Stroke Rounds: Clamping Methods Equal in CABG?

Postop stroke risk similar in single-center observation, but the issue remains controversial.

The partial clamping method for on-pump coronary artery bypass grafting (CABG) was not associated with higher risk of stroke as a complication in an observational study, but experts said the data don’t settle the issue.

The 30-day observed postoperative stroke rates came out a similar 1.5% with single aortic clamping and 1.4% with combined partial aortic clamping (17 of 1,107 patients versus 10 of 712 patients, P>0.99), as predicted from the nearly identical preoperative stroke prediction scores in the single center cohort.

Mortality rates at 30 days were likewise “equally low” (1.9% versus 1.8%, respectively,P>0.99), Danny Chu, MD, of the University of Pittsburgh, and colleagues reported online in JAMA Surgery.

“In patients with significantly compromised myocardial function who are undergoing complex cardiac operations, partial aortic clamping may provide a safe alternative,” the group concluded.

The issue has been controversial, they noted, because a small single-institutionrandomized trial showed better cerebral protection with single aortic clamping, whereas “several high-volume, high-performing cardiac surgery centers continued to perform on-pump CABG using the partial aortic clamping technique with relatively low stroke rates.”

The reason for conflicting studies is “not the aortic clamping; it is the patient,” each with her or his unique atherosclerotic burden in the ascending aorta and arch, Michael D. Crittenden, MD, of the VA Health Care System in St. Louis, Mo., argued in an accompanying editorial.

“Aortic manipulation is one of many risk factors for embolic stroke,” he wrote. “Clearly, patients undergoing anaortic surgery are not spared this complication. The study by Chu and colleagues highlights the fact that there are factors beyond aortic manipulation that we have yet to control.”

Timothy Gardner, MD, medical director of Christiana Care Health System’s Center for Heart & Vascular Health in Newark, Del., and a past president of the American Heart Association, wasn’t so equivocal.

From Chu’s findings, “it would be incorrect to assume that partial aortic clamping is safe for all patients,” he told MedPage Today.

“Experienced cardiac surgeons understand the importance of reducing aortic manipulation in a patients with atherosclerotic involvement of the ascending aorta,” he said. “As has been demonstrated in many reports, such patients are best managed with a single aortic clamping for both distal and proximal grafting.

“In the report by Chu et al, the single clamp patients were older and had increased risk factors for stroke compared to the partial clamp patient group. There likely was some selection bias in the surgeons’ decision to use the single clamp technique versus partial clamping.”

The retrospective cohort study included 1,819 patients receiving conventional on-pump, arrested-heart CABG for the first time as an isolated, non-emergent procedure at a single U.S. major academic medical center.

Among those patients seen during the study period from January 1, 2005, to December 31, 2013, the procedure was done with a single aortic clamp for 1,107 and with side-biting partial aortic clamping for 712.

“To validate our findings, a prospective randomized trial designed to assess aortic clamping strategy for performing proximal coronary anastomosis as well as risk of postoperative stroke and distal embolic burden in CABG operations appears justified,” Chu’s group acknowledged.

“In the meantime, let’s hope that surgeons are not mislead by the authors’ unqualified conclusion statement that ‘no significant differences in post-op stroke were identified regardless of aortic clamping method used,'” Gardner cautioned

Statins Linked to Improved Lung Cancer Survival

Mortality modestly lower for statin users in observational study..

Sustained statin use was associated with modestly better survival in lung cancer, an observational study in Great Britain showed.

People already on statins before diagnosis had a hazard ratio of 0.88 for lung cancer–specific mortality compared with other lung cancer patients after adjustment for various factors (P<0.001), Chris Cardwell, PhD, of Royal Victoria Hospital in Belfast, Ireland, and colleagues found.

Use after diagnosis was associated with a similar adjusted hazard ratio of 0.89 for lung cancer–specific mortality, albeit not statistically significant at P=0.09, the group reported in the May issue ofCancer Epidemiology, Biomarkers & Prevention.

That association was stronger after 12 prescriptions (adjusted HR 0.81, P=0.03) and when limited to lipophilic statins (adjusted HR 0.81, P=0.01), particularly simvastatin (Zocor), although attenuated in some sensitivity analyses.

Although these “associations could be causal or could reflect residual confounding or other biases,” the researchers pointed out “preclinical evidence for anticancer properties of statins from lung cancer cell lines and mouse models.”

Observational studies have also linked statins to better cancer-specific mortality in breast, prostate, and colorectal cancers.

“These results require confirmation in further large epidemiologic studies, particularly those with complete stage data, which could inform the decision to conduct a trial of simvastatin in lung cancer patients,” Cardwell’s group concluded.

Their study included 3,638 newly-diagnosed lung cancer patients in the English cancer registry from 1998 to 2009, linked to prescription records in the U.K. Clinical Practice Research Datalink and national mortality data up to 2012.

Risk of serious atrial fibrillation and stroke with use of bisphosphonates: evidence from a meta-analysis.

Clinical studies have suggested an association between bisphosphonate use and the onset of atrial fibrillation (AF). However, data on the risk of developing AF, stroke, and cardiovascular mortality with the use of bisphosphonate are conflicting. The objective of this study was to evaluate the risk of serious AF (events that required hospital admission), stroke, and cardiovascular mortality with the use of bisphosphonates through a systematic review of the literature.
METHODS: We searched the PubMed, CENTRAL, and EMBASE databases for observational studies and randomized controlled trials (RCTs) on the use of bisphosphonates from 1966 to April 2012 that reported the number of patients who developed serious AF, stroke, and cardiovascular mortality at follow-up. The random-effects Mantel-Haenszel test was used to evaluate relative risk-adverse cardiovascular outcomes with the use of bisphosphonates.
RESULTS: Six observational studies (n = 149,856) and six RCTs (n = 41,375) were included for analysis. On pooling observational studies, there was an increased risk of AF (OR, 1.27; 95% CI, 1.16-1.39) among bisphosphonate users. Further, analysis of RCTs revealed a statistically significant increase in the risk of serious AF (OR, 1.40; 95% CI, 1.02-1.93) and no increase in the risk of stroke (OR, 1.07; 95% CI, 0.85-1.34) or cardiovascular mortality (OR, 0.92; 95% CI, 0.68-1.26) with the use of bisphosphonates.
CONCLUSIONS: Evidence from RCTs and observational studies suggests a significantly increased risk of AF requiring hospitalization, but no increase in risk of stroke or cardiovascular mortality, with the use of bisphosphonate.


Vitamin D’s disease role queried


Vitamin D supplements
Vitamin D supplements are recommended for young children and the elderly

Scientists have cast doubt on the value of vitamin D supplements to protect against diseases such as cancers, diabetes and dementia.

Writing in The Lancet Diabetes and Endocrinology, French researchers suggest low vitamin D levels do not cause ill health, although they did not look at bone diseases.

More clinical trials on non-skeletal diseases are needed, they say.

Vitamin D supplements are recommended for certain groups.

“Start Quote

What this suggests is that decreases in vitamin D levels are a marker of deteriorating health. ”

Prof Philippe AutierInternational Prevention Research Institute

Recent evidence has shown it may also have a role to play in preventing non-bone-related diseases such as Parkinson’s, dementia, cancers and inflammatory diseases.

Prof Philippe Autier, from the International Prevention Research Institute in Lyon, carried out a review of data from 290 prospective observational studies and 172 randomised trials looking at the effects of vitamin D levels on health outcomes, excluding bone health, up to December 2012.


A large number of the observational studies suggested that there were benefits from high vitamin D – that it could reduce the risk of cardiovascular events by up to 58%, diabetes by up to 38% and colorectal cancer by up to 33%.

But the results of the clinical trials – where participants were given vitamin D supplements – found no reduction in risk, even in people who started out with low vitamin D levels.

And a further analysis of recent randomised trials found no positive effect of vitamin D supplements on diseases occurring.

Prof Autier said: “What this discrepancy suggests is that decreases in vitamin D levels are a marker of deteriorating health.

What is a vitamin D deficiency?

A vitamin D level less than 25nmol/L in the blood is a deficiency, but experts increasingly believe that lower than 60nmol/L can also be damaging to health.

Most people get enough vitamin D by being exposed to the sun for 10 to 15 minutes a day.

A small amount of vitamin D also comes from foods such as oily fish and dairy products.

Recently England’s chief medical officer said free vitamins should be given to all young children because more and more of them were being diagnosed with the bone disease rickets, lack of calcium and other bone and muscle diseases.

“Ageing and inflammatory processes involved in disease occurrence… reduce vitamin D concentrations, which would explain why vitamin D deficiency is reported in a wide range of disorders.”

High risk

In the UK, vitamin D supplements are recommended for groups at higher risk of deficiency, including all pregnant and breastfeeding women, children under five years old, people aged over 65, and people at risk of not getting enough exposure to sunlight.

People with dark skin, such as people of African-Caribbean and South Asian origin, and people who wear full-body coverings, as well as pale-skinned people are also known to be at higher risk.

In recent years, there has been a four-fold increase in admissions to UK hospital with rickets – a disease that causes bones to become soft and deformed.

Dr Colin Michie, consultant senior lecturer in paediatrics and chair of the nutrition committee at the Royal College of Paediatrics and Child Health, said the review had little to contribute to the problem in the UK because it excluded the measurement of bone health.

“It has been known for almost a century that vitamin D supplements given to those with deficient vitamin D levels results in improved bone health, preventing hypocalcemic seizure and rickets.”

He added that it was important to provide appropriate supplements, such as vitamin D, to improve bone health.

More research

Peter Selby, consultant physician and honorary professor of metabolic bone disease at Manchester Royal Infirmary, said the French review was limited.

“It could very well be that the apparent negative results of this study have been obtained simply because they have not been looking at people with sufficient degree of vitamin D insufficiency to have any meaningful biological effect.”

But he said the authors were right to say that more interventional research looking at disease outcomes was necessary.

The Scientific Advisory Committee on Nutrition (SACN), an independent group of scientific experts who advise the government on nutrition, is currently reviewing the dietary recommendations for vitamin D for all population groups in the UK.

Their report on vitamin D is expected to go out for public consultation in 2014.

Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women.

Observational studies have found lower rates of coronary heart disease (CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has not been confirmed in clinical trials.

Objective.—  To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease.

Design.—  Randomized, blinded, placebo-controlled secondary prevention trial.

Setting.—  Outpatient and community settings at 20 US clinical centers.

Participants.—  A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years.

Intervention.—  Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n=1380) or a placebo of identical appearance (n=1383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end of 3 years.

Main Outcome Measures.—  The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also considered.

Results.—  Overall, there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5. More women in the hormone group than in the placebo group experienced venous thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences in several other end points for which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38).

Conclusions.—  During an average follow-up of 4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. The treatment did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving this treatment to continue.

MANY OBSERVATIONAL studies have found lower rates of coronary heart disease (CHD) in women who take postmenopausal estrogen than in women not receiving this therapy.1– 5 This association has been reported to be especially strong for secondary prevention in women with CHD, with hormone users having 35% to 80% fewer recurrent events than nonusers.6– 12 If this association is causal, estrogen therapy could be an important method for preventing CHD in postmenopausal women. However, the observed association between estrogen therapy and reduced CHD risk might be attributable to selection bias if women who choose to take hormones are healthier and have a more favorable CHD profile than those who do not.13– 15 Observational studies cannot resolve this uncertainty.

Only a randomized trial can establish the efficacy and safety of postmenopausal hormone therapy for preventing CHD. The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized, double-blind, placebo-controlled trial of daily use of conjugated equine estrogens plus medroxyprogesterone acetate (progestin) on the combined rate of nonfatal myocardial infarction (MI) and CHD death among postmenopausal women with coronary disease. We enrolled women with established coronary disease because their high risk for CHD events and the strong reported association between hormone use and risk of these events make this an important and efficient study population in which to evaluate the effect of hormone therapy.


In this clinical trial, postmenopausal women younger than 80 years with established coronary disease who received estrogen plus progestin did not experience a reduction in overall risk of nonfatal MI and CHD death or of other cardiovascular outcomes. How can this finding be reconciled with the large body of evidence from observational and pathophysiologic studies suggesting that estrogen therapy reduces risk for CHD?

Contrast With Findings of Observational Studies

Observational studies may be misleading because women who take postmenopausal hormones tend to have a better CHD risk profile13,21– 22and to obtain more preventive care14 than nonusers. The consistency of the apparent benefit in the observational studies could simply be attributable to the consistency of this selection bias. The lower rate of CHD in hormone users compared with nonusers persists after statistical adjustment for differences in CHD risk factors,22 but differences in unmeasured factors remain a possible explanation.

The discrepancy between the findings of HERS and the observational studies may also reflect important differences between the study populations and treatments. Most of the observational studies of postmenopausal hormone therapy enrolled postmenopausal women who were relatively young and healthy and who took unopposed estrogen.1– 3,23 In contrast, participants in HERS were older, had coronary disease at the outset, and were treated with estrogen plus progestin. However, some observational studies did examine women with prior CHD, and all of these reported a beneficial association with postmenopausal hormone therapy.6– 12 Similarly, some observational studies did examine the effect of postmenopausal estrogen plus progestin therapy on CHD risk in women, and these generally report a lower rate of CHD events in hormone users that is similar to that reported for estrogen alone4– 5,22,24– 27; however, details in these studies about the specific progestin formulations and dosing regimens used are limited.

Possible Adverse Effects of Medroxyprogesterone Acetate

Several potential mechanisms whereby estrogen therapy might reduce risk for CHD have been proposed, including favorable effects on lipoproteins, coronary atherosclerosis, endothelial function, and arterial thrombosis.28– 29 Progestins down-regulate estrogen receptors and may also have direct, progestin receptor–mediated effects that oppose these actions of estrogen30; medroxyprogesterone acetate may do this to a greater extent than other progestins. In the Postmenopausal Estrogen-Progestin Interventions Trial, medroxyprogesterone acetate blunted the estrogen-associated increase in HDL cholesterol substantially more than did micronized progesterone.31 Oral medroxyprogesterone acetate appears to significantly attenuate the beneficial effects of estrogen on coronary atherosclerosis in nonhuman primates,32 while subcutaneous progesterone does not.33 Animal data also suggest that medroxyprogesterone acetate may inhibit the beneficial effects of estrogen on endothelial-dependent vasodilation,34 but this has not been documented in women.35 Despite these mechanistic data suggesting an adverse effect of medroxyprogesterone acetate, observational studies show a similar reduction in CHD risk in women using medroxyprogesterone acetate plus estrogen as in women taking unopposed estrogen.4

Possible Differences in the Effects of Therapy Over Time

When the results were examined by year since randomization, the estrogen plus progestin regimen appeared to increase risk for primary CHD events in the first year of therapy but to decrease risk in subsequent years. This time trend should be interpreted with caution. It could simply represent random variation, although the level of statistical significance makes this unlikely. More importantly, between-group contrasts that exclude the first several years are not true randomized comparisons, as the remaining study groups may no longer be comparable if, for example, treatment has caused high-risk individuals to have events early in the study.

On the other hand, the time trend is biologically plausible. The early increase in risk for CHD events might be attributable to an immediate prothrombotic, proarrhythmic, or proischemic effect of treatment that is gradually outweighed by a beneficial effect on the underlying progression of atherosclerosis, perhaps as a result of beneficial changes in lipoproteins. In trials of lipid interventions, the delay before CHD risk is reduced has ranged from 0 to 2 years.36– 41 After a lag period, the 11% net reduction in LDL cholesterol and 10% net increase in HDL cholesterol observed in the hormone group would be expected to reduce the risk of CHD events36,42 and may account for the trend toward a late benefit observed in HERS.

A pattern of early harm and later benefit could account for part of the discrepancy between the results of this trial and observational studies of estrogen and CHD. Attrition of susceptible individuals soon after starting estrogen replacement could increase the prevalence of survivors available for inclusion in observational studies; most observational studies are not designed to observe the onset of therapy or to detect an early adverse effect.

Previous Clinical Trial Evidence

The CHD data from previous hormone trials in women have been summarized43 but are of limited value because the studies were small, short term, and not designed to examine CHD as an outcome. The only large prior trial of estrogen therapy to prevent CHD events was the Coronary Drug Project, which studied very high doses of estrogen (5.0 mg or 2.5 mg of conjugated equine estrogen daily) in men with preexisting CHD. The estrogen arms of this trial were stopped early because of an excess of MIs, thromboembolic events, and estrogenic symptoms in the 5.0-mg/d group44 and the lack of benefit on the CHD end point and estrogenic symptoms in the 2.5-mg/d group.45 The relevance of this trial of high-dose estrogen in men to postmenopausal hormone therapy in women is uncertain.

Safety and Other Noncardiovascular Outcomes

Venous thromboembolic events were 3 times more common in the hormone group than in the placebo group. Recent observational studies have reported similar relative risks for idiopathic venous thromboembolism among users of both unopposed estrogen46– 49 and estrogen plus progestin therapy.47,49 The excess incidence of venous thrombotic events in HERS was 4.1 per 1000 woman-years of observation, an order of magnitude higher than the excess reported in the observational studies; the higher rate is probably a consequence of the facts that women enrolled in HERS were older and had multiple risk factors for venous thrombosis and that only idiopathic events were counted in the observational studies.

We found an increased risk of gallbladder disease in the hormone group that is likely attributable to the estrogen therapy. Metabolic studies indicate that estrogen enhances hepatic lipoprotein uptake and inhibits bile acid synthesis, resulting in increased biliary cholesterol and cholelithiasis.50

Observational studies have suggested that therapy with postmenopausal estrogen for 5 years or less is not associated with an increased risk of breast cancer but that longer duration of therapy might be associated with a small increase in risk.51 The HERS trial was not large enough and therapy did not continue for long enough to address this issue.

The incidence of fractures in the hormone group was only slightly lower than in the placebo group. Wide CIs around the fracture risk estimates reveal inadequate statistical power and do not exclude a reduction in risk of hip fracture of as much as 51% or a reduction in risk of other fracture of as much as 27%.

Strengths and Limitations of the Trial

The CHD risk factor profile of women enrolled in HERS is similar to that of a random sample of US women with probable heart disease, suggesting that the findings of HERS may be generalized to that population.52 However, HERS did not evaluate the effect of estrogen plus progestin therapy in women without CHD, and it is not known whether our findings apply to healthy women. It is also not known whether use of a different progestin or of estrogen alone would have been beneficial.

HERS exceeded the recruitment goal by 18%, carried out a successful randomization, collected objective, blindly adjudicated disease outcome data, and achieved 100% vital status ascertainment. Compliance with hormone treatment, while lower than projected, was sufficient to produce LDL and HDL cholesterol changes that compare favorably with previous studies.31 The 95% CIs for the effect of treatment assignment on primary CHD events (RH, 0.99; 95% CI, 0.80-1.22) make it unlikely that HERS missed a benefit of more than 20% for the overall 4.1-year period of observation. However, this statistic does not address the possible late benefit of treatment suggested by the time trend analysis, which is plausible based on the finding of a 1- to 2-year lag period observed in lipid trials36– 41; a longer study would be more definitive for investigating this possibility.

Future Directions

HERS is the first large trial of the effect of postmenopausal estrogen plus progestin therapy on risk for CHD events. The findings differ from those of observational studies and studies with surrogate outcomes, emphasizing the importance of basing treatment policies on randomized controlled trials.53 Other randomized trials of postmenopausal hormone therapy are likely to answer some of the questions raised by HERS. The Women’s Health Initiative Randomized Trial54 includes a group of women who have undergone hysterectomy and receive unopposed estrogen as well as women with intact uterus who receive the same estrogen plus progestin regimen used in HERS. Participants are not required to have CHD and are generally younger than the HERS cohort. The Women’s Health Initiative Randomized Trial plans to enroll 27500 women and to report the results in 2005 after 9 years of treatment. Further information will also emerge from HERS as we continue disease event surveillance.

Several interventions have been proven to reduce risk for CHD events in patients with coronary disease, including aspirin, β-blockers, lipid lowering, and smoking cessation.55 The need for encouraging these interventions for women with coronary disease is illustrated by the facts that 90% of the HERS cohort had LDL cholesterol exceeding 2.59 mmol/L (100 mg/dL) at baseline and that only 32% were receiving β-blockers.


First, in the population studied in HERS, ie, postmenopausal women with established coronary disease and an average age of 66.7 years, daily use of conjugated equine estrogens and medroxyprogesterone acetate did not reduce the overall risk for MI and CHD death or any other cardiovascular outcome during an average of 4.1 years of follow-up. This therapy did increase the risk of venous thromboembolic events and gallbladder disease.

Second, we did not evaluate the cardiovascular effect of treatment with unopposed estrogen, commonly used in women who have had a hysterectomy, or other estrogen plus progestin formulations. We also did not study women without coronary disease.

Third, based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving hormone treatment to continue. Extended follow-up of the HERS cohort and additional randomized trials are needed to clarify the cardiovascular effects of postmenopausal hormone therapy.



Effects of statin medication on mortality risk associated with type 2 diabetes in older persons: the population-based AGES-Reykjavik Study.


Objective To examine if the beneficial effect of statin medication on mortality seen in randomised clinical trials of type 2 diabetes applies equally to observational studies in the general population of older people.

Design A prospective, population-based cohort study.

Setting Reykjavik, Iceland.

Participants 5152 men and women from the Age, Gene/Environment Susceptibility-Reykjavik Study, mean age 77 years, range of 66–96 years.

Main outcome measure Cardiovascular and all-cause mortalities and the RR of dying according to statin use and history of coronary heart disease (CHD) in persons with type 2 diabetes and those without diabetes with a median follow-up time of 5.3 years, until end of 2009.

Results The prevalence of type 2 diabetes was 12.4% of which 35% used statins. Statin use was associated with a 50% (95% CI 8% to 72%) lower cardiovascular mortality and 53% (29% to 68%) lower all-cause mortalities in persons with diabetes. For those without diabetes, statin use was associated with a 16% (−24% to 43%) lower cardiovascular and 30% (11% to 46%) lower all-cause mortalities. Persons with diabetes using statins had a comparable risk of cardiovascular and all-cause mortality to that of the general population without diabetes. The effect was independent of the level of glycaemic control.

Conclusion This observational study lends important support to existing data from randomised clinical trials. These data suggest that in the general population of older people with diabetes, statin medication markedly reduces the excess cardiovascular and all-cause mortality risk, irrespective of the presence or absence of coronary heart disease or glucose-lowering medication.

Source: BMJ


Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies.


Objective To assess the effect of 25-hydroxyvitamin D (25-OHD) levels on pregnancy outcomes and birth variables.

Design Systematic review and meta-analysis.

Data sources Medline (1966 to August 2012), PubMed (2008 to August 2012), Embase (1980 to August 2012), CINAHL (1981 to August 2012), the Cochrane database of systematic reviews, and the Cochrane database of registered clinical trials.

Study selection Studies reporting on the association between serum 25-OHD levels during pregnancy and the outcomes of interest (pre-eclampsia, gestational diabetes, bacterial vaginosis, caesarean section, small for gestational age infants, birth weight, birth length, and head circumference).

Data extraction Two authors independently extracted data from original research articles, including key indicators of study quality. We pooled the most adjusted odds ratios and weighted mean differences. Associations were tested in subgroups representing different patient characteristics and study quality.

Results 3357 studies were identified and reviewed for eligibility. 31 eligible studies were included in the final analysis. Insufficient serum levels of 25-OHD were associated with gestational diabetes (pooled odds ratio 1.49, 95% confidence interval 1.18 to 1.89), pre-eclampsia (1.79, 1.25 to 2.58), and small for gestational age infants (1.85, 1.52 to 2.26). Pregnant women with low serum 25-OHD levels had an increased risk of bacterial vaginosis and low birthweight infants but not delivery by caesarean section.

Conclusion Vitamin D insufficiency is associated with an increased risk of gestational diabetes, pre-eclampsia, and small for gestational age infants. Pregnant women with low 25-OHD levels had an increased risk of bacterial vaginosis and lower birth weight infants, but not delivery by caesarean section.


Source: BMJ


Septic Shock? Reach for Norepinephrine After Fluid Resuscitation.

A meta-analysis shows that dopamine is associated with increased risk for death and arrhythmic events compared with norepinephrine.

Although current guidelines recommend either dopamine or norepinephrine as the vasopressors of choice for septic shock, a recent meta-analysis of six interventional studies suggested that norepinephrine is the superior agent (JW Emerg Med Apr 22 2011). Investigators conducted a meta-analysis of the same six interventional studies — excluding patients with nonseptic shock — and five observational studies; the analysis involved a total of 2768 adult patients.

Observational studies showed significant heterogeneity in results overall and no difference in mortality between patients treated with dopamine and those treated with norepinephrine. After exclusion of one trial that accounted for the heterogeneity, dopamine was associated with an increased risk for death at 28 days over norepinephrine (relative risk, 1.23). Interventional trials were homogeneous and likewise showed a significantly increased risk for death with dopamine use (RR, 1.12). Two interventional studies that reported arrhythmic events showed a significant increase in these events in the dopamine groups (RR, 2.34).

An editorialist suggests that dopamine, a more powerful β-agonist than norepinephrine, could still be considered in patients with septic shock, hypotension (systolic blood pressure <90 mm Hg), and either a low cardiac index (<2.5 L/minute/m2) or low heart rate (<90 beats per minute).

Comment: This study supports norepinephrine as the vasopressor of choice for adult patients with septic shock. Dopamine is relegated to a secondary role, perhaps to be used when cardiac output is insufficient despite optimal use of norepinephrine.

Source: Journal Watch Emergency Medicine


Statins as Anticancer Drugs?

In an observational study with limitations, statin use by cancer patients was associated with lower 3-year mortality.

In some basic science studies, statins inhibit cancer growth through various pathways. These observations raise the following question: Could statins lower cancer-related mortality? Danish researchers used national databases to address this question.

Among nearly 300,000 people who received cancer diagnoses between 1995 and 2007, 6% had used statins regularly before and after their diagnoses. During average follow-up of 3 years (but as long as 15 years in some cases), two thirds of the patients died. In analyses adjusted for several confounding variables, statin use was associated with a significant 15% drop in all-cause and cancer-related deaths. Mortality reductions were noted for most cancer types (although differences did not reach statistical significance for every type).

Comment: This observational study suggests that statins might influence tumor growth favorably in patients with cancer. In contrast, a recent meta-analysis of randomized trials showed that statins did not increase or decrease the incidence of cancer (PLoS One 2012; 7:e29849). An editorialist notes that the current analysis could not be controlled for several potentially important confounding factors and recommends caution in interpreting the findings. Until these results are confirmed or refuted by additional research, clinicians will have to decide whether to apply them to cancer patients; at the least, one might argue that patients who already are taking statins (and tolerating them) at the time of cancer diagnosis should continue.

Source: Journal Watch General Medicine

Sulfonylurea Drugs Associated with Increased Cardiovascular Risk vs. Metformin .

An observational study of patients beginning diabetes treatment finds that sulfonylureas carry a roughly 20% greater risk for major cardiovascular events than metformin. The work appears in the Annals of Internal Medicine.

Researchers used federal data from the Veterans Health Administration to ascertain outcomes in 250,000 veterans (almost all of whom were men) starting monotherapy for diabetes with a sulfonylurea (either glyburide or glipizide) or metformin. The primary outcome — a composite of hospitalization for acute MI or for stroke, or death — was more common among sulfonylurea users by 2.2 events per 1000 person-years of observation after adjustment for multiple factors, such as blood pressure and BMI.

An editorialist considers the findings “credible and important,” but ultimately “hypothesis-generating” in the absence of a randomized trial.

Source: Annals of Internal Medicine