CLINICAL QUESTION: Can oseltamivir be used to prevent influenza infection?

BACKGROUND: Oseltamivir reduces the replication of influenza A and B by inhibiting influenza neuraminidase, an essential enzyme involved in the final packaging of new viral particles. Rimantadine and amantadine have been used for prophylaxis but are only effective against influenza A; adverse effects and cost limit their use. Oseltamivir is currently indicated to treat acute influenza infection if given within the first 2 days of symptoms. The present study evaluated oseltamivir for the prevention of influenza in healthy persons.

POPULATION STUDIED: The researchers studied 1562 healthy subjects with a mean age of 35 years (range = 18 to 65 years); 63% were women. Key exclusion criteria included having had an influenza vaccination in the previous year or an acute respiratory illness accompanied by a fever in the week before drug administration. Patients with any indication for influenza immunization according to 1998 Centers for Disease Control (CDC) and Prevention guidelines were also excluded.

STUDY DESIGN AND VALIDITY: Two identical randomized placebo-controlled double-blinded multicenter studies were conducted. Because of a low incidence of influenza infection (38/1559, 2.4%), the investigators combined the data before unblinding. Subjects were started on oseltamivir or placebo following an increase in influenzavirus activity at the clinical site. They received either oseltamivir 75 mg once daily, 75 mg twice daily, or placebo for 6 weeks. Return visits occurred at weeks 3, 6, and 8. Participants were instructed to return to the clinic for influenzalike symptoms. Nasal and pharyngeal swabs were collected for influenzavirus culture when patients presented with illness. Influenza antibody testing was done at baseline and 8 weeks.

OUTCOMES MEASURED: The primary end point was laboratory-confirmed influenzalike illness during the 6-week period of drug administration. Influenzalike illness was defined as an oral temperature of Ž37.2°C, with at least one respiratory symptom (cough, sore throat, or nasal congestion) and at least one constitutional symptom (aches, fatigue, headache, or chills or sweats). Laboratory confirmation was defined as culture of influenzavirus or 4-fold increase in antibody titer.

RESULTS: The rates of laboratory-confirmed clinical influenza were significantly lower in the oseltamivir once-daily (6/520, 1.2%) and twice-daily (7/520, 1.3%) groups than in the placebo group (25/519, 4.8%). These differences were statistically significant (P <.001 and P = .001, respectively). The relative risk reduction for influenza of once and twice daily dosing were 76% (95% confidence interval [CI], 46-91) and 72% (95% CI, 40-89), respectively. The number needed to treat (NNT) to prevent one case of influenza is 29. Drop-out rates were low and did not differ between the groups (3.1% to 4.0%), suggesting that the medication was well tolerated. Compliance between the groups did not differ.

CLINICAL QUESTION: Can oseltamivir be used to prevent influenza infection?

BACKGROUND: Oseltamivir reduces the replication of influenza A and B by inhibiting influenza neuraminidase, an essential enzyme involved in the final packaging of new viral particles. Rimantadine and amantadine have been used for prophylaxis but are only effective against influenza A; adverse effects and cost limit their use. Oseltamivir is currently indicated to treat acute influenza infection if given within the first 2 days of symptoms. The present study evaluated oseltamivir for the prevention of influenza in healthy persons.

POPULATION STUDIED: The researchers studied 1562 healthy subjects with a mean age of 35 years (range = 18 to 65 years); 63% were women. Key exclusion criteria included having had an influenza vaccination in the previous year or an acute respiratory illness accompanied by a fever in the week before drug administration. Patients with any indication for influenza immunization according to 1998 Centers for Disease Control (CDC) and Prevention guidelines were also excluded.

STUDY DESIGN AND VALIDITY: Two identical randomized placebo-controlled double-blinded multicenter studies were conducted. Because of a low incidence of influenza infection (38/1559, 2.4%), the investigators combined the data before unblinding. Subjects were started on oseltamivir or placebo following an increase in influenzavirus activity at the clinical site. They received either oseltamivir 75 mg once daily, 75 mg twice daily, or placebo for 6 weeks. Return visits occurred at weeks 3, 6, and 8. Participants were instructed to return to the clinic for influenzalike symptoms. Nasal and pharyngeal swabs were collected for influenzavirus culture when patients presented with illness. Influenza antibody testing was done at baseline and 8 weeks.

OUTCOMES MEASURED: The primary end point was laboratory-confirmed influenzalike illness during the 6-week period of drug administration. Influenzalike illness was defined as an oral temperature of Ž37.2°C, with at least one respiratory symptom (cough, sore throat, or nasal congestion) and at least one constitutional symptom (aches, fatigue, headache, or chills or sweats). Laboratory confirmation was defined as culture of influenzavirus or 4-fold increase in antibody titer.

RESULTS: The rates of laboratory-confirmed clinical influenza were significantly lower in the oseltamivir once-daily (6/520, 1.2%) and twice-daily (7/520, 1.3%) groups than in the placebo group (25/519, 4.8%). These differences were statistically significant (P <.001 and P = .001, respectively). The relative risk reduction for influenza of once and twice daily dosing were 76% (95% confidence interval [CI], 46-91) and 72% (95% CI, 40-89), respectively. The number needed to treat (NNT) to prevent one case of influenza is 29. Drop-out rates were low and did not differ between the groups (3.1% to 4.0%), suggesting that the medication was well tolerated. Compliance between the groups did not differ.

CLINICAL QUESTION: Can oseltamivir be used to prevent influenza infection?

BACKGROUND: Oseltamivir reduces the replication of influenza A and B by inhibiting influenza neuraminidase, an essential enzyme involved in the final packaging of new viral particles. Rimantadine and amantadine have been used for prophylaxis but are only effective against influenza A; adverse effects and cost limit their use. Oseltamivir is currently indicated to treat acute influenza infection if given within the first 2 days of symptoms. The present study evaluated oseltamivir for the prevention of influenza in healthy persons.

POPULATION STUDIED: The researchers studied 1562 healthy subjects with a mean age of 35 years (range = 18 to 65 years); 63% were women. Key exclusion criteria included having had an influenza vaccination in the previous year or an acute respiratory illness accompanied by a fever in the week before drug administration. Patients with any indication for influenza immunization according to 1998 Centers for Disease Control (CDC) and Prevention guidelines were also excluded.

STUDY DESIGN AND VALIDITY: Two identical randomized placebo-controlled double-blinded multicenter studies were conducted. Because of a low incidence of influenza infection (38/1559, 2.4%), the investigators combined the data before unblinding. Subjects were started on oseltamivir or placebo following an increase in influenzavirus activity at the clinical site. They received either oseltamivir 75 mg once daily, 75 mg twice daily, or placebo for 6 weeks. Return visits occurred at weeks 3, 6, and 8. Participants were instructed to return to the clinic for influenzalike symptoms. Nasal and pharyngeal swabs were collected for influenzavirus culture when patients presented with illness. Influenza antibody testing was done at baseline and 8 weeks.

OUTCOMES MEASURED: The primary end point was laboratory-confirmed influenzalike illness during the 6-week period of drug administration. Influenzalike illness was defined as an oral temperature of Ž37.2°C, with at least one respiratory symptom (cough, sore throat, or nasal congestion) and at least one constitutional symptom (aches, fatigue, headache, or chills or sweats). Laboratory confirmation was defined as culture of influenzavirus or 4-fold increase in antibody titer.

RESULTS: The rates of laboratory-confirmed clinical influenza were significantly lower in the oseltamivir once-daily (6/520, 1.2%) and twice-daily (7/520, 1.3%) groups than in the placebo group (25/519, 4.8%). These differences were statistically significant (P <.001 and P = .001, respectively). The relative risk reduction for influenza of once and twice daily dosing were 76% (95% confidence interval [CI], 46-91) and 72% (95% CI, 40-89), respectively. The number needed to treat (NNT) to prevent one case of influenza is 29. Drop-out rates were low and did not differ between the groups (3.1% to 4.0%), suggesting that the medication was well tolerated. Compliance between the groups did not differ.

CLINICAL QUESTION: Is there a difference in efficacy between older and newer antihypertensive medications in preventing cardiovascular morbidity and mortality?

BACKGROUND: It is well known that b-blockers and diuretics decrease cardiovascular morbidity and mortality.¹ However, the efficacy of newer classes of antihypertensive drugs, such as angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists, has not been established.

POPULATION STUDIED: Subjects included 6628 hypertensive men and women aged 70 to 84 years from 312 health centers in Sweden. Hypertension was defined as a reading of >179 mm Hg systolic, >104 mm Hg diastolic, or both.

STUDY DESIGN AND VALIDITY: This was a prospective randomized trial. Patients were assigned treatment to 1 of 3 categories of medications: conventional antihypertensive drugs, ACE inhibitors, or calcium antagonists. Conventional drugs used were oral atenolol 50 mg, metoprolol 100 mg, pindolol 5 mg, or fixed-ratio hydrochlorothiazide 25 mg plus amiloride 2.5 mg, all given once daily. The ACE inhibitors were enalapril 10 mg or lisinopril 10 mg given once daily, and the calcium antagonists were felodipine 2.5 mg or isradipine 2.5 mg given once daily. If the target blood pressure of 160/95 mm Hg had not been reached by 2 months, combination therapy was instituted. Patients on b-blockers or ACE inhibitors were given a diuretic, while those on diuretics or calcium antagonists were given a b-blocker. After the initial dose-titration periods, patients were seen twice each year. At each visit heart rate and blood pressure were measured. Adverse events were evaluated from the patient’s history. Laboratory tests and electrocardiograms were done annually and on an as-needed basis.

OUTCOMES MEASURED: The primary end point was the rate of cardiovascular mortality. Secondary outcomes included the rates of fatal and nonfatal stroke, fatal and nonfatal myocardial infarction, atrial fibrillation, congestive heart failure, diabetes mellitus, and all-cause mortality. Subgroup analysis was performed on people with diabetes.

RESULTS: Most patients in this study had Stage 3 hypertension > 180 mm Hg systolic or 110 mm Hg diastolic). The rates of the primary and secondary end points were similar among the 3 treatment arms. The only difference was fewer fatal and nonfatal myocardial infarctions and less congestive heart failure among patients taking ACE inhibitors than those taking calcium antagonists. Although 46% of patients required more than one drug to control their hypertension, 61% to 66% of the patients in each group were on their original regimen at the end of the trial. Adverse events were common in all 3 groups: 25.5% of patients taking calcium antagonists had ankle edema, 30% on an ACE inhibitor had cough, and 25% to 28% in each group had dizziness.

CLINICAL QUESTION: Is there a difference in efficacy between older and newer antihypertensive medications in preventing cardiovascular morbidity and mortality?

BACKGROUND: It is well known that b-blockers and diuretics decrease cardiovascular morbidity and mortality.¹ However, the efficacy of newer classes of antihypertensive drugs, such as angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists, has not been established.

POPULATION STUDIED: Subjects included 6628 hypertensive men and women aged 70 to 84 years from 312 health centers in Sweden. Hypertension was defined as a reading of >179 mm Hg systolic, >104 mm Hg diastolic, or both.

STUDY DESIGN AND VALIDITY: This was a prospective randomized trial. Patients were assigned treatment to 1 of 3 categories of medications: conventional antihypertensive drugs, ACE inhibitors, or calcium antagonists. Conventional drugs used were oral atenolol 50 mg, metoprolol 100 mg, pindolol 5 mg, or fixed-ratio hydrochlorothiazide 25 mg plus amiloride 2.5 mg, all given once daily. The ACE inhibitors were enalapril 10 mg or lisinopril 10 mg given once daily, and the calcium antagonists were felodipine 2.5 mg or isradipine 2.5 mg given once daily. If the target blood pressure of 160/95 mm Hg had not been reached by 2 months, combination therapy was instituted. Patients on b-blockers or ACE inhibitors were given a diuretic, while those on diuretics or calcium antagonists were given a b-blocker. After the initial dose-titration periods, patients were seen twice each year. At each visit heart rate and blood pressure were measured. Adverse events were evaluated from the patient’s history. Laboratory tests and electrocardiograms were done annually and on an as-needed basis.

OUTCOMES MEASURED: The primary end point was the rate of cardiovascular mortality. Secondary outcomes included the rates of fatal and nonfatal stroke, fatal and nonfatal myocardial infarction, atrial fibrillation, congestive heart failure, diabetes mellitus, and all-cause mortality. Subgroup analysis was performed on people with diabetes.

RESULTS: Most patients in this study had Stage 3 hypertension > 180 mm Hg systolic or 110 mm Hg diastolic). The rates of the primary and secondary end points were similar among the 3 treatment arms. The only difference was fewer fatal and nonfatal myocardial infarctions and less congestive heart failure among patients taking ACE inhibitors than those taking calcium antagonists. Although 46% of patients required more than one drug to control their hypertension, 61% to 66% of the patients in each group were on their original regimen at the end of the trial. Adverse events were common in all 3 groups: 25.5% of patients taking calcium antagonists had ankle edema, 30% on an ACE inhibitor had cough, and 25% to 28% in each group had dizziness.

CLINICAL QUESTION: Is there a difference in efficacy between older and newer antihypertensive medications in preventing cardiovascular morbidity and mortality?

BACKGROUND: It is well known that b-blockers and diuretics decrease cardiovascular morbidity and mortality.¹ However, the efficacy of newer classes of antihypertensive drugs, such as angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists, has not been established.

POPULATION STUDIED: Subjects included 6628 hypertensive men and women aged 70 to 84 years from 312 health centers in Sweden. Hypertension was defined as a reading of >179 mm Hg systolic, >104 mm Hg diastolic, or both.

STUDY DESIGN AND VALIDITY: This was a prospective randomized trial. Patients were assigned treatment to 1 of 3 categories of medications: conventional antihypertensive drugs, ACE inhibitors, or calcium antagonists. Conventional drugs used were oral atenolol 50 mg, metoprolol 100 mg, pindolol 5 mg, or fixed-ratio hydrochlorothiazide 25 mg plus amiloride 2.5 mg, all given once daily. The ACE inhibitors were enalapril 10 mg or lisinopril 10 mg given once daily, and the calcium antagonists were felodipine 2.5 mg or isradipine 2.5 mg given once daily. If the target blood pressure of 160/95 mm Hg had not been reached by 2 months, combination therapy was instituted. Patients on b-blockers or ACE inhibitors were given a diuretic, while those on diuretics or calcium antagonists were given a b-blocker. After the initial dose-titration periods, patients were seen twice each year. At each visit heart rate and blood pressure were measured. Adverse events were evaluated from the patient’s history. Laboratory tests and electrocardiograms were done annually and on an as-needed basis.

OUTCOMES MEASURED: The primary end point was the rate of cardiovascular mortality. Secondary outcomes included the rates of fatal and nonfatal stroke, fatal and nonfatal myocardial infarction, atrial fibrillation, congestive heart failure, diabetes mellitus, and all-cause mortality. Subgroup analysis was performed on people with diabetes.

RESULTS: Most patients in this study had Stage 3 hypertension > 180 mm Hg systolic or 110 mm Hg diastolic). The rates of the primary and secondary end points were similar among the 3 treatment arms. The only difference was fewer fatal and nonfatal myocardial infarctions and less congestive heart failure among patients taking ACE inhibitors than those taking calcium antagonists. Although 46% of patients required more than one drug to control their hypertension, 61% to 66% of the patients in each group were on their original regimen at the end of the trial. Adverse events were common in all 3 groups: 25.5% of patients taking calcium antagonists had ankle edema, 30% on an ACE inhibitor had cough, and 25% to 28% in each group had dizziness.