved though antioxidant actions, thereby preserving nitric oxide bioactivity.^54,55

In the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial,⁵⁶ carvedilol was associated with better maintenance of glycemic control in diabetic hypertensive patients than was metoprolol. Insulin sensitivity improved with carvedilol but not with metoprolol, and fewer patients on carvedilol progressed to microalbuminuria.

Nebivolol

Nebivolol is a novel selective beta-blocker with a much higher affinity for beta-1 adrenergic receptors than for beta-2 adrenergic receptors. Among all the beta-blockers in clinical use today, nebivolol has the highest selectivity for beta-1 receptors.⁸

Nebivolol causes vasodilation through activation of the l-arginine/nitric oxide pathway.^57–59 Blockade of synthesis of nitric oxide leads to local arterial stiffness. Endothelial dysfunction is characterized by decreased bioavailability of nitric oxide and has been shown to be a strong predictor of cardiovascular outcomes. By generating nitric oxide, nebivolol reduces peripheral vascular resistance, overcoming a significant side effect of earlier beta-blockers that lowered blood pressure but ultimately increased peripheral vascular tone and resistance.⁸

In an experiment in a bovine model,⁶⁰ nebivolol significantly reduced the pulse-wave velocity (a measure of arterial stiffness), while atenolol had no effect. Moreover, evidence for the role of the l-arginine/nitric oxide pathway in the vasodilatory effect of nebivolol was demonstrated by co-infusion of N^G-monomethyl-L-arginine, a specific endothelial nitric oxide synthetase inhibitor that attenuated the reduction of pulse-wave velocity by nebivolol.

In studies in hypertensive patients, nebivolol was associated with a better metabolic profile than atenolol, with none of the adverse effects on insulin sensitivity that atenolol had.⁶¹ In the Study of Effects of Nebivolol Interventions on Outcomes and Rehospitalization in Seniors With Heart Failure (SENIORS) trial, significantly fewer patients receiving nebivolol died or were admitted to the hospital for cardiovascular reasons compared with those receiving placebo.⁶²

Although these findings are encouraging, we do not yet know if these effects will translate into a significant reduction in cardiovascular outcomes in clinical trials. Large, prospective hypertension outcome trials, particularly to evaluate primary prevention of cardiovascular outcomes, are needed for an evidence-based approach to using the newer beta-blockers as preferred first-line therapy for hypertension.

WHAT RECENT GUIDELINES SAY ABOUT BETA-BLOCKERS

The British National Institute for Health and Clinical Excellence and the British Hypertension Society, in their 2004 guidelines, recommended beta-blockers as one of several first-line antihypertensive medications in young, nonblack patients.⁶³ On the other hand, they advised clinicians to be aware of the reported increase in onset of diabetes mellitus in patients treated with these medications. After the LIFE²⁴ and ASCOT²⁶ study results were published, these guidelines were amended to exclude beta-blockers as preferred routine initial therapy for hypertension.⁶⁴

More recently, the 2007 European Society of Hypertension and European Society of Cardiology reconsidered the role of beta-blockers, recommending them as an option in both initial and subsequent antihypertensive treatment strategies.⁶⁵

The current guidelines from the National Heart, Lung, and Blood Institute,⁶⁶ which were published in 2003, were highly influenced by the results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),² and favor diuretics as the first-line therapy. However, they indicate that beta-blockers are a suitable alternative, particularly when a compelling cardiac indication is present.⁵³ We hope that the next update, expected late in 2009, will re-address this issue in the light of more recent data.