Clinical Health Updates

Generic and brand-name drugs equally effective for cardiovascular disease

Clinical Question:
Are generic and brand-name drugs equally effective in the treatment of adults with cardiovascular disease?

Bottom Line:
In the management of adult cardiovascular disease, current evidence firmly demonstrates that generic equivalents are as clinically effective as their brand name counterparts, including beta-blockers, diuretics, calcium-channel blockers, antiplatelet agents, statins, angiotensin-converting enzyme (ACE) inhibitors, alpha-blockers, anti-arrhythmic agents, and warfarin. Interestingly, more than half the editorials published in various journals during the same period as this systematic review expressed negative opinions about the value of generic drugs. (LOE = 1a)

Reference:
Kesselheim AS, Misono AS, Lee JL, et al. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease. A systematic review and meta-analysis. JAMA 2008;300:2514-2526.

Study Design:
Systematic review

Funding:
Government

Setting:
Various (meta-analysis)

Summary:
Use of generic drugs, which are bioequivalent to brand-name drugs, can help contain prescription drug spending. However, there is concern among patients and physicians that brand-name drugs may be clinically superior to generic drugs. The authors summarized clinical evidence comparing generic and brand-name drugs used in cardiovascular disease and to assess the perspectives of editorialists on this issue. Systematic searches of peer-reviewed publications in MEDLINE, EMBASE, and International Pharmaceutical Abstracts from January 1984 to August 2008. Studies compared generic and brand-name cardiovascular drugs using clinical efficacy and safety end points. We separately identified editorials addressing generic substitution. They extracted variables related to the study design, setting, participants, clinical end points, and funding. Methodological quality of the trials was assessed by Jadad and Newcastle-Ottawa scores, and a meta-analysis was performed to determine an aggregate effect size. For editorials, we categorized authors’ positions on generic substitution as negative, positive, or neutral. They identified 47 articles covering 9 subclasses of cardiovascular medications, of which 38 (81%) were randomized controlled trials (RCTs). Clinical equivalence was noted in 7 of 7 RCTs (100%) of beta-blockers, 10 of 11 RCTs (91%) of diuretics, 5 of 7 RCTs (71%) of calcium channel blockers, 3 of 3 RCTs (100%) of antiplatelet agents, 2 of 2 RCTs (100%) of statins, 1 of 1 RCT (100%) of angiotensin-converting enzyme inhibitors, and 1 of 1 RCT (100%) of alpha-blockers. Among narrow therapeutic index drugs, clinical equivalence was reported in 1 of 1 RCT (100%) of class 1 antiarrhythmic agents and 5 of 5 RCTs (100%) of warfarin. Aggregate effect size (n = 837) was -0.03 (95% confidence interval, -0.15 to 0.08), indicating no evidence of superiority of brand-name to generic drugs. Among 43 editorials, 23 (53%) expressed a negative view of generic drug substitution.

Less bleeding with fondaparinux vs enoxaparin for ACS with PCI

Clinical Question:
In patients with acute coronary syndromes who are managed with percutaneous coronary intervention, is fondaparinux as safe and effective as enoxaparin?

Bottom Line:
For patients with acute coronary syndromes (ACS) who undergo percutaneous coronary intervention (PCI), fondaparinux is equally as effective as enoxaparin and results in less major bleeding.

Reference:
Mehta SR, Granger CB, Eikelboom JW, et al. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes undergoing percutaneous coronary intervention. J Amer Coll Cardiol 2007;50(18):1742-1751.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
This study was a preplanned analysis of patients from the OASIS-5 trial (Fifth Organization to Assess Strategies in Ischemic Syndromes), which evaluated the efficacy and safety of subcutaneous fondaparinux (2.5 mg daily) versus enoxaparin (1 mg/kg twice daily) in patients with unstable angina or non-ST-segment elevation myocardial infarction. Primary end points were rates of major bleeding and the composite of death, myocardial infarction, or stroke at days 9, 30, and 180. Results were analyzed by intention to treat. Patients were matched for baseline characteristics. PCI was done in 6238 patients of the 12,715 enrolled in the main trial who underwent cardiac catheterization during the period of study drug administration. Fondaparinux and enoxaparin were given for a mean of 2.4 days and 2.6 days, respectively, before PCI. More than 90% of patients received a thienopyridine, and approximately 40% were treated with glycoprotein (GP) IIb/IIIa inhibitors. At 30 days and 6 months, there was no difference in the rate of the composite primary end point or in the rates of the individual events. Major bleeding at day 9 was significantly lower among patients receiving fondaparinux [2.4% vs 5.1%; number needed to treat = 40; 95% CI, 25 – 86]. This difference persisted at 180 days. The reduction in bleeding with fondaparinux was seen both in patients who did and did not receive treatment with a GP IIb/IIIa inhibitor.

Fenofibrate (Fenoflex) reduces laser photocoagulation (FIELD)

Clinical Question:
Does fenofibrate (Fenoflex) reduce the need for laser photocoagulation in patients with type 2 diabetes?

Bottom Line:
In patients with type 2 diabetes mellitus fenofibrate (Antara, Lofibra, Tricor) modestly reduces the number of laser treatments for retinopathy.

Reference:
Keech AC, Mitchell P, Summanen PA, et al, for the FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007;370(9600):1687-1697.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Laser treatment for diabetic retinopathy is often associated with visual field reduction and other ocular side-effects. The investigators assessed whether long-term lipid-lowering therapy with fenofibrate could reduce the progression of retinopathy and the need for laser treatment in patients with type 2 diabetes mellitus. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a multinational randomised trial of 9795 patients aged 50-75 years with type 2 diabetes mellitus. Eligible patients were randomly assigned to receive fenofibrate 200 mg/day (n=4895) or matching placebo (n=4900). At each clinic visit, information concerning laser treatment for diabetic retinopathy-a prespecified tertiary endpoint of the main study-was gathered. Adjudication by ophthalmologists masked to treatment allocation defined instances of laser treatment for macular oedema, proliferative retinopathy, or other eye conditions. In a substudy of 1012 patients, standardised retinal photography was done and photographs graded with Early Treatment Diabetic Retinopathy Study (ETDRS) criteria to determine the cumulative incidence of diabetic retinopathy and its component lesions. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN64783481. Laser treatment was needed more frequently in participants with poorer glycaemic or blood pressure control than in those with good control of these factors, and in those with a greater burden of clinical microvascular disease, but the need for such treatment was not affected by plasma lipid concentrations. The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group (164 [3.4%] patients on fenofibrate vs 238 [4.9%] on placebo; hazard ratio [HR] 0.69, 95% CI 0.56-0.84; p=0.0002; absolute risk reduction 1.5% [0.7-2.3]). In the ophthalmology substudy, the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the two groups overall (46 [9.6%] patients on fenofibrate vs 57 [12.3%] on placebo; p=0.19) or in the subset of patients without pre-existing retinopathy (43 [11.4%] vs 43 [11.7%]; p=0.87). By contrast, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo (three [3.1%] patients vs 14 [14.6%]; p=0.004). An exploratory composite endpoint of 2-step progression of retinopathy grade, macular oedema, or laser treatments was significantly lower in the fenofibrate group than in the placebo group (HR 0.66, 95% CI 0.47-0.94; p=0.022).

LMWH better than unfractionated heparin for preventing DVT in medical patients

Clinical Question:
Which pharmacological agents most effectively prevent venous thromboembolism in hospitalized medical patients?

Bottom Line:
Low-molecular-weight heparin (LMWH) was more effective than unfractionated heparin (UFH) for reducing deep venous thrombosis (DVT) and injection site hematoma. Bleeding rates were comparable with the 2 agents.

Reference:
Wein L, Wein S, Haas SJ, Shaw J, Krum H. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients: a meta-analysis of randomized controlled trials. Arch Intern Med 2007;167(14):1476-1486.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
There is uncertainty regarding which pharmacological agents most effectively prevent venous thromboembolism in hospitalized medical patients. The authors performed a meta-analysis to determine this. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from 1950, 1966, and 1800, respectively, through June 30, 2006, for randomized controlled trials that involved medical patients comparing unfractionated heparin (UFH) or low-molecular-weight heparin or heparinoid (LMWH) with a control, LMWH with UFH, or selective factor Xa inhibitors with a comparator. Study selection, validity assessment, and data abstraction were performed by 2 independent reviewers (L.W. and S.W.). Data synthesis was undertaken by 1 blinded investigator (S.J.H.). Thirty-six studies were included. Compared with the control, UFH was associated with a reduced risk of deep venous thrombosis (DVT) (risk ratio [RR], 0.33; 95% confidence interval [CI], 0.26-0.42) and pulmonary embolism (RR, 0.64; 95% CI, 0.50-0.82), as was LMWH (RR, 0.56; 95% CI, 0.45-0.70; and RR, 0.37; 95% CI, 0.21-0.64, respectively). A UFH dosage of 5000 U 3 times daily was more effective in preventing DVT than a UFH dosage of 5000 U twice daily when compared with the control (RR, 0.27; 95% CI, 0.20-0.36; vs RR, 0.52; 95% CI, 0.28-0.96). Neither UFH nor LMWH reduced mortality. When directly compared with UFH, LMWH was associated with a lower risk of DVT (RR, 0.68; 95% CI, 0.52-0.88) and injection site hematoma (RR, 0.47; 95% CI, 0.36-0.62), but no difference was seen between the 2 agents in the risk of bleeding or thrombocytopenia.

Second-line antibiotics more effective than first-line in AECB

Clinical Question:
Are second-line antibiotics more effective for the treatment of acute exacerbation of chronic bronchitis than first-line antibiotics?

Bottom Line:
Compared to first-line antibiotics, second-line antibiotics are more effective, but not less safe, when administered to patients with AECB. The available data did not allow for stratified analyses according to the presence of risk factors for poor outcome, such as increased age, impaired lung function, airway obstruction, and frequency of exacerbations; this fact should be taken into consideration when interpreting the findings of this metaanalysis.

Reference:
Dimopoulos G, Siempos II, Korbila IP, Manta KG, Falagas ME. Comparison of first-line with second-line antibiotics for acute exacerbations of chronic bronchitis: a meta-analysis of randomized controlled trials. Chest 2007;132:447-55.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
Although first-line antibiotics are still recommended by most guidelines as the treatment of choice for patients with AECB, increasing resistance to these antibiotics has prompted many clinicians to reconsider that choice. The authors identified 12 randomized controlled trials with 2261 adults that compared first-line antibiotics (amoxicillin, ampicillin, pivampicillin, trimethoprim sulfamethoxazole, and doxycycline) with broad-spectrum antibiotics (amoxicillin/clavulanic acid, cefaclor, macrolides, and quinolones). Nine studies were double-blinded and 3 were single-blinded; the study quality was judged as good for for all but 2 studies. However, only 2 studies reported data on the basis of intention to treat. Also, many studies included both inpatients and outpatients, which might cloud the analysis. The mean age of patients was approximately 60 years for most studies. The primary outcome was treatment success; only 5 studies reported mortality data, and there were too few deaths for useful analysis (7 – 10 in each group). First-line antibiotics were less likely to result in treatment success than broad-spectrum antibiotics (odds ratio = 0.51; 95% CI, 0.34 – 0.75). The authors performed subgroup analyses and found similar results when they included only double-blinded studies, only studies after 1991, and only studies rated as “good quality.” They did not find an advantage to second-line antibiotics when the analysis was limited to older studies.

Azithromycin (Zithromax) effective for cystic fibrosis with chronic pseudomonas

Clinical Question:
Are macrolide antibiotics beneficial for patients with cystic fibrosis and Pseudomonas aeruginosa?

Bottom Line:
Macrolide antibiotics (azithromycin) reduced the frequency of clinical exacerbations and improved the quality of life in patients with cystic fibrosis (CF) chronically infected with Pseudomonas aeruginosa.

Reference:
Saiman L, Marshall BC, Mayer-Hamblett N, et al. Azithromycin patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2003; 290:1749-756.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Treatment strategies for cystic fibrosis (CF) lung disease include antibiotics, mucolytics, and anti-inflammatory therapies. Increasing evidence suggests that macrolide antibiotics might be beneficial in patients with CF. The authors determined if an association between azithromycin use and pulmonary function exists in patients with CF. A multicenter, randomized, double-blind, placebo-controlled trial conducted from December 15, 2000, to May 2, 2002, at 23 CF care centers in the United States. Of the 251 screened participants with a diagnosis of CF, 185 (74%) were randomized. Eligibility criteria included age 6 years or older, infection with Pseudomonas aeruginosa for 1 or more years, and a forced expiratory volume in 1 second (FEV1) of 30% or more. Participants were stratified by FEV1 (> or =60% predicted vs <60% n =” 87)”> or =40 kg) of oral azithromycin 3 days a week for 168 days; placebo group (n = 98) received identically packaged tablets. Change in FEV1 from day 0 to completion of therapy at day 168 and determination of safety. Secondary outcomes included pulmonary exacerbations and weight gain. The azithromycin group had a mean 0.097-L (SD, 0.26) increase in FEV1 at day 168 compared with 0.003 L (SD, 0.23) in the placebo group (mean difference, 0.094 L; 95% confidence interval [CI], 0.023-0.165; P =.009). Nausea occurred in 17% more participants in the azithromycin group (P =.01), diarrhea in 15% more (P =.009), and wheezing in 13% more (P =.007). Participants in the azithromycin group had less risk of experiencing an exacerbation than participants in the placebo group (hazard ratio, 0.65; 95% CI, 0.44-0.95; P =.03) and weighed at the end of the study an average 0.7 kg more than participants receiving placebo (95% CI, 0.1-1.4 kg; P =.02).

Pantoprozole more effective than somatostatin for peptic ulcer rebleeding

Clinical Question:
Is somatostatin more effective than pantoprazole for reducing peptic ulcer bleeding following endoscopic hemostasis?

Bottom Line:
In patients with a bleeding ulcer, after successful endoscopic hemostasis, despite equipotent acid suppression, pantoprazole continuous infusion was superior to somatostatin to prevent bleeding recurrence and quick disappearance of the endoscopic stigmata. Nevertheless, no differences were seen in the need for surgery and mortality.

Reference:
Tsibouris P, Zintzaras E, Lappas C, et al. High-dose pantoprazole continuous infusion is superior to somatostatin after endoscopic hemostasis in patients with peptic ulcer bleeding. Am J Gastroeneterol 2007;102:1192-1199.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
The best antisecretory treatment after endoscopic hemostasis in patients with ulcer bleeding is still in quest. The authors compared pantoprazole and somatostatin continuous infusion after endoscopic hemostasis in patients with bleeding peptic ulcers. A total of 164 consecutive patients with a bleeding peptic ulcer, after successful endoscopic hemostasis, were randomly assigned to receive, double blindly, continuous IV infusion of pantoprazole 8 mg/h for 48 h after a bolus of 40 mg (group P) or somatostatin 250 microg/h for 48 h after a bolus of 250 microg (group-S). Twenty-four-hour pH-metry was performed in the last 30 patients in each group. Endoscopy was performed, in case of bleeding nonrecurrence, every 48 h until disappearance of stigmata. Bleeding recurrence: group S 14 patients (17%) versus group P 4 (5%) (P=0.046). In multivariate analysis, bleeding recurrence was 4.57 (CI 1.31-15.91) times more frequent in group S (P=0.02). There was no difference in the need for surgery and mortality. Acid suppression over pH 6: group S 82.9% of the time versus group P 81.5% (P=0.97). Acid suppression over pH 6 for >85% of the time: group S 14 (47%) patients versus group P 17 (57%) (P=0.44). Disappearance of endoscopic stigmata after 48 h: group S 25/68 patients (37%) versus group P 72/78 (92%) (P<0.0001). No major side effects identified in either study group.

Methylprednisolone improves outcomes in ARDS

Clinical Question:
Does prolonged methylprednisolone administered to patients with ARDS reduce lung injury and improve patient outcomes?

Bottom Line:
Methylprednisolone initiated early in the course of acute respiratory distress syndrome (ARDS) reduces the duration of mechanical ventilation and mortality in the intensive care unit (ICU).

Reference:
Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized trial. Chest 2007;131:954-963.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
The authors determined the effects of low-dose prolonged methylprednisolone infusion on lung function in patients with early severe Acute Respiratory Distress Syndrome (ARDS). Randomized, double-blind, placebo-controlled trial was done. They did at ICUs of five hospitals in Memphis. Ninety-one patients with severe early ARDS (

Low dose (40 mg/d) doxycycline effective for acne rosacea

Clinical Question:
Is low-dose doxycycline effective in the treatment of acne rosacea?

Bottom Line:
Low-dose doxycycline (40 mg controlled-release) is more effective than placebo in the treatment of acne rosacea. Side effects were minimal. Less than one fourth of actively treated patients reported near or complete clearing of their lesions, however, so many patients may still request alternative treatment, including a higher dose of doxycycline. (LOE = 1b)

Reference:
Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol 2007;56:791-802.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
The optimal dose of doxycycline necessary to treat acne rosacea is unknown. These investigators enrolled 537 patients in 2 separate studies conducted at different times to randomly receive in a double-blind manner (concealed allocation assignment) doxycycline (40 mg controlled-release daily) or matched placebo. Eligible patients were otherwise healthy adults, 18 years or older, with moderate to severe rosacea (10 to 40 papules and pustules, telangiectasia, moderate to severe erythema, and 2 or fewer nodules). Individuals blinded to treatment group assignment assessed the primary efficacy end point, defined as the mean change from baseline in total inflammatory lesion count (papules + pustules + nodules). The mean total lesion count at baseline was 20. In addition, patients were rated according to whether their disease was completely clear or near clear. Follow-up occurred for 97% of subjects at 16 weeks. Using intention-to-treat analysis, the mean change from baseline lesion score was significantly lower in the doxycycline group than in the placebo group (-1.8 vs -5.9 and -9.5 vs -4.3 in studies 1 and 2, respectively). Significantly more subjects in the doxycycline group also reported near or complete clearing of their lesions (22.3% vs 12.3%; number needed to treat = 9; 95% CI, 6-23). Adverse events were minimal to mild in both treatment groups.

Combo sumatriptan-naproxen slightly better than either alone for acute migraine

Clinical Question:
Is a single tablet containing sumatriptan and naproxen superior to either agent alone in the treatment of acute migraine in adults?

Bottom Line:
Sumatriptan, 85 mg, plus naproxen sodium, 500 mg, as a single tablet for acute treatment of migraine resulted in more favorable clinical benefits compared with either monotherapy, with an acceptable and well-tolerated adverse effect profile.

Reference:
Brandes JL, Kudrow D, Stark SR, et al. Sumatriptan-naproxen for the acute treatment of migraine: A randomized trial. JAMA 2007;297:1443-1454.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Multiple pathogenic mechanisms may be involved in generating the migraine symptom complex, and multimechanism-targeted therapy may confer advantages over monotherapy. The authors evaluated the efficacy and safety of a fixed-dose tablet containing sumatriptan succinate and naproxen sodium relative to efficacy and safety of each monotherapy and placebo for the acute treatment of migraine. Two replicate, randomized, double-blind, single-attack, parallel-group studies conducted among 1461 (study 1) and 1495 (study 2) patients at 118 US clinical centers who were diagnosed as having migraine and received study treatment for a moderate or severe migraine attack. Patients were randomized in a 1:1:1:1 ratio to receive a single tablet containing sumatriptan, 85 mg, and naproxen sodium, 500 mg; sumatriptan, 85 mg (monotherapy); naproxen sodium, 500 mg (monotherapy); or placebo, to be used after onset of a migraine with moderate to severe pain. Primary outcome measures included the percentages of patients with headache relief 2 hours after dosing, absence of photophobia, absence of phonophobia, and absence of nausea for the comparison between sumatriptan-naproxen sodium and placebo, and the percentages of patients with sustained pain-free response for the comparison between sumatriptan-naproxen sodium and each monotherapy. Sumatriptan-naproxen sodium was more effective than placebo for headache relief at 2 hours after dosing (study 1, 65% vs 28%; P<.001 and study 2, 57% vs 29%; P<.001), absence of photophobia at 2 hours (58% vs 26%; P<.001 and 50% vs 32%; P<.001), and absence of phonophobia at 2 hours (61% vs 38%; P<.001 and 56% vs 34%; P<.001). The absence of nausea 2 hours after dosing was higher with sumatriptan-naproxen sodium than placebo in study 1 (71% vs 65%; P = .007), but in study 2 rates of absence of nausea did not differ between sumatriptan-naproxen sodium and placebo (65% vs 64%; P = .71). For 2- to 24-hour sustained pain-free response, sumatriptan-naproxen sodium was superior at P<.01 (25% and 23% in studies 1 and 2, respectively) to sumatriptan monotherapy (16% and 14% in studies 1 and 2), naproxen sodium monotherapy (10% and 10% in studies 1 and 2), and placebo (8% and 7% in studies 1 and 2). The incidence of adverse events was similar between sumatriptan-naproxen sodium and sumatriptan monotherapy.