Terry Ann Jankowski, MLS

Evidence summary

A Cochrane review of 7 RCTs, with a total of 46,885 children, examined the effect of pneumococcal vaccine on the incidence of otitis media.¹ The authors didn’t pool the results because of large heterogeneity among the studies. Only 2 trials used the licensed 7-valent PCV Prevnar; both enrolled infants vaccinated according to the routine schedule before 12 months of age.

The largest study (37,686 children followed to 42 months of age) showed a 7.8% reduction in the number of office visits for otitis media after pneumococcal vaccination (95% CI, 5.4%-10.1%).² The incidence of ROM—defined as at least 3 episodes within 6 months or at least 4 episodes within 1 year—decreased 9% (95% CI, 4%-14%) among vaccine recipients.² The study also demonstrated a 24% decrease in the need for tympanostomy tubes (95% CI, 12%-35%).² The other 7-valent PCV trial (1662 children) showed a 6% risk reduction in AOM (95% CI, -4% to 16%) in the vaccinated group.¹

A retrospective cohort study in New York and Tennessee that enrolled 176,000 children vaccinated according to the recommended schedule starting at 2 months of age found reductions in ROM of 28% (95% CI, 11%-33%) for New York’s vaccinated cohort and 17% (95% CI, 6%-19%) for the Tennessee cohort. ROM was defined as at least 3 episodes within 6 months or at least 4 episodes within 1 year. The study also showed a 23% decrease in tympanostomy tube placement in New York (95% CI, 1%-35%) and a 16% decrease in Tennessee (95% CI, 3%-21%).³

A simplified vaccination schedule linked to fewer cases of otitis media
A single-blinded prospective cohort study of 1571 children examined the effectiveness of a simplified PCV-7 schedule. Children vaccinated with the licensed 7-valent PCV at 3, 5, and 11 months of age showed a 17% reduction in AOM (95% CI, 2%-39%) compared with unvaccinated controls.⁴

Vaccination starting at 12 months shows mixed results
Results from 3 trials that vaccinated children older than 1 year were mixed.¹ An analysis of 264 healthy 12- to 35-month-olds given a 9-valent PCV found a 17% reduction in AOM (95% CI, -2% to 33%). However, in 2 other trials, of 74 and 383 children, the vaccine didn’t decrease the incidence of AOM.¹

Children in these 2 trials were 1 to 7 years of age and all had had at least 2 episodes of otitis media in the year before enrollment. Both trials employed 2 doses of the licensed 7-valent PCV in children younger than 2 years and 1 dose of the 7-valent vaccine followed by a dose of the 23-valent vaccine in children older than 2 years.¹

Recommendations

A clinical practice guideline issued jointly by the American Academy of Pediatrics and American Academy of Family Physicians recognizes the benefit of PCV vaccination for preventing AOM.⁵ Although preventing AOM is not the primary indication, PCV vaccination at 2, 4, 6, and 12 to 15 months of age is part of the routine childhood immunization series recommended by the Advisory Committee on Immunization Practices.⁶

Evidence summary

A Cochrane review of 7 RCTs, with a total of 46,885 children, examined the effect of pneumococcal vaccine on the incidence of otitis media.¹ The authors didn’t pool the results because of large heterogeneity among the studies. Only 2 trials used the licensed 7-valent PCV Prevnar; both enrolled infants vaccinated according to the routine schedule before 12 months of age.

The largest study (37,686 children followed to 42 months of age) showed a 7.8% reduction in the number of office visits for otitis media after pneumococcal vaccination (95% CI, 5.4%-10.1%).² The incidence of ROM—defined as at least 3 episodes within 6 months or at least 4 episodes within 1 year—decreased 9% (95% CI, 4%-14%) among vaccine recipients.² The study also demonstrated a 24% decrease in the need for tympanostomy tubes (95% CI, 12%-35%).² The other 7-valent PCV trial (1662 children) showed a 6% risk reduction in AOM (95% CI, -4% to 16%) in the vaccinated group.¹

A retrospective cohort study in New York and Tennessee that enrolled 176,000 children vaccinated according to the recommended schedule starting at 2 months of age found reductions in ROM of 28% (95% CI, 11%-33%) for New York’s vaccinated cohort and 17% (95% CI, 6%-19%) for the Tennessee cohort. ROM was defined as at least 3 episodes within 6 months or at least 4 episodes within 1 year. The study also showed a 23% decrease in tympanostomy tube placement in New York (95% CI, 1%-35%) and a 16% decrease in Tennessee (95% CI, 3%-21%).³

A simplified vaccination schedule linked to fewer cases of otitis media
A single-blinded prospective cohort study of 1571 children examined the effectiveness of a simplified PCV-7 schedule. Children vaccinated with the licensed 7-valent PCV at 3, 5, and 11 months of age showed a 17% reduction in AOM (95% CI, 2%-39%) compared with unvaccinated controls.⁴

Vaccination starting at 12 months shows mixed results
Results from 3 trials that vaccinated children older than 1 year were mixed.¹ An analysis of 264 healthy 12- to 35-month-olds given a 9-valent PCV found a 17% reduction in AOM (95% CI, -2% to 33%). However, in 2 other trials, of 74 and 383 children, the vaccine didn’t decrease the incidence of AOM.¹

Children in these 2 trials were 1 to 7 years of age and all had had at least 2 episodes of otitis media in the year before enrollment. Both trials employed 2 doses of the licensed 7-valent PCV in children younger than 2 years and 1 dose of the 7-valent vaccine followed by a dose of the 23-valent vaccine in children older than 2 years.¹

Recommendations

A clinical practice guideline issued jointly by the American Academy of Pediatrics and American Academy of Family Physicians recognizes the benefit of PCV vaccination for preventing AOM.⁵ Although preventing AOM is not the primary indication, PCV vaccination at 2, 4, 6, and 12 to 15 months of age is part of the routine childhood immunization series recommended by the Advisory Committee on Immunization Practices.⁶

Evidence summary

A Cochrane review of 7 RCTs, with a total of 46,885 children, examined the effect of pneumococcal vaccine on the incidence of otitis media.¹ The authors didn’t pool the results because of large heterogeneity among the studies. Only 2 trials used the licensed 7-valent PCV Prevnar; both enrolled infants vaccinated according to the routine schedule before 12 months of age.

The largest study (37,686 children followed to 42 months of age) showed a 7.8% reduction in the number of office visits for otitis media after pneumococcal vaccination (95% CI, 5.4%-10.1%).² The incidence of ROM—defined as at least 3 episodes within 6 months or at least 4 episodes within 1 year—decreased 9% (95% CI, 4%-14%) among vaccine recipients.² The study also demonstrated a 24% decrease in the need for tympanostomy tubes (95% CI, 12%-35%).² The other 7-valent PCV trial (1662 children) showed a 6% risk reduction in AOM (95% CI, -4% to 16%) in the vaccinated group.¹

A retrospective cohort study in New York and Tennessee that enrolled 176,000 children vaccinated according to the recommended schedule starting at 2 months of age found reductions in ROM of 28% (95% CI, 11%-33%) for New York’s vaccinated cohort and 17% (95% CI, 6%-19%) for the Tennessee cohort. ROM was defined as at least 3 episodes within 6 months or at least 4 episodes within 1 year. The study also showed a 23% decrease in tympanostomy tube placement in New York (95% CI, 1%-35%) and a 16% decrease in Tennessee (95% CI, 3%-21%).³

A simplified vaccination schedule linked to fewer cases of otitis media
A single-blinded prospective cohort study of 1571 children examined the effectiveness of a simplified PCV-7 schedule. Children vaccinated with the licensed 7-valent PCV at 3, 5, and 11 months of age showed a 17% reduction in AOM (95% CI, 2%-39%) compared with unvaccinated controls.⁴

Vaccination starting at 12 months shows mixed results
Results from 3 trials that vaccinated children older than 1 year were mixed.¹ An analysis of 264 healthy 12- to 35-month-olds given a 9-valent PCV found a 17% reduction in AOM (95% CI, -2% to 33%). However, in 2 other trials, of 74 and 383 children, the vaccine didn’t decrease the incidence of AOM.¹

Children in these 2 trials were 1 to 7 years of age and all had had at least 2 episodes of otitis media in the year before enrollment. Both trials employed 2 doses of the licensed 7-valent PCV in children younger than 2 years and 1 dose of the 7-valent vaccine followed by a dose of the 23-valent vaccine in children older than 2 years.¹

Recommendations

A clinical practice guideline issued jointly by the American Academy of Pediatrics and American Academy of Family Physicians recognizes the benefit of PCV vaccination for preventing AOM.⁵ Although preventing AOM is not the primary indication, PCV vaccination at 2, 4, 6, and 12 to 15 months of age is part of the routine childhood immunization series recommended by the Advisory Committee on Immunization Practices.⁶

Evidence summary

Little research has been performed on sulfonamide antibiotic and sulfonamide diuretic allergic cross-reactivity. What we do know is that there are 2 classes of sulfonamides—those with an aromatic amine (the antimicrobial sulfonamides) and those without (eg, the diuretics acetazolamide, furosemide, hydrochlorothiazide, and indapamide). Hypersensitivity reactions occur when the aromatic amine group is oxidized into hydroxylamine metabolites by the liver. Sulfonamides that do not contain this aromatic amine group undergo different metabolic pathways, suggesting that allergic reactions that do occur in this group are not due to cross-reactivity in sulfa-allergic patients. But that point is far from settled by the research.

On one side, a large cohort study shows some cross-reactivity

A large retrospective cohort study using Britain’s General Practice Research Database identified 20,226 patients seen from 1987 through March 1999 who were prescribed a systemic sulfonamide antibiotic, and then at least 60 days later received a nonantibiotic sulfonamide (eg, thiazide diuretic, furosemide, oral hypoglycemic).¹ Researchers reviewed records to determine whether patients described as having an allergic reaction to a sulfonamide antibiotic were at increased risk of having a subsequent allergic reaction to a sulfonamide nonantibiotic.

Patients were identified as being allergic using both narrow definitions (anaphylaxis, bronchospasm, urticaria, laryngospasm, or angioedema) and broad ones. As only 18 patients out of the 20,226 patients were reported as having an allergic reaction using the narrow definition, analysis was based on the broad definition. Added to the broad category were asthma, eczema, and other “adverse” drug effects that were not specified by the author.

Using this broad definition, researchers identified allergies to sulfonamide antibiotics in 969 patients. Of this group, 96 patients (9.9%) had a subsequent reaction to a sulfonamide nonantibiotic, which included drugs from the loop and thiazide diuretic classes (including bumetanide, chlorothiazide, furosemide, hydrochlorothiazide, indapamide, and torsemide). It was unclear if any patients taking a carbonic anhydrase inhibitor experienced an allergic reaction. For comparison purposes, of the 19,257 patients who were not identified as having an allergy to a sulfonamide antibiotic, again using the broad definition, 315 (1.6%), had a subsequent allergic reaction to a sulfonamide nonantibiotic, for an unadjusted odds ratio of 6.6 (95% confidence interval [CI], 5.2–8.4).

When the results were adjusted for age, sex, history of asthma, use of medications for asthma or corticosteroids, the adjusted odds ratio for individuals experiencing an allergy to a nonantibiotic sulfonamide in those persons with a history of allergy to a sulfonamide antibiotic was 2.8 (95 % CI, 2.1–3.7). Of note, the adjusted odds ratio for the occurrence of a penicillin allergy in a patient with a history of sulfonamide antibiotic allergy was significantly higher at 3.9 (95% CI, 3.5–4.3).

Some limitations of the study included uncertainty of cause and effect of prescribed medications and subsequent reactions, possible inconsistency of physician diagnosis and coding, and lack of precision in the diagnosis of allergic reactions. There is also the possibility of “suspicion bias,” where patients with a history of allergies may be more closely monitored for subsequent reactions than nonallergic patients.

On the other side, small studies reveal little risk of cross-reaction

Researchers involved in a retrospective study of 363 hospital charts examined 34 patients with a self-reported history of sulfa allergy who were subsequently given acetazolamide (a carbonic anhydrase inhibitor), furosemide (a loop diuretic), or both.² The nature of the self-reported sulfa allergic reaction was documented in 79% of the 34 patients. These reported reactions included urticarial rash, nonspecified rash, dyspnea, swelling, nausea or vomiting, throat swelling, red eyes, and bullae. Two patients who were given acetazolamide developed urticaria. No allergic reactions occurred for those patients given furosemide.

The researchers concluded that there was little clinical or pharmacological evidence to suggest that a self-reported sulfa allergy was likely to produce a life-threatening cross-reaction with acetazolamide or furosemide. Small numbers and the lack of a standard definition for an allergic reaction limited the strength of their conclusion.

A small single-blind study of 28 patients with a history of fixed drug eruption to sulfonamide antibiotics examined the usefulness of patch testing as an alternative to controlled oral challenge testing.³ Before patch testing, a sulfonamide antibiotic allergy was confirmed by each patient with an oral challenge of sulfamethoxazole, sulfadiazine, or sulfamethazole. Potential cross-reactivity to several nonantibiotic sulfonamides (including furosemide) was also investigated using controlled oral challenge testing of these agents. Every patient tolerated a subsequent oral challenge with furosemide.

Literature reviews limited by small numbers

Two literature reviews examined the small number of case series, case reports, and “other articles” and concluded little evidence supports the presence of cross-reactivity between sulfonamide antibiotics and non-sulfonamide antibiotics.^3,4 These reviews were limited by their search criteria and lack of explicit critical appraisal.

A literature review of Medline from 1966 to early 2004 revealed 21 case series, case reports, and “other articles” that evaluated the presence of cross-reactivity.³ When the authors of this literature reviewed drilled down to diuretics, they found 5 case reports for cross-reactivity to acetazolamide, 2 case reports for furosemide, 1 case series, and 2 case reports for indapamide (a thiazide diuretic). After reviewing the studies, the authors concluded that little evidence suggested a problem with cross-reactivity either with acetazolamide or furosemide and that there may be an association of cross-reactivity between sulfonamide antibiotics and indapamide. This study was limited by its small numbers and lack of explicit critical appraisal.

In another literature review—in which the main focus was cross-reactivity between sulfonamide antibiotics and celecoxib—the authors concluded that little evidence supported definitive cross-reactivity between sulfonamide antibiotics and diuretics.⁴ The limitations of this study were similar to those of the previous study.

Recommendations from others

The manufacturer insert for furosemide states, under the heading “General Precautions,” that “patients allergic to sulfonamides may also be allergic to furosemide.”⁵ A similar warning occurs for hydrochlorothiazide under the heading “Contraindications.”⁶

Evidence summary

Little research has been performed on sulfonamide antibiotic and sulfonamide diuretic allergic cross-reactivity. What we do know is that there are 2 classes of sulfonamides—those with an aromatic amine (the antimicrobial sulfonamides) and those without (eg, the diuretics acetazolamide, furosemide, hydrochlorothiazide, and indapamide). Hypersensitivity reactions occur when the aromatic amine group is oxidized into hydroxylamine metabolites by the liver. Sulfonamides that do not contain this aromatic amine group undergo different metabolic pathways, suggesting that allergic reactions that do occur in this group are not due to cross-reactivity in sulfa-allergic patients. But that point is far from settled by the research.

On one side, a large cohort study shows some cross-reactivity

A large retrospective cohort study using Britain’s General Practice Research Database identified 20,226 patients seen from 1987 through March 1999 who were prescribed a systemic sulfonamide antibiotic, and then at least 60 days later received a nonantibiotic sulfonamide (eg, thiazide diuretic, furosemide, oral hypoglycemic).¹ Researchers reviewed records to determine whether patients described as having an allergic reaction to a sulfonamide antibiotic were at increased risk of having a subsequent allergic reaction to a sulfonamide nonantibiotic.

Patients were identified as being allergic using both narrow definitions (anaphylaxis, bronchospasm, urticaria, laryngospasm, or angioedema) and broad ones. As only 18 patients out of the 20,226 patients were reported as having an allergic reaction using the narrow definition, analysis was based on the broad definition. Added to the broad category were asthma, eczema, and other “adverse” drug effects that were not specified by the author.

Using this broad definition, researchers identified allergies to sulfonamide antibiotics in 969 patients. Of this group, 96 patients (9.9%) had a subsequent reaction to a sulfonamide nonantibiotic, which included drugs from the loop and thiazide diuretic classes (including bumetanide, chlorothiazide, furosemide, hydrochlorothiazide, indapamide, and torsemide). It was unclear if any patients taking a carbonic anhydrase inhibitor experienced an allergic reaction. For comparison purposes, of the 19,257 patients who were not identified as having an allergy to a sulfonamide antibiotic, again using the broad definition, 315 (1.6%), had a subsequent allergic reaction to a sulfonamide nonantibiotic, for an unadjusted odds ratio of 6.6 (95% confidence interval [CI], 5.2–8.4).

When the results were adjusted for age, sex, history of asthma, use of medications for asthma or corticosteroids, the adjusted odds ratio for individuals experiencing an allergy to a nonantibiotic sulfonamide in those persons with a history of allergy to a sulfonamide antibiotic was 2.8 (95 % CI, 2.1–3.7). Of note, the adjusted odds ratio for the occurrence of a penicillin allergy in a patient with a history of sulfonamide antibiotic allergy was significantly higher at 3.9 (95% CI, 3.5–4.3).

Some limitations of the study included uncertainty of cause and effect of prescribed medications and subsequent reactions, possible inconsistency of physician diagnosis and coding, and lack of precision in the diagnosis of allergic reactions. There is also the possibility of “suspicion bias,” where patients with a history of allergies may be more closely monitored for subsequent reactions than nonallergic patients.

On the other side, small studies reveal little risk of cross-reaction

Researchers involved in a retrospective study of 363 hospital charts examined 34 patients with a self-reported history of sulfa allergy who were subsequently given acetazolamide (a carbonic anhydrase inhibitor), furosemide (a loop diuretic), or both.² The nature of the self-reported sulfa allergic reaction was documented in 79% of the 34 patients. These reported reactions included urticarial rash, nonspecified rash, dyspnea, swelling, nausea or vomiting, throat swelling, red eyes, and bullae. Two patients who were given acetazolamide developed urticaria. No allergic reactions occurred for those patients given furosemide.

The researchers concluded that there was little clinical or pharmacological evidence to suggest that a self-reported sulfa allergy was likely to produce a life-threatening cross-reaction with acetazolamide or furosemide. Small numbers and the lack of a standard definition for an allergic reaction limited the strength of their conclusion.

A small single-blind study of 28 patients with a history of fixed drug eruption to sulfonamide antibiotics examined the usefulness of patch testing as an alternative to controlled oral challenge testing.³ Before patch testing, a sulfonamide antibiotic allergy was confirmed by each patient with an oral challenge of sulfamethoxazole, sulfadiazine, or sulfamethazole. Potential cross-reactivity to several nonantibiotic sulfonamides (including furosemide) was also investigated using controlled oral challenge testing of these agents. Every patient tolerated a subsequent oral challenge with furosemide.

Literature reviews limited by small numbers

Two literature reviews examined the small number of case series, case reports, and “other articles” and concluded little evidence supports the presence of cross-reactivity between sulfonamide antibiotics and non-sulfonamide antibiotics.^3,4 These reviews were limited by their search criteria and lack of explicit critical appraisal.

A literature review of Medline from 1966 to early 2004 revealed 21 case series, case reports, and “other articles” that evaluated the presence of cross-reactivity.³ When the authors of this literature reviewed drilled down to diuretics, they found 5 case reports for cross-reactivity to acetazolamide, 2 case reports for furosemide, 1 case series, and 2 case reports for indapamide (a thiazide diuretic). After reviewing the studies, the authors concluded that little evidence suggested a problem with cross-reactivity either with acetazolamide or furosemide and that there may be an association of cross-reactivity between sulfonamide antibiotics and indapamide. This study was limited by its small numbers and lack of explicit critical appraisal.

In another literature review—in which the main focus was cross-reactivity between sulfonamide antibiotics and celecoxib—the authors concluded that little evidence supported definitive cross-reactivity between sulfonamide antibiotics and diuretics.⁴ The limitations of this study were similar to those of the previous study.

Recommendations from others

The manufacturer insert for furosemide states, under the heading “General Precautions,” that “patients allergic to sulfonamides may also be allergic to furosemide.”⁵ A similar warning occurs for hydrochlorothiazide under the heading “Contraindications.”⁶

Evidence summary

Little research has been performed on sulfonamide antibiotic and sulfonamide diuretic allergic cross-reactivity. What we do know is that there are 2 classes of sulfonamides—those with an aromatic amine (the antimicrobial sulfonamides) and those without (eg, the diuretics acetazolamide, furosemide, hydrochlorothiazide, and indapamide). Hypersensitivity reactions occur when the aromatic amine group is oxidized into hydroxylamine metabolites by the liver. Sulfonamides that do not contain this aromatic amine group undergo different metabolic pathways, suggesting that allergic reactions that do occur in this group are not due to cross-reactivity in sulfa-allergic patients. But that point is far from settled by the research.

On one side, a large cohort study shows some cross-reactivity

A large retrospective cohort study using Britain’s General Practice Research Database identified 20,226 patients seen from 1987 through March 1999 who were prescribed a systemic sulfonamide antibiotic, and then at least 60 days later received a nonantibiotic sulfonamide (eg, thiazide diuretic, furosemide, oral hypoglycemic).¹ Researchers reviewed records to determine whether patients described as having an allergic reaction to a sulfonamide antibiotic were at increased risk of having a subsequent allergic reaction to a sulfonamide nonantibiotic.

Patients were identified as being allergic using both narrow definitions (anaphylaxis, bronchospasm, urticaria, laryngospasm, or angioedema) and broad ones. As only 18 patients out of the 20,226 patients were reported as having an allergic reaction using the narrow definition, analysis was based on the broad definition. Added to the broad category were asthma, eczema, and other “adverse” drug effects that were not specified by the author.

Using this broad definition, researchers identified allergies to sulfonamide antibiotics in 969 patients. Of this group, 96 patients (9.9%) had a subsequent reaction to a sulfonamide nonantibiotic, which included drugs from the loop and thiazide diuretic classes (including bumetanide, chlorothiazide, furosemide, hydrochlorothiazide, indapamide, and torsemide). It was unclear if any patients taking a carbonic anhydrase inhibitor experienced an allergic reaction. For comparison purposes, of the 19,257 patients who were not identified as having an allergy to a sulfonamide antibiotic, again using the broad definition, 315 (1.6%), had a subsequent allergic reaction to a sulfonamide nonantibiotic, for an unadjusted odds ratio of 6.6 (95% confidence interval [CI], 5.2–8.4).

When the results were adjusted for age, sex, history of asthma, use of medications for asthma or corticosteroids, the adjusted odds ratio for individuals experiencing an allergy to a nonantibiotic sulfonamide in those persons with a history of allergy to a sulfonamide antibiotic was 2.8 (95 % CI, 2.1–3.7). Of note, the adjusted odds ratio for the occurrence of a penicillin allergy in a patient with a history of sulfonamide antibiotic allergy was significantly higher at 3.9 (95% CI, 3.5–4.3).

Some limitations of the study included uncertainty of cause and effect of prescribed medications and subsequent reactions, possible inconsistency of physician diagnosis and coding, and lack of precision in the diagnosis of allergic reactions. There is also the possibility of “suspicion bias,” where patients with a history of allergies may be more closely monitored for subsequent reactions than nonallergic patients.

On the other side, small studies reveal little risk of cross-reaction

Researchers involved in a retrospective study of 363 hospital charts examined 34 patients with a self-reported history of sulfa allergy who were subsequently given acetazolamide (a carbonic anhydrase inhibitor), furosemide (a loop diuretic), or both.² The nature of the self-reported sulfa allergic reaction was documented in 79% of the 34 patients. These reported reactions included urticarial rash, nonspecified rash, dyspnea, swelling, nausea or vomiting, throat swelling, red eyes, and bullae. Two patients who were given acetazolamide developed urticaria. No allergic reactions occurred for those patients given furosemide.

The researchers concluded that there was little clinical or pharmacological evidence to suggest that a self-reported sulfa allergy was likely to produce a life-threatening cross-reaction with acetazolamide or furosemide. Small numbers and the lack of a standard definition for an allergic reaction limited the strength of their conclusion.

A small single-blind study of 28 patients with a history of fixed drug eruption to sulfonamide antibiotics examined the usefulness of patch testing as an alternative to controlled oral challenge testing.³ Before patch testing, a sulfonamide antibiotic allergy was confirmed by each patient with an oral challenge of sulfamethoxazole, sulfadiazine, or sulfamethazole. Potential cross-reactivity to several nonantibiotic sulfonamides (including furosemide) was also investigated using controlled oral challenge testing of these agents. Every patient tolerated a subsequent oral challenge with furosemide.

Literature reviews limited by small numbers

Two literature reviews examined the small number of case series, case reports, and “other articles” and concluded little evidence supports the presence of cross-reactivity between sulfonamide antibiotics and non-sulfonamide antibiotics.^3,4 These reviews were limited by their search criteria and lack of explicit critical appraisal.

A literature review of Medline from 1966 to early 2004 revealed 21 case series, case reports, and “other articles” that evaluated the presence of cross-reactivity.³ When the authors of this literature reviewed drilled down to diuretics, they found 5 case reports for cross-reactivity to acetazolamide, 2 case reports for furosemide, 1 case series, and 2 case reports for indapamide (a thiazide diuretic). After reviewing the studies, the authors concluded that little evidence suggested a problem with cross-reactivity either with acetazolamide or furosemide and that there may be an association of cross-reactivity between sulfonamide antibiotics and indapamide. This study was limited by its small numbers and lack of explicit critical appraisal.

In another literature review—in which the main focus was cross-reactivity between sulfonamide antibiotics and celecoxib—the authors concluded that little evidence supported definitive cross-reactivity between sulfonamide antibiotics and diuretics.⁴ The limitations of this study were similar to those of the previous study.

Recommendations from others

The manufacturer insert for furosemide states, under the heading “General Precautions,” that “patients allergic to sulfonamides may also be allergic to furosemide.”⁵ A similar warning occurs for hydrochlorothiazide under the heading “Contraindications.”⁶

Evidence summary

“Early” diagnosis of renovascular hypertension is best defined as diagnosis while blood pressure is controlled by medications or when renal function remains normal.

Hypertension. A meta-analysis (3 RCTs, total n=210 patients) examining balloon angioplasty for RAS and poorly controlled hypertension showed modest but significant effect on blood pressure control.¹ Comparing the angioplasty group with medical management, the mean reduction in blood pressure was –7 mm Hg systolic (95% confidence interval [CI], –12 to –1) and –3 mm Hg diastolic (95% CI, –6 to –1). Patients treated with balloon angioplasty were more likely to use fewer antihypertensive medications (unable to synthesize data for quantity) and to have fewer major cardiovascular and renovascular complications (not defined specifically) (odds ratio [OR]=0.27; 95% CI, 0.06–1.23; P=.09).¹ One cohort study of 150 patients found that stenting bilateral (vs unilateral) RAS predicted a more beneficial blood pressure response (OR=4.6; P=.009).²

Renal impairment. The value of RAS intervention for patients with hypertension and worsening renal function is unclear. One RCT of 106 patients with atherosclerotic RAS and serum creatinine (Cr) of <2.3 mg/dL compared PTRA with medical therapy of hypertension. By an intentionto-treat analysis, there was no significant difference in renal function at 12 months between the groups.³ A nonblinded RCT of 85 patients found no change in mortality or renal function with intervention. Three groups were compared: observation of 52 patients with unilateral RAS (>50%), intervention on 12 patients with bilateral RAS, and observation of 21 patients with bilateral RAS. All groups reported 32% mortality at 2 years. Only 3 of the 27 deaths were directly related to renal disease (2 from the observation group with unilateral RAS and one from the intervention group).⁴ Cohor studies, using different measures of renal function, report improvement, stabilization, or worsening following intervention.^5-7

Congestive heart failure and flash pulmonary edema. Patients who have recurrent episodes of congestive heart failure or flash pulmonary edema with severe RAS have marked functional improvement following PTRA with stenting. One retrospective cohort study (n=39) reported a decrease in hospitalizations (from 2.4 ±1.4 per year to 0.3 ±0.7 per year; P<.001) and improvement in New York Heart Association heart failure functional classification (2.9 ±0.9 to 1.6 ±0.9).⁸

Diagnosis. MRA (sensitivity 99%, specificity 93%) and CT angiography (sensitivity 97%, specificity 95%) are the most accurate and cost-effective, based on a large meta-analysis.⁹

Complications. Serious or potentially serious complications (ie, bleeding, renal artery injury, need for hemodialysis) were seen in 13% to 25% of patients who underwent angioplasty.^2,5,7 Combining 3 studies (n=632), there were 5 procedurerelated deaths.^5,7,10

Worsened patient survival correlated with Cr >1.7 mg/dL or age >70 (OR=9.96, P<.0001 and OR=3.4, P=.001, respectively). Worsened renal survival was present in the same subgroups (OR=7.8, P<.001 and OR=2.7, P<.01, respectively).⁷

Recommendations from others

The American Heart Association lists 3 clinical criteria for revascularization: 1) hypertension (accelerated, refractory, or malignant), 2) renal salvage, 3) cardiac disturbance syndromes (recurrent “flash” pulmonary edema or unstable angina with significant RAS).¹¹ JNC 7 does not recommend looking for RAS unless hypertension is uncontrollable.¹²

The Society of Nuclear Medicine recommends that only moderate- to high-risk individuals be screened for RAS. This guideline clarifies that RAS does not equal renovascular hypertension and that the future “gold standard” diagnosis of renovascular hypertension should be the response to successful revascularization.¹³

Evidence summary

“Early” diagnosis of renovascular hypertension is best defined as diagnosis while blood pressure is controlled by medications or when renal function remains normal.

Hypertension. A meta-analysis (3 RCTs, total n=210 patients) examining balloon angioplasty for RAS and poorly controlled hypertension showed modest but significant effect on blood pressure control.¹ Comparing the angioplasty group with medical management, the mean reduction in blood pressure was –7 mm Hg systolic (95% confidence interval [CI], –12 to –1) and –3 mm Hg diastolic (95% CI, –6 to –1). Patients treated with balloon angioplasty were more likely to use fewer antihypertensive medications (unable to synthesize data for quantity) and to have fewer major cardiovascular and renovascular complications (not defined specifically) (odds ratio [OR]=0.27; 95% CI, 0.06–1.23; P=.09).¹ One cohort study of 150 patients found that stenting bilateral (vs unilateral) RAS predicted a more beneficial blood pressure response (OR=4.6; P=.009).²

Renal impairment. The value of RAS intervention for patients with hypertension and worsening renal function is unclear. One RCT of 106 patients with atherosclerotic RAS and serum creatinine (Cr) of <2.3 mg/dL compared PTRA with medical therapy of hypertension. By an intentionto-treat analysis, there was no significant difference in renal function at 12 months between the groups.³ A nonblinded RCT of 85 patients found no change in mortality or renal function with intervention. Three groups were compared: observation of 52 patients with unilateral RAS (>50%), intervention on 12 patients with bilateral RAS, and observation of 21 patients with bilateral RAS. All groups reported 32% mortality at 2 years. Only 3 of the 27 deaths were directly related to renal disease (2 from the observation group with unilateral RAS and one from the intervention group).⁴ Cohor studies, using different measures of renal function, report improvement, stabilization, or worsening following intervention.^5-7

Congestive heart failure and flash pulmonary edema. Patients who have recurrent episodes of congestive heart failure or flash pulmonary edema with severe RAS have marked functional improvement following PTRA with stenting. One retrospective cohort study (n=39) reported a decrease in hospitalizations (from 2.4 ±1.4 per year to 0.3 ±0.7 per year; P<.001) and improvement in New York Heart Association heart failure functional classification (2.9 ±0.9 to 1.6 ±0.9).⁸

Diagnosis. MRA (sensitivity 99%, specificity 93%) and CT angiography (sensitivity 97%, specificity 95%) are the most accurate and cost-effective, based on a large meta-analysis.⁹

Complications. Serious or potentially serious complications (ie, bleeding, renal artery injury, need for hemodialysis) were seen in 13% to 25% of patients who underwent angioplasty.^2,5,7 Combining 3 studies (n=632), there were 5 procedurerelated deaths.^5,7,10

Worsened patient survival correlated with Cr >1.7 mg/dL or age >70 (OR=9.96, P<.0001 and OR=3.4, P=.001, respectively). Worsened renal survival was present in the same subgroups (OR=7.8, P<.001 and OR=2.7, P<.01, respectively).⁷

Recommendations from others

The American Heart Association lists 3 clinical criteria for revascularization: 1) hypertension (accelerated, refractory, or malignant), 2) renal salvage, 3) cardiac disturbance syndromes (recurrent “flash” pulmonary edema or unstable angina with significant RAS).¹¹ JNC 7 does not recommend looking for RAS unless hypertension is uncontrollable.¹²

The Society of Nuclear Medicine recommends that only moderate- to high-risk individuals be screened for RAS. This guideline clarifies that RAS does not equal renovascular hypertension and that the future “gold standard” diagnosis of renovascular hypertension should be the response to successful revascularization.¹³

Evidence summary

“Early” diagnosis of renovascular hypertension is best defined as diagnosis while blood pressure is controlled by medications or when renal function remains normal.

Hypertension. A meta-analysis (3 RCTs, total n=210 patients) examining balloon angioplasty for RAS and poorly controlled hypertension showed modest but significant effect on blood pressure control.¹ Comparing the angioplasty group with medical management, the mean reduction in blood pressure was –7 mm Hg systolic (95% confidence interval [CI], –12 to –1) and –3 mm Hg diastolic (95% CI, –6 to –1). Patients treated with balloon angioplasty were more likely to use fewer antihypertensive medications (unable to synthesize data for quantity) and to have fewer major cardiovascular and renovascular complications (not defined specifically) (odds ratio [OR]=0.27; 95% CI, 0.06–1.23; P=.09).¹ One cohort study of 150 patients found that stenting bilateral (vs unilateral) RAS predicted a more beneficial blood pressure response (OR=4.6; P=.009).²

Renal impairment. The value of RAS intervention for patients with hypertension and worsening renal function is unclear. One RCT of 106 patients with atherosclerotic RAS and serum creatinine (Cr) of <2.3 mg/dL compared PTRA with medical therapy of hypertension. By an intentionto-treat analysis, there was no significant difference in renal function at 12 months between the groups.³ A nonblinded RCT of 85 patients found no change in mortality or renal function with intervention. Three groups were compared: observation of 52 patients with unilateral RAS (>50%), intervention on 12 patients with bilateral RAS, and observation of 21 patients with bilateral RAS. All groups reported 32% mortality at 2 years. Only 3 of the 27 deaths were directly related to renal disease (2 from the observation group with unilateral RAS and one from the intervention group).⁴ Cohor studies, using different measures of renal function, report improvement, stabilization, or worsening following intervention.^5-7

Congestive heart failure and flash pulmonary edema. Patients who have recurrent episodes of congestive heart failure or flash pulmonary edema with severe RAS have marked functional improvement following PTRA with stenting. One retrospective cohort study (n=39) reported a decrease in hospitalizations (from 2.4 ±1.4 per year to 0.3 ±0.7 per year; P<.001) and improvement in New York Heart Association heart failure functional classification (2.9 ±0.9 to 1.6 ±0.9).⁸

Diagnosis. MRA (sensitivity 99%, specificity 93%) and CT angiography (sensitivity 97%, specificity 95%) are the most accurate and cost-effective, based on a large meta-analysis.⁹

Complications. Serious or potentially serious complications (ie, bleeding, renal artery injury, need for hemodialysis) were seen in 13% to 25% of patients who underwent angioplasty.^2,5,7 Combining 3 studies (n=632), there were 5 procedurerelated deaths.^5,7,10

Worsened patient survival correlated with Cr >1.7 mg/dL or age >70 (OR=9.96, P<.0001 and OR=3.4, P=.001, respectively). Worsened renal survival was present in the same subgroups (OR=7.8, P<.001 and OR=2.7, P<.01, respectively).⁷

Recommendations from others

The American Heart Association lists 3 clinical criteria for revascularization: 1) hypertension (accelerated, refractory, or malignant), 2) renal salvage, 3) cardiac disturbance syndromes (recurrent “flash” pulmonary edema or unstable angina with significant RAS).¹¹ JNC 7 does not recommend looking for RAS unless hypertension is uncontrollable.¹²

The Society of Nuclear Medicine recommends that only moderate- to high-risk individuals be screened for RAS. This guideline clarifies that RAS does not equal renovascular hypertension and that the future “gold standard” diagnosis of renovascular hypertension should be the response to successful revascularization.¹³

Evidence summary

There are currently no large outcome studies evaluating the initial work-up of hypertension; however, 4 international expert panels have published recommendations.^2-5 These panels advise 3 initial objectives: 1) assess lifestyle and identify other cardiovascular risk factors or concomitant disorders that may affect prognosis and guide treatment; 2) search for treatable causes of high blood pressure; and 3) assess for the presence of target organ damage that would change the management of the patient (such as chronic kidney disease or heart disease).

In addition to a thorough history and physical, the following studies are recommended for patients with newly diagnosed hypertension:

Serum potassium and creatinine. All 4 panels recommend measuring serum potassium and creatinine in order to: 1) monitor the effects of diuretics and angiotensin-converting enzyme (ACE) inhibitors used in hypertension therapy, 2) screen for unexplained hypokalemia that may indicate a low-renin form of hypertension, 3) calculate baseline creatinine clearance, and 4) screen for chronic kidney disease.

Fasting blood glucose. All 4 panels recommend measuring a fasting glucose level to screen for diabetes. An abnormal glucose level may also reveal glucose intolerance, one of the diagnostic criteria of metabolic syndrome. Up to 60% of patients with diabetes also have hypertension.⁶

Fasting lipid panel. All 4 expert panels recommend screening for dyslipidemia with a fasting lipid panel to assess cardiovascular risk. A cohort study evaluating 356,222 men aged 35 to 57 years found a continuous, positive, graded correlation between plasma cholesterol levels and coronary risk.⁷

Hematocrit. All 4 panels recommend a hematocrit to screen for anemia, which may be due to chronic kidney disease.

Urinalysis. All 4 panels recommend a urinalysis to screen for renal disease.

Electrocardiogram (ECG). All 4 panels recommend an ECG to screen for findings associated with hypertension, including left ventricular hypertrophy (LVH), myocardial infarction, and rhythm abnormalities. A cohort study followed 2363 patients for 14 years who had untreated hypertension and were without pre-existing cardiovascular disease. After controlling for age, sex, diabetes, and mean blood pressure, LVH by ECG conferred a significant increased risk for cerebrovascular events (relative risk=1.79; 95% confidence interval [CI], 1.17–2.76).⁸ However, in a cohort of 4684 subjects from the Framingham Heart Study, ECG had a sensitivity of only 6.9% for the detection of LVH (specificity 98.8%; positive likelihood ratio=5.3; negative likelihood ratio=0.94).⁸

Echocardiography. Two panels^3,4 and an online text¹⁰ recommend echocardiography, preferably limited echo, as an optional study. A systematic review of studies comparing the sensitivities and specificities of ECG and echo found that each was highly specific for the detection of LVH (77%–97%), but the sensitivity of echocardiography (88%–93%) exceeded that of ECG (21%–54%). However, LVH detected by ECG is a better predictor of cardiovascular complications.¹¹ Because echocardiography may help assess disease duration and guide management, both panels recommend it for patients with severe or refractory hypertension but without other target organ damage.

Microalbuminuria. All panels listed microalbuminuria testing as an optional study for patients without diabetes because of its association with an increased incidence of cerebrovascular disease.¹² It is unclear whether microalbuminuria results from the increased intraglomerular pressure in hypertension or if it represents glomerular damage.¹³

Sodium, calcium, uric acid. There is no consensus on the routine inclusion of several studies: serum sodium (recommended by 2 panels and an online text^4,5,10 ), serum calcium (recommended by 1 panel and the text^2,10), and uric acid (1 panel³ recommends it while the text¹⁰ lists it as optional).

Recommendations from others

Recommendations from major organizations are included in Evidence Summary, above.

Acknowledgments

The opinions and assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.

Evidence summary

There are currently no large outcome studies evaluating the initial work-up of hypertension; however, 4 international expert panels have published recommendations.^2-5 These panels advise 3 initial objectives: 1) assess lifestyle and identify other cardiovascular risk factors or concomitant disorders that may affect prognosis and guide treatment; 2) search for treatable causes of high blood pressure; and 3) assess for the presence of target organ damage that would change the management of the patient (such as chronic kidney disease or heart disease).

In addition to a thorough history and physical, the following studies are recommended for patients with newly diagnosed hypertension:

Serum potassium and creatinine. All 4 panels recommend measuring serum potassium and creatinine in order to: 1) monitor the effects of diuretics and angiotensin-converting enzyme (ACE) inhibitors used in hypertension therapy, 2) screen for unexplained hypokalemia that may indicate a low-renin form of hypertension, 3) calculate baseline creatinine clearance, and 4) screen for chronic kidney disease.

Fasting blood glucose. All 4 panels recommend measuring a fasting glucose level to screen for diabetes. An abnormal glucose level may also reveal glucose intolerance, one of the diagnostic criteria of metabolic syndrome. Up to 60% of patients with diabetes also have hypertension.⁶

Fasting lipid panel. All 4 expert panels recommend screening for dyslipidemia with a fasting lipid panel to assess cardiovascular risk. A cohort study evaluating 356,222 men aged 35 to 57 years found a continuous, positive, graded correlation between plasma cholesterol levels and coronary risk.⁷

Hematocrit. All 4 panels recommend a hematocrit to screen for anemia, which may be due to chronic kidney disease.

Urinalysis. All 4 panels recommend a urinalysis to screen for renal disease.

Electrocardiogram (ECG). All 4 panels recommend an ECG to screen for findings associated with hypertension, including left ventricular hypertrophy (LVH), myocardial infarction, and rhythm abnormalities. A cohort study followed 2363 patients for 14 years who had untreated hypertension and were without pre-existing cardiovascular disease. After controlling for age, sex, diabetes, and mean blood pressure, LVH by ECG conferred a significant increased risk for cerebrovascular events (relative risk=1.79; 95% confidence interval [CI], 1.17–2.76).⁸ However, in a cohort of 4684 subjects from the Framingham Heart Study, ECG had a sensitivity of only 6.9% for the detection of LVH (specificity 98.8%; positive likelihood ratio=5.3; negative likelihood ratio=0.94).⁸

Echocardiography. Two panels^3,4 and an online text¹⁰ recommend echocardiography, preferably limited echo, as an optional study. A systematic review of studies comparing the sensitivities and specificities of ECG and echo found that each was highly specific for the detection of LVH (77%–97%), but the sensitivity of echocardiography (88%–93%) exceeded that of ECG (21%–54%). However, LVH detected by ECG is a better predictor of cardiovascular complications.¹¹ Because echocardiography may help assess disease duration and guide management, both panels recommend it for patients with severe or refractory hypertension but without other target organ damage.

Microalbuminuria. All panels listed microalbuminuria testing as an optional study for patients without diabetes because of its association with an increased incidence of cerebrovascular disease.¹² It is unclear whether microalbuminuria results from the increased intraglomerular pressure in hypertension or if it represents glomerular damage.¹³

Sodium, calcium, uric acid. There is no consensus on the routine inclusion of several studies: serum sodium (recommended by 2 panels and an online text^4,5,10 ), serum calcium (recommended by 1 panel and the text^2,10), and uric acid (1 panel³ recommends it while the text¹⁰ lists it as optional).

Recommendations from others

Recommendations from major organizations are included in Evidence Summary, above.

Acknowledgments

The opinions and assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.

Evidence summary

There are currently no large outcome studies evaluating the initial work-up of hypertension; however, 4 international expert panels have published recommendations.^2-5 These panels advise 3 initial objectives: 1) assess lifestyle and identify other cardiovascular risk factors or concomitant disorders that may affect prognosis and guide treatment; 2) search for treatable causes of high blood pressure; and 3) assess for the presence of target organ damage that would change the management of the patient (such as chronic kidney disease or heart disease).

In addition to a thorough history and physical, the following studies are recommended for patients with newly diagnosed hypertension:

Serum potassium and creatinine. All 4 panels recommend measuring serum potassium and creatinine in order to: 1) monitor the effects of diuretics and angiotensin-converting enzyme (ACE) inhibitors used in hypertension therapy, 2) screen for unexplained hypokalemia that may indicate a low-renin form of hypertension, 3) calculate baseline creatinine clearance, and 4) screen for chronic kidney disease.

Fasting blood glucose. All 4 panels recommend measuring a fasting glucose level to screen for diabetes. An abnormal glucose level may also reveal glucose intolerance, one of the diagnostic criteria of metabolic syndrome. Up to 60% of patients with diabetes also have hypertension.⁶

Fasting lipid panel. All 4 expert panels recommend screening for dyslipidemia with a fasting lipid panel to assess cardiovascular risk. A cohort study evaluating 356,222 men aged 35 to 57 years found a continuous, positive, graded correlation between plasma cholesterol levels and coronary risk.⁷

Hematocrit. All 4 panels recommend a hematocrit to screen for anemia, which may be due to chronic kidney disease.

Urinalysis. All 4 panels recommend a urinalysis to screen for renal disease.

Electrocardiogram (ECG). All 4 panels recommend an ECG to screen for findings associated with hypertension, including left ventricular hypertrophy (LVH), myocardial infarction, and rhythm abnormalities. A cohort study followed 2363 patients for 14 years who had untreated hypertension and were without pre-existing cardiovascular disease. After controlling for age, sex, diabetes, and mean blood pressure, LVH by ECG conferred a significant increased risk for cerebrovascular events (relative risk=1.79; 95% confidence interval [CI], 1.17–2.76).⁸ However, in a cohort of 4684 subjects from the Framingham Heart Study, ECG had a sensitivity of only 6.9% for the detection of LVH (specificity 98.8%; positive likelihood ratio=5.3; negative likelihood ratio=0.94).⁸

Echocardiography. Two panels^3,4 and an online text¹⁰ recommend echocardiography, preferably limited echo, as an optional study. A systematic review of studies comparing the sensitivities and specificities of ECG and echo found that each was highly specific for the detection of LVH (77%–97%), but the sensitivity of echocardiography (88%–93%) exceeded that of ECG (21%–54%). However, LVH detected by ECG is a better predictor of cardiovascular complications.¹¹ Because echocardiography may help assess disease duration and guide management, both panels recommend it for patients with severe or refractory hypertension but without other target organ damage.

Microalbuminuria. All panels listed microalbuminuria testing as an optional study for patients without diabetes because of its association with an increased incidence of cerebrovascular disease.¹² It is unclear whether microalbuminuria results from the increased intraglomerular pressure in hypertension or if it represents glomerular damage.¹³

Sodium, calcium, uric acid. There is no consensus on the routine inclusion of several studies: serum sodium (recommended by 2 panels and an online text^4,5,10 ), serum calcium (recommended by 1 panel and the text^2,10), and uric acid (1 panel³ recommends it while the text¹⁰ lists it as optional).

Recommendations from others

Recommendations from major organizations are included in Evidence Summary, above.

Acknowledgments

The opinions and assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.

Evidence summary

Five recent RCTs have demonstrated similar mortality and cardiovascular morbidity in atrial fibrillation patients treated with either a rate-control or rhythm-control strategy.^1-5

The AFFIRM trial, the largest (n=4060), was a nonblinded, randomized, multicenter study with an average follow-up of 3.5 years.¹ The patients were aged 65 years or older and had at least 1 other risk factor for stroke. The rhythm-control group was given an antiarrhythmic medication chosen by the treating physician, while the rate-control group was given either a beta-blocker, a calcium-channel blocker, digoxin, or a combination of these as needed. Heart-rate goals were a resting pulse under 80 beats per minute, and a pulse after a 6-minute walk under 110 beats per minute. An intention-totreat analysis was followed.

There was no difference between the 2 groups for the composite endpoints of death, disabling stroke, disabling anoxic encephalopathy, major bleeding, or cardiac arrest. A nonsignificant trend was observed for mortality favoring the rate-control group (relative risk [RR]=1.15; 95% confidence interval [CI], 0.99–1.34). Quality-of-life measures were equivalent in the 2 groups at all points in the study.¹

More patients in the rhythm-control group required hospitalization (number needed to harm [NNH]=12.3; P<.001) and had adverse drug effects (P.001 for each of pulmonary events [NNH=18], gastrointestinal events [NNH=17], bradycardia [NNH=56], and prolonged QT [NNH=63]). This trial did not include younger patients without stroke risk factors, or those with paroxysmal atrial fibrillation.¹

The 4 other RCTs also found no greater benefit with a rhythm-control strategy vs rate-control for most patients with atrial fibrillation.^2-5

Two systematic reviews have looked at the efficacy of medications for ventricular rate control in atrial fibrillation.^6,7 The first analyzed 54 trials involving 17 agents and focused on digoxin calcium-channel blockers and beta-blockers. The second systematic review evaluated 45 trials with similar agents. Both reviews were unable to perform mathematical pooling due to the heterogeneity of the studies. However, both showed strong evidence for superior ventricular rate control at both exercise and rest with verapamil and diltiazem compared with placebo.^6,7

All beta-blockers tested were effective in rate-control during exercise and most (excluding labetalol and celiprolol) were effective at rest.^6,7 Digoxin was ineffective during exercise and less effective than beta-blockers or calcium-channel blockers at rest.^6-8 The combination of digoxin plus a calcium-channel blocker or beta-blocker may have increased benefit compared with either drug alone.⁶ Evidence was insufficient to recommend propafenone, clonidine, or amiodarone for rate control.⁷

In select patients, a rhythm-control approach may be desirable. A meta-analysis of 60 RCTs evaluated 8 drugs for acute cardioversion. Ibutilide, flecainide, dofetilide, propafenone, and amiodarone were found to have the strongest evidence of efficacy.⁶ There was moderate evidence for quinidine and insufficient evidence for disopyramide and sotalol.⁶ Studies of pharmacologic conversion suffer from small ample size, short follow-up, and variable duration of atrial fibrillation.⁶ A review of limited research reveals an 80% to 85% immediate success rate for DC cardioversion, with rare side-effects of ventricular tachycardia, transient AV node dysfunction, and significant skin blistering.⁶

For patients who elect a rhythm-control approach, RCTs demonstrate the need for continued long-term anticoagulation in high-risk patients even if they are maintained in sinus rhythm.^1,4,5 (High-risk patients are defined as those aged >65 years, or those <65 years with 1 or more stroke risk factors: diabetes, hypertension, heart failure, prior transient ischemic attack or stroke or systemic embolism, or echocardiographic evidence of a left atrium >50 mm, a shortening fraction <25%, or an ejection fraction <40%.)

Recommendation from others

The American Academy of Family Practice/American College of Physicians’ clinical guidelines support a rate-control strategy for most patients with atrial fibrillation and recommend atenolol, metoprolol, diltiazem, or verapamil as the first-choice drugs.⁸ Digoxin is recommended as a second-line agent. DC cardioversion and pharmacologic conversion for patients who desire a rhythm-control strategy are described as “appropriate options.”⁸

Evidence summary

Five recent RCTs have demonstrated similar mortality and cardiovascular morbidity in atrial fibrillation patients treated with either a rate-control or rhythm-control strategy.^1-5

The AFFIRM trial, the largest (n=4060), was a nonblinded, randomized, multicenter study with an average follow-up of 3.5 years.¹ The patients were aged 65 years or older and had at least 1 other risk factor for stroke. The rhythm-control group was given an antiarrhythmic medication chosen by the treating physician, while the rate-control group was given either a beta-blocker, a calcium-channel blocker, digoxin, or a combination of these as needed. Heart-rate goals were a resting pulse under 80 beats per minute, and a pulse after a 6-minute walk under 110 beats per minute. An intention-totreat analysis was followed.

There was no difference between the 2 groups for the composite endpoints of death, disabling stroke, disabling anoxic encephalopathy, major bleeding, or cardiac arrest. A nonsignificant trend was observed for mortality favoring the rate-control group (relative risk [RR]=1.15; 95% confidence interval [CI], 0.99–1.34). Quality-of-life measures were equivalent in the 2 groups at all points in the study.¹

More patients in the rhythm-control group required hospitalization (number needed to harm [NNH]=12.3; P<.001) and had adverse drug effects (P.001 for each of pulmonary events [NNH=18], gastrointestinal events [NNH=17], bradycardia [NNH=56], and prolonged QT [NNH=63]). This trial did not include younger patients without stroke risk factors, or those with paroxysmal atrial fibrillation.¹

The 4 other RCTs also found no greater benefit with a rhythm-control strategy vs rate-control for most patients with atrial fibrillation.^2-5

Two systematic reviews have looked at the efficacy of medications for ventricular rate control in atrial fibrillation.^6,7 The first analyzed 54 trials involving 17 agents and focused on digoxin calcium-channel blockers and beta-blockers. The second systematic review evaluated 45 trials with similar agents. Both reviews were unable to perform mathematical pooling due to the heterogeneity of the studies. However, both showed strong evidence for superior ventricular rate control at both exercise and rest with verapamil and diltiazem compared with placebo.^6,7

All beta-blockers tested were effective in rate-control during exercise and most (excluding labetalol and celiprolol) were effective at rest.^6,7 Digoxin was ineffective during exercise and less effective than beta-blockers or calcium-channel blockers at rest.^6-8 The combination of digoxin plus a calcium-channel blocker or beta-blocker may have increased benefit compared with either drug alone.⁶ Evidence was insufficient to recommend propafenone, clonidine, or amiodarone for rate control.⁷

In select patients, a rhythm-control approach may be desirable. A meta-analysis of 60 RCTs evaluated 8 drugs for acute cardioversion. Ibutilide, flecainide, dofetilide, propafenone, and amiodarone were found to have the strongest evidence of efficacy.⁶ There was moderate evidence for quinidine and insufficient evidence for disopyramide and sotalol.⁶ Studies of pharmacologic conversion suffer from small ample size, short follow-up, and variable duration of atrial fibrillation.⁶ A review of limited research reveals an 80% to 85% immediate success rate for DC cardioversion, with rare side-effects of ventricular tachycardia, transient AV node dysfunction, and significant skin blistering.⁶

For patients who elect a rhythm-control approach, RCTs demonstrate the need for continued long-term anticoagulation in high-risk patients even if they are maintained in sinus rhythm.^1,4,5 (High-risk patients are defined as those aged >65 years, or those <65 years with 1 or more stroke risk factors: diabetes, hypertension, heart failure, prior transient ischemic attack or stroke or systemic embolism, or echocardiographic evidence of a left atrium >50 mm, a shortening fraction <25%, or an ejection fraction <40%.)

Recommendation from others

The American Academy of Family Practice/American College of Physicians’ clinical guidelines support a rate-control strategy for most patients with atrial fibrillation and recommend atenolol, metoprolol, diltiazem, or verapamil as the first-choice drugs.⁸ Digoxin is recommended as a second-line agent. DC cardioversion and pharmacologic conversion for patients who desire a rhythm-control strategy are described as “appropriate options.”⁸

Evidence summary

Five recent RCTs have demonstrated similar mortality and cardiovascular morbidity in atrial fibrillation patients treated with either a rate-control or rhythm-control strategy.^1-5

The AFFIRM trial, the largest (n=4060), was a nonblinded, randomized, multicenter study with an average follow-up of 3.5 years.¹ The patients were aged 65 years or older and had at least 1 other risk factor for stroke. The rhythm-control group was given an antiarrhythmic medication chosen by the treating physician, while the rate-control group was given either a beta-blocker, a calcium-channel blocker, digoxin, or a combination of these as needed. Heart-rate goals were a resting pulse under 80 beats per minute, and a pulse after a 6-minute walk under 110 beats per minute. An intention-totreat analysis was followed.

There was no difference between the 2 groups for the composite endpoints of death, disabling stroke, disabling anoxic encephalopathy, major bleeding, or cardiac arrest. A nonsignificant trend was observed for mortality favoring the rate-control group (relative risk [RR]=1.15; 95% confidence interval [CI], 0.99–1.34). Quality-of-life measures were equivalent in the 2 groups at all points in the study.¹

More patients in the rhythm-control group required hospitalization (number needed to harm [NNH]=12.3; P<.001) and had adverse drug effects (P.001 for each of pulmonary events [NNH=18], gastrointestinal events [NNH=17], bradycardia [NNH=56], and prolonged QT [NNH=63]). This trial did not include younger patients without stroke risk factors, or those with paroxysmal atrial fibrillation.¹

The 4 other RCTs also found no greater benefit with a rhythm-control strategy vs rate-control for most patients with atrial fibrillation.^2-5

Two systematic reviews have looked at the efficacy of medications for ventricular rate control in atrial fibrillation.^6,7 The first analyzed 54 trials involving 17 agents and focused on digoxin calcium-channel blockers and beta-blockers. The second systematic review evaluated 45 trials with similar agents. Both reviews were unable to perform mathematical pooling due to the heterogeneity of the studies. However, both showed strong evidence for superior ventricular rate control at both exercise and rest with verapamil and diltiazem compared with placebo.^6,7

All beta-blockers tested were effective in rate-control during exercise and most (excluding labetalol and celiprolol) were effective at rest.^6,7 Digoxin was ineffective during exercise and less effective than beta-blockers or calcium-channel blockers at rest.^6-8 The combination of digoxin plus a calcium-channel blocker or beta-blocker may have increased benefit compared with either drug alone.⁶ Evidence was insufficient to recommend propafenone, clonidine, or amiodarone for rate control.⁷

In select patients, a rhythm-control approach may be desirable. A meta-analysis of 60 RCTs evaluated 8 drugs for acute cardioversion. Ibutilide, flecainide, dofetilide, propafenone, and amiodarone were found to have the strongest evidence of efficacy.⁶ There was moderate evidence for quinidine and insufficient evidence for disopyramide and sotalol.⁶ Studies of pharmacologic conversion suffer from small ample size, short follow-up, and variable duration of atrial fibrillation.⁶ A review of limited research reveals an 80% to 85% immediate success rate for DC cardioversion, with rare side-effects of ventricular tachycardia, transient AV node dysfunction, and significant skin blistering.⁶

For patients who elect a rhythm-control approach, RCTs demonstrate the need for continued long-term anticoagulation in high-risk patients even if they are maintained in sinus rhythm.^1,4,5 (High-risk patients are defined as those aged >65 years, or those <65 years with 1 or more stroke risk factors: diabetes, hypertension, heart failure, prior transient ischemic attack or stroke or systemic embolism, or echocardiographic evidence of a left atrium >50 mm, a shortening fraction <25%, or an ejection fraction <40%.)

Recommendation from others

The American Academy of Family Practice/American College of Physicians’ clinical guidelines support a rate-control strategy for most patients with atrial fibrillation and recommend atenolol, metoprolol, diltiazem, or verapamil as the first-choice drugs.⁸ Digoxin is recommended as a second-line agent. DC cardioversion and pharmacologic conversion for patients who desire a rhythm-control strategy are described as “appropriate options.”⁸