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.

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.

LMWH = UFH for thrombocytopenia

Clinical Question:
What is the risk for thrombocytopenia with unfractionated heparin versus low-molecular-weight heparin in patients treated for acute venous thromboembolism?

Bottom Line:
There was no difference in risk of thrombocytopenia between unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) in patients with acute deep venous thrombosis (DVT) or pulmonary embolism (PE).

Reference:
Morris TA, Castrejon S, Devendra G, Gamst AC. No difference in risk for thrombocytopenia during treatment of pulmonary embolism and deep venous thrombosis with either low-molecular-weight heparin or unfractionated heparin: a metaanalysis. Chest 2007:132(4):1131-1139.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
A thorough search of English language literature was done to identify randomized controlled trials comparing the incidence of thrombocytopenia with UFH versus LMWH in patients with objectively diagnosed DVT or PE. Two independent reviewers evaluated studies for inclusion and quality. Studies were rated on the basis of 9 criteria; a score of 8 was needed to be considered high enough quality for inclusion. Thrombocytopenia was defined as platelet counts between 80,000 mm3 to 120,000 mm3 or a decrease in platelets by at least 50%. A secondary analysis included all definitions of thrombocytopenia specified in the respective articles. The diagnosis of heparin-induced thrombocytopenia (HIT) required an objective test, such as a heparin-induced serotonin release assay, heparin-induced platelet aggregation, or heparin-platelet factor 4 (PF4) enzyme-linked immunosorbent assay. Heparin-induced thrombocytopenia thrombosis (HITT) was defined as thrombocytopenia with new arterial or venous thrombosis.

Thirteen studies including 5275 patients were included for analysis of the primary outcome, 4 for the outcome of HIT, and 5 for HITT. The incidence of thrombocytopenia was 1.2% for enoxaparin-treated patients and 1.5% for those receiving UFH. Only a total of 5 patients had serologically confirmed HIT (2 receiving LMWH, 3 receiving UFH), and only 1 patient in the UFH group had HITT. These results may be limited by the lack of routine serologic testing for HIT among patients with thrombocytopenia.

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.

Prophylactic dialysis reduces long-term dialysis in pts with renal failure after coronary angiography

Clinical Question:
In patients with advanced renal failure, does prophylactic hemodialysis after coronary angiography reduce the need for long-term dialysis?

Bottom Line:
Prophylactic hemodialysis after coronary angiography in patients with renal failure reduces the need for long-term dialysis without causing complications.

Reference:
Lee P, Chou K, Liu C, et al. Renal protection for coronary angiography in advanced renal failure patients by prophylactic hemodialysis. A randomized controlled trial. J Am Coll Cardiol 2007;50(11):1015-1020.

Study Design:
Randomized controlled trial (nonblind)

Synopsis:
Patients requiring coronary angiography who had a serum creatinine concentration greater than 3.5 mg/dL (and had been stable for 1 month) were randomized to receive hemodialysis or no hemodialysis following angiography. Acetylcysteine and mannitol were not permitted during the study. Angiography was done with nonionic contrast. The primary end point was the change in creatinine clearance (CrCl) between baseline and day 4 following angiography.
Ninety patients were randomized, and 8 of them were excluded because of insufficient follow up, taking drugs not permitted by protocol, or having a second contrast procedure within 28 hours. Intention-to-treat analysis was not used. Patients were matched for baseline characteristics. Half the patients required percutaneous coronary intervention. At day 4, patients receiving prophylactic dialysis had less decline in CrCl (-0.4 vs -2.2 ml/min/1.73m2). Temporary dialysis was required in 2% of the dialysis group versus 14% of the control group, and maintenance dialysis following discharge was required in 13% of the control patients but none of the dialysis patients [number needed to treat = 8; 95% CI, 4 – 64]. Prophylactic dialysis resulted in shorter hospital stays (6 days vs 13 days; P = .017). No major complications occurred as a result of dialysis.

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.

Little information on racial differences between antihypertensives

Clinical Question:
Are there racial differences in response to antihypertensive medications?

Bottom Line:
There are few high-quality studies of different antihypertensive medications that compare clinical outcomes of patients across different racial and ethnic groups. Most of the existing studies find no difference in outcomes between white and nonwhite patients.

Reference:
Park IU, Taylor AL. Race and ethnicity in trials of antihypertensive therapy to prevent cardiovascular outcomes: a systematic review. Ann Fam Med. 2007;5(5):444-452.

Study Design:
Systematic review

Synopsis:
These authors systematically reviewed multiple databases looking for clinical trials of antihypertensive medications that compared treatment response among patients of different racial groups and ethnicities. The searches were supplemented by hand-searching reference lists of other systematic reviews and practice guidelines, and by speaking with experts, but the authors don’t describe looking for unpublished data. They excluded studies that did not report clinically important outcomes like mortality or cardiovascular events. Two authors independently determined if studies were to be included in this review and they resolved disagreements by consensus. The authors then extracted data on race, ethnicity, and outcomes from each trial. Finally, they contacted the original study authors to obtain missing information. Of the 28 studies making the final cut, only 8 described outcomes in nonwhite patients and only 5 compared outcomes across groups. The quality scores of the studies ranged from 3 to 5, using the Jadad score (range = 0 – 5). Given the variability in inclusion criteria, follow-up duration, treatments, and so forth, the authors appropriately refrained form pooling the results. Of the 5 studies comparing outcomes across ethnic and racial groups, 4 found no difference in outcomes. Only ALLHAT (JAMA 2002;288(23):2981-2997) found blacks experienced greater benefits from diuretics than nonblack patients.