Clinical Health Updates

Morphine improves chronic, intractable cough

Clinical Question:
Does morphine decrease chronic, intractable cough?

Bottom Line:
Morphine sulfate is an effective antitussive in intractable chronic cough at the doses of 5 to 10 mg twice daily

Reference:
Morice AH, Menon MS, Mulrennan SA, et al. Opiate therapy in chronic cough. Am J Respir Crit Care Med 2007;175:312-315.

Study Design:
Cross-over trial (randomized)

Synopsis:
Cough is the most common complaint for which medical attention is sought, and chronic cough can be both physically and mentally debilitating. There is currently no evidence supporting the use of antitussives in chronic treatment-resistant cough. The authors tested the hypothesis that morphine sulfate in the dose of 5 mg twice daily would bring about a reduction in cough frequency and severity in patients failing to respond to specific measures. Patients recruited from the Hull Cough Clinic were enrolled into a randomized double-blind placebo-controlled study using 4 weeks of slow-release morphine sulfate and a corresponding period of matched placebo. An open-labeled extension of the core study allowed dose escalation to 10 mg twice daily. Cough was assessed using the Leicester Cough Questionnaire, daily symptom diary, and citric acid cough challenge. Twenty-seven patients completed the core study. A significant improvement of 3.2 points over baseline was noted on the Leicester Cough Questionnaire (p < 0.01). A rapid and highly significant reduction by 40% in daily cough scores was noted among patients on slow-release morphine sulfate (p < 0.01). Objective testing of the cough reflex using citric acid cough challenge tests did not show any significant changes. Eighteen patients continued into the extension study. Two-thirds of these patients opted to increase the morphine to 10 mg twice daily. At the end of 3 months, there was a similar improvement in cough between the 5- and 10-mg groups.

Antioxidants may increase mortality

Clinical Question:
Do antioxidant supplements reduce all-cause mortality for adults?

Bottom Line:
Current evidence suggests that regular supplementation with the antioxidants beta carotene, vitamin A, and vitamin E increases mortality risk in adults. The potential roles of vitamin C and selenium on mortality need further study.

Reference:
Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention. Systematic review and meta-analysis. JAMA 2007;297:842-857.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
Antioxidant supplements are used for prevention of several diseases. The authors assessed the effect of antioxidant supplements on mortality in randomized primary and secondary prevention trials. They searched electronic databases and bibliographies published by October 2005. All randomized trials involving adults comparing beta carotene, vitamin A, vitamin C (ascorbic acid), vitamin E, and selenium either singly or combined vs placebo or vs no intervention were included in our analysis. Randomization, blinding, and follow-up were considered markers of bias in the included trials. The effect of antioxidant supplements on all-cause mortality was analyzed with random-effects meta-analyses and reported as relative risk (RR) with 95% confidence intervals (CIs). Meta-regression was used to assess the effect of covariates across the trials. Included are 68 randomized trials with 232 606 participants (385 publications). When all low- and high-bias risk trials of antioxidant supplements were pooled together there was no significant effect on mortality (RR, 1.02; 95% CI, 0.98-1.06). Multivariate meta-regression analyses showed that low-bias risk trials (RR, 1.16; 95% CI, 1.05-1.29) and selenium (RR, 0.998; 95% CI, 0.997-0.9995) were significantly associated with mortality. In 47 low-bias trials with 180 938 participants, the antioxidant supplements significantly increased mortality (RR, 1.05; 95% CI, 1.02-1.08). In low-bias risk trials, after exclusion of selenium trials, beta carotene (RR, 1.07; 95% CI, 1.02-1.11), vitamin A (RR, 1.16; 95% CI, 1.10-1.24), and vitamin E (RR, 1.04; 95% CI, 1.01-1.07), singly or combined, significantly increased mortality. Vitamin C and selenium had no significant effect on mortality.

Pergolide (Permax), cabergoline (Dostinex) increase risk of heart valve damage

Clinical Question:
Do certain dopamine agonists increase the risk of heart valve damage?

Bottom Line:
The risk of cardiac valve damage (cardiac-valve regurgitation) is elevated in patients taking pergolide (Permax) or cabergoline (Dostinex), especially if the dose is higher than 3 mg per day and the drug is taken for more than 6 months. The absolute risk is modest: approximately 2.5 additional cases of valve damage for every 1000 patients who take one of the drugs for 1 year.

Reference:
Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E. Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med 2007;356:29-38.

Study Design:
Case-control

Synopsis:
Case reports and echocardiographic studies suggest that the ergot-derived dopamine agonists pergolide and cabergoline, used in the treatment of Parkinson’s disease and the restless legs syndrome, may increase the risk of cardiac-valve regurgitation. The authors used data from the United Kingdom General Practice Research Database to identify a population-based cohort comprising 11,417 subjects 40 to 80 years of age who were prescribed antiparkinsonian drugs between 1988 and 2005. They conducted a nested case-control analysis within this cohort in which each patient with newly diagnosed cardiac-valve regurgitation was matched with up to 25 control subjects from the cohort, according to age, sex, and year of entry into the cohort. Incidence-rate ratios for cardiac-valve regurgitation with the use of different dopamine agonists were estimated by conditional logistic-regression analysis. Of 31 case patients with newly diagnosed cardiac-valve regurgitation, 6 were currently exposed to pergolide, 6 were currently exposed to cabergoline, and 19 had not been exposed to any dopamine agonist within the previous year. The rate of cardiac-valve regurgitation was increased with current use of pergolide (incidence-rate ratio, 7.1; 95% confidence interval [CI], 2.3 to 22.3) and cabergoline (incidence-rate ratio, 4.9; 95% CI, 1.5 to 15.6), but not with current use of other dopamine agonists.

Increased use of COX-2 assoc with more overall GI bleeds

Clinical Question:
What is the effect of more restrictive prescribing guidelines on gastrointestinal complications?

Bottom Line:
Although COX-2 inhibitors may be slightly less likely to cause gastrointestinal (GI) complications, the overall increase in the use of nonsteroidal anti-inflammatory drugs (NSAIDs) seen after their introduction appears to have led to an overall increase in the number of GI complications in the population (not to mention the thousands of cardiovascular deaths attributed to this class of drugs). Although physicians complain about prescribing restrictions, sometimes for good reason, in this case they seem to be of benefit.

Reference:
Mamdani M, Warren L, Kopp A, et al. Changes in rates of upper gastrointestinal hemorrhage after the introduction of cyclooxygenase-2 inhibitors in British Columbia and Ontario. CMAJ 2006;175:1535-1538.

Study Design:
Ecologic

Synopsis:
Population rates of upper gastrointestinal (GI) hemorrhage have been observed to increase with the introduction and rapid uptake of selective cyclooxygenase-2 (COX-2) inhibitors. Changes in COX-2 inhibitor use and upper GI bleeding rates in regions with relatively restrictive drug policies (e.g., British Columbia) have not been compared with changes in regions with relatively less restrictive drug policies (e.g., Ontario). The authors collected administrative data for about 1.4 million people aged 66 years and older in British Columbia and Ontario for the period January 1996 to November 2002. We examined temporal changes in the prevalence of NSAID use and admissions to hospital because of upper GI hemorrhage in both provinces using cross-sectional time series analysis. During the period studied, the prevalence of NSAID use in British Columbia’s population of older people increased by 25% (from 8.7% to 10.9%; p < 0.01), as compared with a 51% increase in Ontario (from 10.9% to 16.5%; p < 0.01). Hospital admissions because of upper GI hemorrhage increased significantly in Ontario by about 16% on average, or about 2 admissions per 10 000 elderly people, above expected values (p < 0.01). A similar increase was not observed in British Columbia.

Vitamin E bad or good?

Clinical Question:
Does Vitamin E play a role in the development of diabetes, hypertension and vascular dysfunction?

Bottom Line:
Treatment with either alpha- or mixed tocopherols significantly increased BP, pulse pressure and heart rate in individuals with type 2 diabetes.

Reference:
The effect of vitamin E on blood pressure in individuals with type 2 diabetes: a randomized, double-blind, placebo-controlled trial.Ward NC, Wu JH, Clarke MW, Puddey IB, Burke V, Croft KD, Hodgson JM. J Hypertens. 2007 Jan;25(1):227-34

Study Design:
Randomized Controlled Trial (Double-Blind)

Synopsis:
Oxidative stress has been suggested to play a role in the development of diabetes, hypertension and vascular dysfunction. Vitamin E, a major lipid-soluble dietary antioxidant, has two major dietary forms, alpha-tocopherol and gamma-tocopherol. The potential importance of gamma-tocopherol has largely been overlooked. The authors investigated the effect of alpha-tocopherol and gamma-tocopherol supplementation on 24-h ambulatory blood pressure (BP) and heart rate, vascular function and oxidative stress in individuals with type 2 diabetes. Fifty-eight individuals with type 2 diabetes were randomized in a double-blind, placebo-controlled trial. Participants were randomized to a daily dose of 500 mg/day RRR-alpha-tocopherol, 500 mg/day mixed tocopherols (60% gamma-tocopherol) or placebo for 6 weeks. Primary endpoints were 24-h ambulatory BP and heart rate, endothelium-dependent and independent vasodilation and plasma and urinary F2-isoprostanes. Treatment with alpha-tocopherol significantly increased systolic BP [7.0 (5.2, 8.8) mmHg, P < 0.0001], diastolic BP [5.3 (4.0, 6.5) mmHg, P < 0.0001], pulse pressure [1.8 (0.6, 3.0) mmHg, P < 0.005] and heart rate [2.0 (0.6, 3.3) bpm, P < 0.005] versus placebo. Treatment with mixed tocopherols significantly increased systolic BP [6.8 (4.9, 8.6) mmHg, P < 0.0001], diastolic BP [3.6 (2.3, 4.9) mmHg, P < 0.0001], pulse pressure [3.2 (2.0, 4.4) mmHg, P < 0.0001] and heart rate [1.8 (0.5, 3.2) bpm, P < 0.01] versus placebo. Treatment with alpha-tocopherol or mixed tocopherols significantly reduced plasma F2-isoprostanes versus placebo, but had no effect on urinary F2-isoprostanes. Endothelium-dependent and independent vasodilation was not affected by either treatment.

Smaller benefit of statins without heart disease

Clinical Question:
Is there a benefit of statin therapy to lower cholesterol in patients without cardiovascular disease?

Bottom Line:
In patients without CV disease, statin therapy of elevated low-density lipoprotein (LDL) cholesterol will decrease their risk of a first major coronary event and, to a lesser extent, a first cerebrovascular event. Overall mortality and mortality related to heart disease will not be affected by treatment.

Reference:
Thavendiranathan P, Bagai A, Brookhart MA, Choudhry NK. Primary prevention of cardiovascular diseases with statin therapy. Arch Intern Med 2006;166:2307-2313.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
While the role of hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) in secondary prevention of cardiovascular (CV) events and mortality is established, their value for primary prevention is less clear. The authors clarified the role of statins for patients without CV disease, they performed a meta-analysis of randomized controlled trials (RCTs). MEDLINE, EMBASE, Cochrane Collaboration, and American College of Physicians Journal Club databases were searched for RCTs published between 1966 and June 2005. They included RCTs with follow-up of 1 year or longer, more than 100 major CV events, and 80% or more of the population without CV disease. From each trial, demographic data, lipid profile, CV outcomes, mortality, and adverse outcomes were recorded. Summary relative risk (RR) ratios with 95% confidence intervals (CIs) were calculated using a random effects model. Seven trials with 42,848 patients were included. Ninety percent had no history of CV disease. Mean follow-up was 4.3 years. Statin therapy reduced the RR of major coronary events, major cerebrovascular events, and revascularizations by 29.2% (95% CI, 16.7%-39.8%) (P<.001), 14.4% (95% CI, 2.8%-24.6%) (P = .02), and 33.8% (95% CI, 19.6%-45.5%) (P<.001), respectively. Statins produced a nonsignificant 22.6% RR reduction in coronary heart disease mortality (95% CI, 0.56-1.08) (P = .13). No significant reduction in overall mortality (RR, 0.92 [95% CI, 0.84-1.01]) (P = .09) or increases in cancer or levels of liver enzymes or creatine kinase were observed.

Folic acid supplementation does not reduce CVD risk nor mortality

Clinical Question:
Does folic acid supplementation decrease morbidity or mortality from cardiovascular diseases?

Bottom Line:
Folic acid supplementation has not been shown to reduce risk of cardiovascular diseases or all-cause mortality among participants with prior history of vascular disease. Several ongoing trials with large sample sizes might provide a definitive answer to this important clinical and public health question.

Reference:
Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases. A meta-analysis of randomized controlled trials. JAMA 2006;296:2720-2726.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
Epidemiologic studies have suggested that folate intake decreases risk of cardiovascular diseases. However, the results of randomized controlled trials on dietary supplementation with folic acid to date have been inconsistent. The authors evaluated the effects of folic acid supplementation on risk of cardiovascular diseases and all-cause mortality in randomized controlled trials among persons with preexisting cardiovascular or renal disease. Studies were retrieved by searching MEDLINE (January 1966-July 2006) using the Medical Subject Headings cardiovascular disease, coronary disease, coronary thrombosis, myocardial ischemia, coronary stenosis, coronary restenosis, cerebrovascular accident, randomized controlled trial, clinical trials, homofolic acid, and folic acid, and the text words folic acid and folate. Bibliographies of all retrieved articles were also searched, and experts in the field were contacted. From 165 relevant retrieved reports, 12 randomized controlled trials compared folic acid supplementation with either placebo or usual care for a minimum duration of 6 months and with clinical cardiovascular disease events reported as an end point. Data on study design, characteristics of participants, changes in homocysteine levels, and cardiovascular disease outcomes were independently abstracted by 2 investigators using a standardized protocol. Studies including data from 16 958 participants with preexisting vascular disease were analyzed using a random-effects model. The overall relative risks (95% confidence intervals) of outcomes for patients treated with folic acid supplementation compared with controls were 0.95 (0.88-1.03) for cardiovascular diseases, 1.04 (0.92-1.17) for coronary heart disease, 0.86 (0.71-1.04) for stroke, and 0.96 (0.88-1.04) for all-cause mortality. The relative risk was consistent among participants with preexisting cardiovascular or renal disease.

Acetaminophen=celecoxib in DJD

Clinical Question:
Are celecoxib and paracetamol equivalent in providing pain relief in patients with degenerative joint disease?

Bottom Line:
In this short-term study emphasizing individual response, acetaminophen and celecoxib (Celebrex) are virtually indistinguishable in improving pain, stiffness, and function in patients with clinically diagnosed degenerative joint disease (DJD). SR paracetamol is more useful than celecoxib for most patients of whom management is uncertain.

Reference:
Yelland MJ, Nikles CJ, McNairn N, Del Mar CB, Schluter PJ, Brown RM. Celecoxib compared with sustained-release paracetamol for osteoarthritis: a series of n-of-1 trials. Rheumatology 2007;46:135-140.

Study Design:
Cross-over trial (randomized)

Synopsis:
To assess the use of n-of-1 trials for short-term choice of drugs for osteoarthritis, with particular reference to comparing the efficacy of sustained-release [SR] paracetamol with celecoxib in individual patients. The authors did an evaluation of community-based patients undergoing n-of-1 trials which consisted of double-blind, crossover comparisons of celecoxib 200 or 400 mg/day with sustained-release paracetamol 1330 mg three times a day in three pairs of 2 week treatment periods per drug with random order of the drugs within pairs. Outcomes evaluated were pain and stiffness in sites nominated by the patient, functional limitation scores, preferred medication, side effects and changes in drug use after an n-of-1 trial. Participants were 59 patients with osteoarthritis in multiple sites (hip 6, knee 24, hand 6, shoulder/neck 8, back 14, foot 5), with pain for >/=1 month severe enough to warrant consideration of long-term use of celecoxib but for whom there was doubt about its efficacy. Forty-one n-of-1 trials were completed. Although on average, celecoxib showed better scores than SR paracetamol [0.2 (0.1) for pain, 0.3 (0.1) for stiffness and 0.3 (0.1) for functional limitation], 33 of the 41 individual patients (80%) failed to identify the differences between SR paracetamol and celecoxib in terms of overall symptom relief. Of the eight patients who were able to identify the differences, seven had better relief with celecoxib and one with SR paracetamol. In 25 out of 41 [61%] patients, subsequent management was consistent with their trial results.

DHEA, testosterone not effective in aging patients

Clinical Question:
Do DHEA and testosterone have anti-aging properties?

Bottom Line:
There is no evidence that supplementation with dehydroepiandrosterone (DHEA) or testosterone has any meaningful clinical benefit for older patients with low serum levels of those hormones. Neither DHEA nor low-dose testosterone replacement in elderly people has physiologically relevant beneficial effects on body composition, physical performance, insulin sensitivity, or quality of life.

Reference:
Nair KS, Rizza RA, O’Brien P, et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 2006;355:1647-1659.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Dehydroepiandrosterone (DHEA) and testosterone are widely promoted as antiaging supplements, but the long-term benefits, as compared with potential harm, are unknown. The authors performed a 2-year, placebo-controlled, randomized, double-blind study involving 87 elderly men with low levels of the sulfated form of DHEA and bioavailable testosterone and 57 elderly women with low levels of sulfated DHEA. Among the men, 29 received DHEA, 27 received testosterone, and 31 received placebo. Among the women, 27 received DHEA and 30 received placebo. Outcome measures included physical performance, body composition, bone mineral density (BMD), glucose tolerance, and quality of life. As compared with the change from baseline to 24 months in the placebo group, subjects who received DHEA for 2 years had an increase in plasma levels of sulfated DHEA by a median of 3.4 microg per milliliter (9.2 micromol per liter) in men and by 3.8 microg per milliliter (10.3 micromol per liter) in women. Among men who received testosterone, the level of bioavailable testosterone increased by a median of 30.4 ng per deciliter (1.1 nmol per liter), as compared with the change in the placebo group. A separate analysis of men and women showed no significant effect of DHEA on body-composition measurements. Neither hormone altered the peak volume of oxygen consumed per minute, muscle strength, or insulin sensitivity. Men who received testosterone had a slight increase in fat-free mass, and men in both treatment groups had an increase in BMD at the femoral neck. Women who received DHEA had an increase in BMD at the ultradistal radius. Neither treatment improved the quality of life or had major adverse effects.

Rofecoxib, diclofenac and indomethacin increase risk of CVD

Clinical Question:
Which NSAIDs increase the risk of cardiovascular disease (CVD)?

Bottom Line:
Rofecoxib (Vioxx), diclofenac (Voltaren, Cataflam), and indomethacin (Indocin) are associated with a significant increased risk of CVD. It is likely that all NSAIDs carry some risk, but the risks may vary between medicines. Current evidence does not point to an increased risk for low dose (over the counter) ibuprofen and this remains safe to use at recommended doses.

Reference:
McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase. A systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 2006;296:1633-44.

Study Design:
Systematic review

Synopsis:
Evidence that rofecoxib increases the risk of myocardial infarction has led to scrutiny of other nonsteroidal anti-inflammatory drugs (NSAIDs). Regulatory agencies have provided variable advice regarding the cardiovascular risks with older nonselective NSAIDs. To undertake a systematic review and meta-analysis of controlled observational studies to compare the risks of serious cardiovascular events with individual NSAIDs and cyclooxygenase 2 inhibitors. Searches were conducted of electronic databases (1985-2006), scientific meeting proceedings, epidemiological research Web sites, and bibliographies of eligible studies. Eligible studies were of case-control or cohort design, reported on cardiovascular events (predominantly myocardial infarction) with cyclooxygenase 2 inhibitor, NSAID use, or both with nonuse/remote use of the drugs as the reference exposure. Of 7086 potentially eligible titles, 17 case-control and 6 cohort studies were included. Thirteen studies reported on cyclooxygenase 2 inhibitors, 23 on NSAIDs, and 13 on both groups of drugs. Two people independently extracted data and assessed study quality with disagreements resolved by consensus. Data were combined using a random-effects model. A dose-related risk was evident with rofecoxib, summary relative risk with 25 mg/d or less, 1.33 (95% confidence interval [CI], 1.00-1.79) and 2.19 (95% CI, 1.64-2.91) with more than 25 mg/d. The risk was elevated during the first month of treatment. Celecoxib was not associated with an elevated risk of vascular occlusion, summary relative risk 1.06 (95% CI, 0.91-1.23). Among older nonselective drugs, diclofenac had the highest risk with a summary relative risk of 1.40 (95% CI, 1.16-1.70). The other drugs had summary relative risks close to 1: naproxen, 0.97 (95% CI, 0.87-1.07); piroxicam, 1.06 (95% CI, 0.70-1.59); and ibuprofen, 1.07 (95% CI, 0.97-1.18).