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.

Vitamin B12 effective in treatment of recurrent aphthous stomatitis

Clinical Question:
Is vitamin B12 effective in the treatment of adults with recurrent aphthous stomatitis?

Bottom Line:
Compared with placebo, sublingual vitamin B12 significantly reduced the average duration of recurrent aphthous stomatitis, the number of aphthous ulcers, and the subjective level of pain. Treatment was only effective after 5 months, so shorter treatment courses may not be effective.

Reference:
Volkov I, Rudoy I, Freud T, et al. Effectiveness of vitamin B12 in treating recurrent aphthous stomatitis: A randomized, double-blind, placebo-controlled trial. J Am Board Fam Med 2009;22(1):9-16.

Study Design:
Randomized controlled trial (double-blinded)

Funding:
Industry

Setting:
Outpatient (primary care)

Allocation:
Concealed

Summary:
The frequency of recurrent aphthous stomatitis (RAS), the most common oral mucosa lesions seen in primary care, is up to 25% in the general population. However, there has been no optimal therapeutic approach. The objective was to confirm the previous clinical observation of the beneficial treatment of RAS with vitamin B(12). They did a randomized, double-blind, placebo-controlled trial was done using primary care patients. A sublingual a dose of 1000 mcg of vitamin B(12) was used in patients in the intervention group for 6 months. In total, 58 patients suffering from RAS participated in the study: 31 were included in the intervention group and 27 were included in control group. All parameters of RAS among patients in the intervention group were recorded and compared with the control group. The duration of outbreaks, the number of ulcers, and the level of pain were reduced significantly (P < .05) at 5 and 6 months of treatment with vitamin B(12), regardless of initial vitamin B(12) levels in the blood. During the last month of treatment a significant number of participants in the intervention group reached “no aphthous ulcers status” (74.1% vs 32.0%; P < .01).

Intensive control of glucose does not improve T2DM outcomes (VADT)

Clinical Question:
Does intensive control of glucose improve outcomes in patients with type 2 diabetes?

Bottom Line:
Like the ACCORD and ADVANCE studies, this trial provides additional evidence that intensive glucose control does not improve outcomes in patients with type 2 diabetes mellitus. It is important to note that these patients had well-controlled hypertension (mean blood pressure = 126/68) and well-controlled hyperlipidemia (mean low-density lipoprotein = 80 mg/dL). (LOE = 1b)

Reference:
Duckworth W, Abraira C, Moritz T, et al, for the VADT Investigators. Glucose control and vascular complications in veterans with Type 2 diabetes. N Engl J Med 2009(2);360:129-139.

Study Design:
Randomized controlled trial (single-blinded)

Funding:
Industry + govt

Setting:
Outpatient (any)

Allocation:
Concealed

Summary:
The effects of intensive glucose control on cardiovascular events in patients with long-standing type 2 diabetes mellitus remain uncertain. The recent ACCORD (N Engl J Med 2008;358:2545) and ADVANCE (N Engl J Med 2008;358:2560) trials found that tight glucose control does not reduce the risk of macrovascular complications and may actually increase all-cause mortality in patients with type 2 diabetes mellitus. The authors randomly assigned 1791 military veterans (mean age, 60.4 years) who had a suboptimal response to therapy for type 2 diabetes to receive either intensive or standard glucose control. Other cardiovascular risk factors were treated uniformly. The mean number of years since the diagnosis of diabetes was 11.5, and 40% of the patients had already had a cardiovascular event. The goal in the intensive-therapy group was an absolute reduction of 1.5 percentage points in the glycated hemoglobin level, as compared with the standard-therapy group. The primary outcome was the time from randomization to the first occurrence of a major cardiovascular event, a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene. The median follow-up was 5.6 years. Median glycated hemoglobin levels were 8.4% in the standard-therapy group and 6.9% in the intensive-therapy group. The primary outcome occurred in 264 patients in the standard-therapy group and 235 patients in the intensive-therapy group (hazard ratio in the intensive-therapy group, 0.88; 95% confidence interval [CI], 0.74 to 1.05; P=0.14). There was no significant difference between the two groups in any component of the primary outcome or in the rate of death from any cause (hazard ratio, 1.07; 95% CI, 0.81 to 1.42; P=0.62). No differences between the two groups were observed for microvascular complications. The rates of adverse events, predominantly hypoglycemia, were 17.6% in the standard-therapy group and 24.1% in the intensive-therapy group.

Pneumococcal conjugate vaccine prevents meningitis

Clinical Question:
What is the effect of pneumococcal conjugate vaccine on pneumococcal meningitis?

Bottom Line:
Although the pneumococcal conjugate vaccine (PCV7) has reduced the overall likelihood of pneumococcal meningitis, particularly in infants and older adults, there are worrisome recent trends regarding non-PCV7 serotype disease and antibiotic resistance that bear close watching. (LOE = 2c)

Reference:
Hsu HE, Shutt KA, Moore MR, et al. Effect of pneumococcal conjugate vaccine on pneumococcal meningitis. N Engl J Med 2009;360(3):244-256.

Study Design:
Time series

Funding:
Government

Setting:
Population-based

Summary:
Invasive pneumococcal disease declined among children and adults after the introduction of the pediatric heptavalent pneumococcal conjugate vaccine (PCV7) in 2000, but its effect on pneumococcal meningitis is unclear. They examined trends in pneumococcal meningitis from 1998 through 2005 using active, population-based surveillance data from eight sites in the United States. Isolates were grouped into PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F), PCV7-related serotypes (6A, 9A, 9L, 9N, 18A, 18B, 18F, 19B, 19C, 23A, and 23B), and non-PCV7 serotypes (all others). Changes in the incidence of pneumococcal meningitis were assessed against baseline values from 1998-1999. The researcher identified 1379 cases of pneumococcal meningitis. The incidence declined from 1.13 cases to 0.79 case per 100,000 persons between 1998-1999 and 2004-2005 (a 30.1% decline, P<0.001). Among persons younger than 2 years of age and those 65 years of age or older, the incidence decreased during the study period by 64.0% and 54.0%, respectively (P<0.001 for both groups). Rates of PCV7-serotype meningitis declined from 0.66 case to 0.18 case (a 73.3% decline, P<0.001) among patients of all ages. Although rates of PCV7-related-serotype disease decreased by 32.1% (P=0.08), rates of non-PCV7-serotype disease increased from 0.32 to 0.51 (an increase of 60.5%, P<0.001). The percentages of cases from non-PCV7 serotypes 19A, 22F, and 35B each increased significantly during the study period. On average, 27.8% of isolates were nonsusceptible to penicillin, but fewer isolates were nonsusceptible to chloramphenicol (5.7%), meropenem (16.6%), and cefotaxime (11.8%). The proportion of penicillin-nonsusceptible isolates decreased between 1998 and 2003 (from 32.0% to 19.4%, P=0.01) but increased between 2003 and 2005 (from 19.4% to 30.1%, P=0.03).

Moderate coffee consumption safe after AMI

Clinical question
Is coffee consumption safe after acute myocardial infarction?

Bottom line
Coffee consumption does not increase the risk of cardiovascular events following acute myocardial infarction (AMI).

Reference
Silletta MG, Marfisi R, Levantesi G, et al, for the GISSI-Prevenzione Investigators. Coffee consumption and risk of cardiovascular events after acute myocardial infarction. Circulation 2007;116(25):2944-2951.

Study design: Cohort (prospective)

Synopsis
The relation between coffee consumption and cardiovascular disease has been studied extensively, but results are still debated. In addition, little evidence is available on patients with established coronary heart disease. Prospectively ascertained information among 11,231 Italian patients (9584 males and 1647 females) with recent (< or = 3 months) myocardial infarction enrolled in the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico)-Prevenzione trial was used. Usual dietary habits were assessed at baseline and updated at 0.5 and 1.5 years. Coffee consumption was categorized as never/almost never, < 2 cups per day, 2 to 4 cups per day, and > 4 cups per day. Medication use and fasting glucose were assessed at 0.5, 1, 1.5, 2.5, and 3.5 years. Risk was evaluated with Cox proportional hazards with time-varying covariates. The main outcome measure was the cumulative incidence of cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke). A total of 1167 cardiovascular events occurred during 36,961 person-years of follow-up. After multivariable adjustment for potential confounders in the time-dependent analysis, the relative risk of cardiovascular events across categories of coffee consumption was 1.02 (95% CI 0.87 to 1.20) for < 2 cups per day, 0.91 (95% CI 0.75 to 1.09) for 2 to 4 cups per day, and 0.88 (95% CI 0.64 to 1.20) for > 4 cups per day compared with abstainers (P for trend=0.18). Ultimately, coffee consumption did not change the risk of coronary heart disease events, stroke, and sudden death.

ACE = ARB for secondary CV prevention; combination worse (ONTARGET)

Clinical question
Which is more effective for patients at high risk of cardiovascular disease: ramipril, telmisartan, or both?

Bottom line
The angiotensin-converting enzyme inhibitor (ACEI) ramipril and the angiotensin receptor blocker (ARB) telmisartan are equally effective for secondary cardiovascular prevention. The combination of both drugs is no more effective and causes more adverse effects at greater cost. ACEIs should remain the drug of choice for secondary prevention in high risk cardiovascular patients unless the drug is not tolerated because of angioedema or cough, in which case ARBs provide an effective alternative.

Reference
The ONTARGET Investigators; Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-1559.

Study design: Randomized controlled trial (double-blinded)

Synopsis
In patients who have vascular disease or high-risk diabetes without heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and morbidity from cardiovascular causes, but the role of angiotensin-receptor blockers (ARBs) in such patients is unknown. The author compared the ACE inhibitor ramipril, the ARB telmisartan, and the combination of the two drugs in patients with vascular disease or high-risk diabetes. After a 3-week, single-blind run-in period, patients underwent double-blind randomization, with 8576 assigned to receive 10 mg of ramipril per day, 8542 assigned to receive 80 mg of telmisartan per day, and 8502 assigned to receive both drugs (combination therapy). The primary composite outcome was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure. Mean blood pressure was lower in both the telmisartan group (a 0.9/0.6 mm Hg greater reduction) and the combination-therapy group (a 2.4/1.4 mm Hg greater reduction) than in the ramipril group. At a median follow-up of 56 months, the primary outcome had occurred in 1412 patients in the ramipril group (16.5%), as compared with 1423 patients in the telmisartan group (16.7%; relative risk, 1.01; 95% confidence interval [CI], 0.94 to 1.09). As compared with the ramipril group, the telmisartan group had lower rates of cough (1.1% vs. 4.2%, P<0.001) and angioedema (0.1% vs. 0.3%, P=0.01) and a higher rate of hypotensive symptoms (2.6% vs. 1.7%, P<0.001); the rate of syncope was the same in the two groups (0.2%). In the combination-therapy group, the primary outcome occurred in 1386 patients (16.3%; relative risk, 0.99; 95% CI, 0.92 to 1.07); as compared with the ramipril group, there was an increased risk of hypotensive symptoms (4.8% vs. 1.7%, P<0.001), syncope (0.3% vs. 0.2%, P=0.03), and renal dysfunction (13.5% vs. 10.2%, P<0.001).

BP and cholesterol are associated with vascular mortality

Clinical question
Are cholesterol and blood pressure associated with an increase in vascular mortality?

Bottom line
Total cholesterol was positively associated with IHD mortality in both middle and old age and at all blood pressure levels. The absence of an independent positive association of cholesterol with stroke mortality, especially at older ages or higher blood pressures, is unexplained, and invites further research. Nevertheless, there is conclusive evidence from randomised trials that statins substantially reduce not only coronary event rates but also total stroke rates in patients with a wide range of ages and blood pressures.
Reference
Prospective Studies Collaboration, Lewington S, Whitlock G, Clarke R, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007;370(9602):1829-1839.

Study design: Meta-analysis (other)

Synopsis
These intrepid authors pooled data on nearly 900,000 individual patients enrolled in 61 prospective cohort studies. In these studies, approximately 55,000 patients died. Only 150,000 of the patients had lipid levels available, of whom approximately 5000 died. The authors evaluated the relationship between cholesterol level, blood pressure, age, and gender on vascular mortality (ischemic heart disease, stroke, and “other”). To reduce undue influence of a few outliers, they excluded patients with astronomical cholesterol readings. They don’t report how many patients dropped out of the studies or the number of deaths from all causes. They do, however, report MANY relationships. If you want all the data, get the paper. On the whole, the authors found that the higher the cholesterol level, the greater the risk of vascular death. They also report a nearly linear risk of vascular mortality that increases as the patient gets older, independent of gender. Blood pressure has a similar relationship and blood pressure and cholesterol have additive effects. In contrast with randomized trials that show statins may decrease stroke risk, lipids were weakly and inconsistently associated with stroke deaths. This reinforces the theory that statins may have beneficial effects independent of their effects on lipids.

Omega-3 FFAs not effective for relapse prevention in Crohn disease

Clinical question
Are omega-3 free fatty acids useful in the prevention of relapse in Crohn disease?

Bottom line
Daily supplementation with omega-3 free fatty acids (FFAs) was not effective for the prevention of relapse in Crohn disease.

Reference
Feagan BG, Sandborn WJ, Mittmann U, et al. Omega-3 free fatty acids for the maintenance of remission in Crohn disease. The EPIC randomized controlled trials. JAMA 2008;299:1690-1697.

Study design: Randomized controlled trial (double-blinded)

Synopsis
Maintenance therapy for Crohn disease features the use of immunosuppressive drugs, which are associated with an increased risk of infection. Identification of safe and effective maintenance strategies is a priority. The authors determine whether the oral administration of omega-3 free fatty acids is more effective than placebo for prevention of relapse of Crohn disease. Two randomized, double-blind, placebo-controlled studies (Epanova Program in Crohn’s Study 1 [EPIC-1] and EPIC-2) conducted between January 2003 and February 2007 at 98 centers in Canada, Europe, Israel, and the United States. Data from 363 and 375 patients with quiescent Crohn disease were evaluated in EPIC-1 and EPIC-2, respectively. Patients with a Crohn’s Disease Activity Index (CDAI) score of less than 150 were randomly assigned to receive either 4 g/d of omega-3 free fatty acids or placebo for up to 58 weeks. No other treatments for Crohn disease were permitted. Clinical relapse, as defined by a CDAI score of 150 points or greater and an increase of more than 70 points from the baseline value, or initiation of treatment for active Crohn disease. For EPIC-1, 188 patients were assigned to receive omega-3 free fatty acids and 186 patients to receive placebo. Corresponding numbers for EPIC-2 were 189 and 190 patients, respectively. The rate of relapse at 1 year in EPIC-1 was 31.6% in patients who received omega-3 free fatty acids and 35.7% in those who received placebo (hazard ratio, 0.82; 95% confidence interval, 0.51-1.19; P = .30). Corresponding values for EPIC-2 were 47.8% and 48.8% (hazard ratio, 0.90; 95% confidence interval, 0.67-1.21; P = .48). Serious adverse events were uncommon and mostly related to Crohn disease.

Antibiotics and nasal steroids of little/no benefit for acute sinusitis

Clinical Question:
Are antibiotics or nasal steroids truly beneficial in the treatment of acute maxillary sinusitis?

Bottom Line:
Neither an antibiotic nor a topical steroid alone or in combination was effective as a treatment for acute sinusitis in the primary care setting.

Reference:
Williamson IG, Rumsby K, Benge S, et al. Antibiotics and topical nasal steroid for treatment of acute maxillary sinusitis. A randomized controlled trial. JAMA 2007;298(21):2487-2496.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Acute sinusitis is a common clinical problem that usually results in a prescription for antibiotics but the role of antibiotics is debated. Anti-inflammatory drugs such as topical steroids may be beneficial but are underresearched. The authors determine the effectiveness of amoxicillin and topical budesonide in acute maxillary sinusitis. They did a double-blind, randomized, placebo-controlled factorial trial of 240 adults (aged > or =16 years) with acute nonrecurrent sinusitis (had > or =2 diagnostic criteria: purulent rhinorrhea with unilateral predominance, local pain with unilateral predominance, purulent rhinorrhea bilateral, presence of pus in the nasal cavity) at 58 family practices (74 family physicians) between November 2001 and November 2005. Patients were randomized to 1 of 4 treatment groups: antibiotic and nasal steroid; placebo antibiotic and nasal steroid; antibiotic and placebo nasal steroid; placebo antibiotic and placebo nasal steroid. A dose of 500 mg of amoxicillin 3 times per day for 7 days and 200 mug of budesonide in each nostril once per day for 10 days. Proportion clinically cured at day 10 using patient symptom diaries and the duration and severity of symptoms. The proportions of patients with symptoms lasting 10 or more days were 29 of 100 (29%) for amoxicillin vs 36 of 107 (33.6%) for no amoxicillin (adjusted odds ratio, 0.99; 95% confidence interval, 0.57-1.73). The proportions of patients with symptoms lasting 10 or more days were 32 of 102 (31.4%) for topical budesonide vs 33 of 105 (31.4%) for no budesonide (adjusted odds ratio, 0.93; 95% confidence interval, 0.54-1.62). Secondary analysis suggested that nasal steroids were significantly more effective in patients with less severe symptoms at baseline.

Alpha-blocker or nifedipine may help pass kidney stones

Clinical Question:
Can drug treatment improve passage of ureteral stones?

Bottom Line:
This meta-analysis of low-quality studies shows that ureteral stone passage can be enhanced by treating patients with an alpha-blocker such as tamsulosin (Flomax) or the calcium channel blocker nifedipine (Procardia). Better studies may refute these findings, but for now either approach is an option.

Reference:
Singh A, Alter HJ, Littlepage A. A systematic review of medical therapy to facilitate passage of ureteral calculi. Ann Emerg Med 2007;50(5):552-563.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
The researchers conducting this study combined the results of small studies evaluating the effectiveness of alpha-blockers, a calcium channel blocker, or both, to increase the passage of ureteral calculi. The meta-analysis was well done. Two authors independently searched several databases, including the Cochrane database, to find randomized studies. They also conducted a hand search of urologic journals and conference proceedings. Two authors also independently abstracted data. They identified 22 studies. Only 1 study was considered to be of good quality with a Jadad score of 3 (out of a possible 5), with all the rest scoring 1 or 2. All but 1 of the studies was unblinded, and the researchers did not report on whether allocation was concealed in the studies. There was mild heterogeneity found among the alpha-blocker studies, as well as evidence of publication bias. Alpha-blockers, primarily tamsulosin, were studied in 16 trials enrolling 1235 men. Nine trials evaluated the time to stone expulsion in patients with stones of 3 mm to 18 mm in size and located in the distal portion of the ureter, with a 2-day to 6-day average improvement in time to stone passage. The calcium channel blocker was studied in 9 trials of 686 patients with an average stone size of greater than 5 mm located in all aspects of the ureter. The average reduction in time to stone expulsion was not reported, though stone passage was more likely, on average, with treatment (relative risk = 1.50; 95% CI, 1.34-1.68) over the various periods of follow-up.