Very low LDL targets attainable with statin-based therapy

25 March 2010

MedWire News: Very low target levels of low-density lipoprotein (LDL) cholesterol are achievable through statin-based therapy, a study of very-high-risk heart patients has found.

The study authors report that nearly half of patients in a real-world practice attained the LDL cholesterol goal of less than 70 mg/dl (1.81 mmol/l), as recommended in the revised National Cholesterol Education Program guidelines for very-high-risk patients with coronary artery disease (CAD).

The study was a retrospective, cross-sectional analysis of patients in the Kaiser Permanente Colorado healthcare system aged 18 years and above and with CAD and a predetermined LDL cholesterol goal of less than 70 mg/dl (1.81 mmol/l).

In all, 3226 of 7427 patients (43%) attained the goal, report Amy Kauffman (University of Colorado, Denver, USA) and colleagues in the Journal of Clinical Lipidology.

Patients who achieved their LDL goal were significantly more likely to be receiving a statin – either alone or in combination – than were patients not at goal (92.4% vs 81.3%).

Among those who attained the goal, 61.1% were receiving statin monotherapy, 70.7% were taking a moderate-to-high-potency statin, and 87.4% were taking a generic statin.

The remaining patients at goal were taking combination therapy, most often a statin in combination with ezetimibe (70.6%) or niacin (13.1%).

Multivariate analysis revealed several factors that were independently associated with failure to attain a LDL cholesterol of less than 70 mg/dl (1.81 mmol/l): age less than 65 years, female gender, hyperlipidemia diagnosis, and creatine kinase levels in the range 861–2000 IU/l.

Conversely, factors that independently predicted goal attainment were statin therapy (monotherapy or in combination), a history of gout, a higher body mass index, a greater level of cardiovascular risk, and a higher burden of chronic disease.

“Despite reporting a higher percentage of patients attaining a LDL cholesterol of less than 70 mg/dl treatment goal compared to previous studies, under 50% attained goal in a system which includes aggressive implementation and titration of lipid-lowering therapies and close monitoring and follow-up for all patients,” Kauffman and co-authors remark.

They conclude: “These data demonstrate the difficulty in attaining a LDL cholesterol of less than 70 mg/dl in the vast majority of patients with CAD.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

J Clin Lipidol 2010; Advance online publication

March 4, 2010 — Vitamin D deficiency is almost universal in patients with kidney disease with low blood albumin levels who begin long-term dialysis during the winter, according to the results of a study reported in the March issue of the Clinical Journal of the American Society of Nephrology.

"This research identifies risk factors for nutritional vitamin D deficiency in the dialysis population and may provide clues to its biology in this population," lead author Ishir Bhan, MD, MPH, from Massachusetts General Hospital in Boston, said in a news release.

The goal of this study was to examine whether routinely measured clinical and demographic factors could identify patients starting dialysis who are deficient in vitamin D. The study cohort, which was divided into training (60%) and validation (40%) sets, consisted of 908 patients with 25-hydroxyvitamin D levels who were enrolled in the Accelerated Mortality on Renal Replacement (ArMORR) cohort of incident US patients initiating dialysis.

Using logistic regression modeling, neural networks, and decision trees with vitamin D deficiency as the dependent variable, the investigators generated predictive models from routinely determined clinical and demographic data in the training set. To identify the simplest model that remained predictive, the investigators subjected the models to progressive variable reduction.

Vitamin D deficiency, defined as 25-hydroxyvitamin D levels of less than 30 ng/mL, was present in 79% of the study population. The strongest predictors of vitamin D deficiency were black race, female sex, winter season, and hypoalbuminemia (serum albumin levels ≤ 3.1 g/dL). In the validation set, factors of hypoalbuminemia and dialysis started during the winter season increased the likelihood of vitamin D deficiency from 90% to 100% in black women, from 85% to 100% in black men, from 82% to 94% in white women, and from 66% to 92% in white men.

"Deficiency of 25-hydroxyvitamin D is nearly universal among patients with hypoalbuminemia initiating chronic hemodialysis in winter," the study authors write.

Limitations of this study include lack of generalizability to non-US populations, uncertain direction of causality, and possible residual confounding. In addition, further studies are needed to determine if repleting 25-hydroxyvitamin D levels affect hyperglycemia, blood pressure, infection rates, or mortality rates in end-stage renal disease (ESRD).

"Although this study identified clinical factors that predicted low 25-hydroxyvitamin D levels, it is not yet proven that correcting these levels is clinically beneficial," the study authors conclude. "Prospective studies in ESRD, some of which are now underway, are needed to identify optimal levels of 25-hydroxyvitamin D for a range of functions and to further elucidate its biology. In the absence of clinical trials, clinicians must independently determine if these findings should guide empiric therapy or simply inform future studies."

Some of the study authors have disclosed various financial relationships with the National Kidney Foundation, the National Institutes of Health, and/or Abbott Laboratories.

Clin J Am Soc Nephrol. 2010;5:460-467.

Learning Objectives

Upon completion of this activity, participants will be able to:

1. Report the antiproliferative actions of nitrogen-containing bisphosphonates.
2. Examine the association between bisphosphonate use and breast cancer.

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March 16, 2010 — A third study, and the first to be published, has found a reduction in the risk for breast cancer among postmenopausal women taking bisphosphonates for the treatment of osteoporosis.

The new finding, reported in the March 2 issue of the British Journal of Cancer,comes from a case–control analysis of more than 6000 women in Wisconsin, half of whom were diagnosed with invasive breast cancer. It found that the use of bisphosphonates was associated with a 30% reduction in the risk for breast cancer.

"This large study provides new evidence that the use of bisphosphonates is associated with a potentially important reduction in breast cancer risk," lead author Polly Newcomb, PhD, MPH, head of the Cancer Prevention Program at the Fred Hutchinson Cancer Research Center in Seattle, Washington, said in a statement.

This reduction in breast cancer risk is similar to that already reported in 2 other studies, both of which were presented in December 2009 at the San Antonio Breast Cancer Symposium. One was an analysis of more than 150,000 postmenopausal women participating in several Women's Health Initiative studies, which found that bisphosphonate use reduced the risk for invasive breast cancer by 32%. The other involved an analysis of 4575 postmenopausal women in Israel, which found a 34% reduction.

At the time, the fact that a similar finding came out of 2 geographically different populations was described as "encouraging," by Theresa Guise, MD, professor of medicine and oncology at the Indiana University School of Medicine in Indianapolis, who was not involved in either study. However, she cautioned that "this needs to be confirmed by controlled clinical trials."

There was some discussion at that meeting about possible confounding factors. For example, women who were taking bisphosphonates for osteoporosis would have low bone-mineral density, and this in itself would indicate lower estrogen levels, which would influence the risk for breast cancer.

Accounting for Confounding Factors

In the latest study, Dr. Newcomb and colleagues emphasized that they were able to account for important confounders, such as body mass index and postmenopausal hormone use.

In addition, they analyzed the reasons for which bisphosphonates were prescribed, such as fractures, height loss, and physician-diagnosed osteoporosis. There was a suggestion that the use of bisphosphonates was associated with a reduced risk for breast cancer only among women reporting symptoms of bone loss, but this was not statistically significant.

"This association was not attributed to the primary indication for use, bone density loss, or fractures, which we and others have previously shown as a risk factor for breast cancer," the authors write.

These findings may reflect real benefits due to antitumor mechanisms.

The researchers therefore conclude that "these findings may reflect real benefits due to antitumor mechanisms" of bisphosphonates.

However, the association with a reduction in the risk for breast cancer was seen only among women who were not obese; they were not seen among obese women. This suggests that the inhibitory action of these drugs is related to some threshold effect of hormonal or other growth factors, which are known to be important etiological exposures in breast cancer, the researchers write in their paper.

"Obese women may have elevated estrogen levels, so underlying hormones may influence the ability of bisphosphonates to reduce breast cancer risk," Dr. Newcomb added in a statement.

How bisphosphonates could prevent breast cancer is not known, but these drugs have several actions that might be relevant; they have been shown to cause tumor apoptosis, inhibit angiogenesis, and prevent tumor-cell adhesions. "These drugs may affect cell function and be important in cell growth and death — specifically the death of tumors or even premalignant disease," Dr. Newcomb noted.

There has also been a large study reporting beneficial antitumor effects of bisphosphonates in women who already have breast cancer, which hints of this effect from another 2 studies. A recent editorial in the Journal of Clinical Oncology (2009;27:4043-4046) discussing these findings suggested that in the "seed and soil" hypothesis for cancer development, bisphosphonates might create an "unfavorable soil" in which the development of cancer cells is thwarted.

Dr. Newcomb and colleagues have disclosed no relevant financial relationships. Dr. Guise reports having served on advisory boards for Amgen, Lilly, Novartis, and Roche.

Br J Cancer. 2010;102:799-802. Abstract

Clinical Context

Study Highlights

• In this population-based case-control study, women aged 20 to 69 years, from Wisconsin's mandatory cancer registry, with a new diagnosis of invasive breast cancer from 2003 to 2006 were identified. Similarly aged community women were randomly selected as control subjects.
• The study included 2988 case patients with breast cancer and 3004 control subjects initially; however, 2936 patients and 2975 control subjects were used for analysis.
• Bisphosphonate use and potential confounders were assessed by interview.
• Current use of bisphosphonates was defined as use in the year before the reference year, and former users had taken bisphosphonates at any time before this period.
• Multivariable logistic regression models were used to estimate odds ratios and 95% confidence intervals and tests for linear trend across ordinal values of categoric variables.
• Women with breast cancer vs control subjects were more likely to have a family history of breast cancer, a college degree, to be older at first birth or nulliparous, to have gained more weight since age 18 years, and to use postmenopausal hormones.
• Results demonstrated that the odds ratio for breast cancer in current bisphosphonate users vs nonusers was 0.67 (95% confidence interval, 0.51 - 0.89).
• Increasing duration of use was associated with a greater reduction in risk (P for trend = .01).
• Risk reduction was observed in women who were not obese (P for interaction = .005).
• Limitations of this study included lack of adjustment for unmeasured or unknown confounding factors, inability to evaluate different types of bisphosphonate preparations that may have very different mechanisms of action, inability to evaluate breast cancer subgroups that may experience different responses to bisphosphonates, and prevalence of bisphosphonate use possibly lower than expected because the study population was limited to women younger than 70 years.

Clinical Implications

• Nitrogen-containing bisphosphonates affect cell function and survival duration by inhibiting the mevalonate pathway as well as inducing tumor apoptosis, inhibiting angiogenesis, and preventing tumor cell adhesion.
• Findings demonstrated that bisphosphonates are associated with a reduction in the risk for breast cancer.

Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

Learning Objectives

Upon completion of this activity, participants will be able to:

1. Compare the effect of prophylactic treatment of raised intraocular pressure vs delayed treatment on the subsequent risk for primary open-angle glaucoma.
2. Describe the effect of prophylaxis on different risk groups for primary open-angle glaucoma.

Credits Available

Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™

Family Physicians - maximum of 0.25 AAFP Prescribed credit(s)

All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation.

Physicians should only claim credit commensurate with the extent of their participation in the activity.

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Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Medscape, LLC designates this educational activity for a maximum of 0.25 AMA PRA Category 1 Credit(s)™ . Physicians should only claim credit commensurate with the extent of their participation in the activity. Medscape News CME has been reviewed and is acceptable for up to 300 Prescribed credits by the American Academy of Family Physicians. AAFP accreditation begins September 1, 2009. Term of approval is for 1 year from this date. Each issue is approved for .25 Prescribed credits. Credit may be claimed for 1 year from the date of this issue.

Note: Total credit is subject to change based on topic selection and article length.

Medscape, LLC staff have disclosed that they have no relevant financial relationships.

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There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.

This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page.

Follow these steps to earn CME/CE credit*:

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3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. MedscapeCME encourages you to complete the Activity Evaluation to provide feedback for future programming.

You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates by accessing "Edit Your Profile" at the top of your Medscape homepage.

*The credit that you receive is based on your user profile.

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March 16, 2010 — Early treatment of ocular hypertension appears to reduce the risk for the development of glaucoma, especially in individuals at the highest risk, according to the results of a randomized controlled trial reported in the March issue of Archives of Ophthalmology.

"Elevated intraocular pressure (IOP) (ocular hypertension [OHT]) is a leading risk factor for the development of primary open angle glaucoma (POAG) and the only modifiable risk factor at present," write Michael A. Kass, MD, from Washington University School of Medicine in St. Louis, Missouri, and colleagues for the Ocular Hypertension Treatment Study (OHTS) Group. "It is estimated that 4% to 7% of the US population older than 40 years has OHT. There is substantial controversy on how to manage this large group of individuals who are at higher risk of developing glaucoma than the general population."

The goal of the study was to compare the safety and efficacy of earlier vs later treatment in reducing the risk for POAG in 1636 individuals with ocular hypertension, with baseline IOP ranging from 24 to 32 mm Hg in 1 eye and 21 to 32 mm Hg in the other eye. Participants were randomly assigned to observation or to receive topical ocular hypotensive medication. In the medication group, median duration of treatment was 13.0 years, whereas the observation group had a median duration of 7.5 years without treatment and then received medication for a median of 5.5 years.

To evaluate whether delaying treatment was associated with any harms, the investigators compared the cumulative proportion of participants who went on to have POAG in the original observation group and in the original medication group at a median follow-up of 13 years.

Overall, this proportion was 0.22 in the original observation group (95% confidence interval [CI], 0.19 - 0.25) vs 0.16 (95% CI, 0.13 - 0.19) in the original medication group (P =. 009), or a 27% reduction in glaucoma risk associated with early treatment. For participants at the highest tertile of baseline risk for the development of POAG, based on age, corneal thickness, and baseline IOP, the cumulative proportion of participants who went on to have POAG was 0.40 (95% CI, 0.33 - 0.46) and 0.28 (95% CI, 0.22 - 0.34), respectively.

"There was little evidence of increased adverse events associated with medication," the study authors write. "Absolute reduction was greatest among participants at the highest baseline risk of developing POAG. Individuals at high risk of developing POAG may benefit from more frequent examinations and early preventive treatment."

Limitations of the OHTS study include choice of a target IOP reduction of 20% from baseline, design not that of an epidemiologic study, use of very high thresholds for diagnosing POAG, and use of a convenience sample vs a population-based sample.

"We believe individualized assessment of the risk of developing POAG will be useful to patients and clinicians for deciding on the frequency of examinations and tests as well as the possible administration of preventive treatment," the study authors write. "Clinicians need to consider the patient's age, health status, life expectancy, and personal preferences when making such decisions. Ultimately, the full extent of the penalty for delaying treatment will require longer follow-up to ascertain the incidence and degree of visual impairment by randomization group."

In an accompanying editorial, Alfred Sommer, MD, MHS, from Bloomberg School of Public Health at Johns Hopkins University in Baltimore, Maryland, notes that clinicians should consider whether treating patients with IOP might do more harm than good.

"In the end, the physician is stuck with the persistent problem of whom to treat and whom to watch," Dr. Sommer writes. "The fascinating article by Kass et al provides interesting insights as to many of the issues at stake, but offers little definitive information to guide us. It probably still makes sense that young patients with lots of high risk factors should receive prophylaxis, while elderly patients with few risk factors should not. The endless symposia and debates on how best to manage patients with ocular hypertension will probably continue unabated."

The National Eye Institute and the National Center on Minority Health and Health Disparities, National Institutes of Health; Merck Research Laboratories; Pfizer Inc; and Research to Prevent Blindness supported this study. The study authors and Dr. Sommer have disclosed no relevant financial relationships.

Arch Ophthalmol. 2010;128:276-287.

Depression Is an Inflammatory Disease

A meta-analysis shows higher levels of two cytokines in depressed patients.

People who are chronically ill often get depressed; depressed people are prone to a variety of medical illnesses; and pro-inflammatory cytokines can alter mood and promote illness. To determine whether these proteins play a role in the overlap between depression and inflammation-associated medical disorders, researchers conducted a meta-analysis of 24 case–control studies of basal cytokine levels in a total of 438 unmedicated subjects with major depression and no comorbid illnesses and 350 medically and psychiatrically healthy controls.

Concentrations of tumor necrosis factor-alpha (TNF-) and interleukin (IL)-6 were significantly higher in depressed patients than in controls. The groups showed no significant differences in other interleukins (IL-1β, IL-4, IL-2, IL-8, or IL-10) or in interferon-gamma.

Comment: IL-6 stimulates differentiation and proliferation of immunoglobulin-secreting B-lymphocytes, and TNF- stimulates the release of other pro-inflammatory cytokines and inflammatory prostaglandins. In the brain, these substances inhibit hippocampal neurogenesis; activate the hypothalamic-pituitary-adrenal axis, thus increasing cortisol production; and indirectly increase production of agonists of the N-methyl-D-aspartate receptor, which promotes apoptosis. The central actions of these proteins reduce resiliency of the brain and contribute to the hyperactive stress response that is characteristic of depression, which is further aggravated by loss of hippocampal cells. And, the peripheral actions of these proteins can exacerbate inflammatory diseases, such as diabetes and coronary heart disease. By the same token, the effects of cytokines in the brain can induce depression in patients with these medical diseases. To the extent that inflammation is a component of depression and other systemic conditions, anti-inflammatory drugs might prove helpful (JW Psychiatry Feb 8 2006).

— Steven Dubovsky, MD

Published in Journal Watch Psychiatry March 29, 2010

Triple antiplatelet therapy fails to reduce clinical events

26 March 2010

MedWire News: Triple antiplatelet therapy achieved by adding cilostazol to usual dual antiplatelet therapy with clopidogrel and aspirin did not result in improved 6-month clinical outcomes after drug-eluting stent implantation, the CILON-T investigators reported.

The team put this down to there being a high proportion of hypo-responders even to triple antiplatelet therapy, and highlighted the importance of the observed association between post-treatment platelet reactivity measurements and cardiovascular events.

Lead investigator Hyo-Soo Kim (Seoul National University Hospital, Korea) presented the results at the American College of Cardiology annual scientific sessions held in Atlanta, Georgia, USA.

The CILON-T (CILostazol-based triple antiplatelet therapy ON Ischemic Complication after drug-eluting stenT implantation) trial included 960 patients undergoing percutaneous coronary intervention and drug-eluting stent implantation who were randomly assigned to receive triple antiplatelet therapy with cilostazol, clopidogrel, and aspirin (n=477) or dual antiplatelet therapy with clopidogrel and aspirin (n=483).

Overall, Kim reported, post-treatment platelet reactivity at 6 months was lower with triple than dual antiplatelet therapy, at 210.7 versus 255.7 P2Y12-receptor reaction units (PRU) in the respective groups (p<0.001).

However, there was no difference in the primary composite endpoint of cardiac death, myocardial infarction, ischemic stroke, and target lesion revascularization between groups, which had occurred in 39 (8.5%) patients who received triple antiplatelet therapy and 42 (9.2%) of those who received dual antiplatelet therapy at the 6-month follow-up.

Acknowledging that the study was underpowered to assess hard clinical endpoints, Kim nevertheless proposed that this was at least partly due to the substantial number in the triple antiplatelet therapy group with high post-treatment platelet reactivity.

Indeed, PRU tertiles correlated significantly with the primary endpoint, and there were no thrombotic events (cardiac death, MI, or ischemic stroke) among patients with low PRU values (<210) irrespective of antiplatelet regimen, he emphasized.

“Tailored decision on the adjunctive use of cilostazol according to post-treatment platelet reactivity may be important to reduce clinical events in patients with drug-eluting stent implantation,” Kim concluded.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

American College of Cardiology Annual Scientific Sessions; Atlanta, Georgia: 13–16 March 2010

From Medscape Medical News

US Infants May Have Inadequate Vitamin D Status

Laurie Barclay, MD

Authors and Disclosures

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March 24, 2010 — US infants may have inadequate vitamin D status, according to the results of 2 studies reported in the April issue of Pediatrics.

One study suggests that most US infants are consuming inadequate amounts of vitamin D, based on the 2008 recommendation of the American Academy of Pediatrics (AAP), and a second study showed vitamin D deficiency in a high proportion of infants and their mothers in Boston, Massachusetts.

"There have been few data on the prevalence of US infants meeting AAP vitamin D recommendations," write Cria G. Perrine, PhD, from the Centers for Disease Control and Prevention in Atlanta, Georgia, and colleagues. "In November 2008, the [AAP] doubled the recommended daily intake of vitamin D for infants and children, from 200 IU/day (2003 recommendation) to 400 IU/day. We aimed to assess the prevalence of infants meeting the AAP recommended intake of vitamin D during their first year of life."

The investigators estimated the percentage of infants (n = 1952 - 1633) meeting current AAP vitamin D recommendations at ages 1, 2, 3, 4, 5, 6, 7.5, 9, and 10.5 months, based on data from the Infant Feeding Practices Study II, performed from 2005 to 2007.

Regardless of whether infants were fed breast milk or formula, the use of oral vitamin D supplements was low, ranging from 1% to 13%, and varied by age. Only 5% to 13% of infants fed breast milk but no formula met either the 2003 or the 2008 AAP recommendation. The 2003 recommendation was met by 28% to 35% of mixed-fed infants, but only 9% to 14% would have met the 2008 recommendation. For infants fed formula but not breast milk, 81% to 98% met the 2003 recommendation, but only 20% to 37% would have met the 2008 recommendation.

"Our findings suggest that most US infants are not consuming adequate amounts of vitamin D according to the 2008 AAP recommendation," the study authors write. "Pediatricians and health care providers should encourage parents of infants who are either breastfed or consuming <1>

Limitations of this study include self-reported data subject to recall bias and a lack of generalizability to the national population because the study sample had higher educational levels, fewer children, and longer duration of breastfeeding. In addition, the investigators could not determine the exact quantity of vitamin D that infants obtained from oral supplements.

"Pediatricians and other health care providers can support and promote daily oral vitamin D supplementation of infants by explaining to parents the purpose and benefits of vitamin D supplementation, reminding parents at each visit to give vitamin D supplements to their children, suggesting that parents develop a daily intake routine to help them remember to administer the supplement, asking parents about any adverse effects of supplementation or barriers to giving their infants supplements, and helping parents to overcome any barriers that they report," the study authors conclude.

The goal of the second study, by Anne Merewood, MPH, IBCLC, from Boston Medical Center, and colleagues, was to assess vitamin D status and related factors in a cohort of 459 healthy newborns and their mothers in Boston.

This cross-sectional study was performed from 2005 to 2007 in an urban Boston teaching hospital with 2500 births per year, using a questionnaire and medical-record data to examine factors that may be associated with vitamin D deficiency. Within 72 hours of birth, infant and maternal blood were obtained by venipuncture for measurement of 25-hydroxyvitamin D [25(OH)D] status, assessed by competitive protein binding.

In analyses on 376 newborns and 433 women, the median infant 25(OH)D level was 17.2 ng/mL (95% confidence interval [CI], 16.0 - 18.8 ng/mL; range, <5.0>

Factors associated with increased risk for infant vitamin D deficiency were maternal deficiency (adjusted odds ratio [aOR], 5.28; 95% CI, 2.90 - 9.62), winter birth (aOR, 3.86; 95% CI, 1.74 - 8.55), black race (aOR, 3.36; 95% CI, 1.37 - 8.25), and maternal body mass index of 35 kg/m² or higher (aOR, 2.78; 95% CI, 1.18 - 6.55).

Maternal prenatal vitamin use throughout the second and third trimesters was associated with lower risk for infant deficiency (aOR, 0.30; 95% CI, 0.16 - 0.56), and prenatal vitamin use of 5 or more times per week in the third trimester was associated with lower risk for maternal deficiency (aOR, 0.37; 95% CI, 0.20 - 0.69). Nonetheless, more than 30% of women who took prenatal vitamins were still vitamin D deficient at the time of delivery.

Study limitations include retrospective data collection and that baseline values of 25(OH)D missing for some infants.

"A high proportion of infants and their mothers in New England were vitamin D deficient," the study authors write. "Prenatal vitamins may not contain enough vitamin D to ensure replete status at the time of birth."

The Centers for Disease Control and Prevention study was supported by the US Food and Drug Administration, Centers for Disease Control and Prevention, Office of Women's Health, National Institutes of Health, and Maternal and Child Health Bureau in the US Department of Health and Human Services. The Boston study was supported by grants from Health Resources and Services Administration/Bureau of Maternal and Child Health; US Department of Agriculture/Cooperative State Research, Education, and Extension Service; and General Clinical Research Centers Program of the National Center for Research Resources, National Institutes of Health. The study authors have disclosed no relevant financial relationships.

Pediatrics. 2010;125:627-632, 640-647.

March 23, 2010 (Atlanta, Georgia) — Hospital-onset healthcare-facility-associated Clostridium difficile infections (CDI) have increased in incidence and have surpassed methicillin-resistant Staphylococcus aureus (MRSA) infections, according to a new study of a large cohort of patients from community hospitals.

Becky A. Miller, MD, an infectious disease fellow from Duke University in Durham, North Carolina, presented the findings during an oral session here at the Fifth Decennial International Conference on Healthcare-Associated Infections 2010.

"This is the first time this has been described using patient-level data (i.e., with the number of cases as the numerator and the number of patient days as the denominator)," Dr. Miller told Medscape Infectious Diseases.

"We think this trend, particularly in community hospitals, would not have been captured without our large network of 39 hospitals where we perform infection control and surveillance," she said. "We were also unaware that cases of nosocomial C difficile infection had increased and surpassed MRSA."

The researchers performed a prospective cohort study in 28 community hospitals participating in the Duke Infection Control Outreach Network between January 2008 and December 2009.

The cohort consisted of 3,007,457 patient-days. Numerically, nosocomial CDI was the most common healthcare-associated infection (847 cases), followed closely by nosocomial bloodstream infection (838 cases).

Nosocomial infections due to MRSA and intensive care unit device-related infections were approximately equal, at 680 and 681 cases, respectively.

Patients with nosocomial CDI (n = 840) and nosocomial MRSA (n = 655) were equally likely to be male, and to have diabetes or end-stage renal disease requiring hemodialysis. However, patients who developed nosocomial CDI were, on average, older than patients who developed nosocomial MRSA infection (65 vs 59 years; P < .0001). In addition, time to infection was, on average, 8 days for CDI and 7 days for MRSA infection (P < .0001), and overall mortality was higher among patients with MRSA infection than CDI (P < .0001).

The rate of nosocomial CDI was 0.28 cases per 1000 patient-days, whereas the rate of nosocomial MRSA infection was 0.23 cases per 1000 patient-days. Thus, nosocomial CDI occurred 25% more frequently than nosocomial MRSA infection.

Since 2007, rates of healthcare-associated MRSA infection have steadily decreased, whereas rates of CDI have increased, Dr. Miller said during her presentation.

According to Dr. Miller, C difficile spores are shed in stool, and these spores can persist in the hospital environment for months. "These infections are not being prevented by methods that are clearly working to prevent nosocomial infections due to MRSA," she said. She added that "we think that this study represents the tip of the iceberg, as we did not include nosocomial C difficile cases diagnosed after patients leave the hospital."

In another presentation on C difficile, researchers described a targeted strategy to eliminate C difficile using ultragermicidal bleach wipes. Robert Orenstein, DO, from the Mayo Clinic in Rochester, Minnesota, reported the findings here in a poster session.

"The beauty of this project was that implementation was relatively simple — it required putting together a committed team and emphasizing our goal of improving patient outcomes," Dr. Orenstein told Medscape Infectious Diseases.

The researchers targeted 2 units with a focused intervention of daily cleaning of all patient rooms with Clorox brand ultragermicidal bleach wipes containing 6.15% sodium hypochlorite, and cleaning after the patient had been discharged.

Cleaning was assessed by environmental services supervisors, and Clean-Trace technology was used. Patients and environmental services employees who cleaned the rooms responded to a survey regarding satisfaction and tolerance of the cleaning procedure.

Before the intervention was initiated, the incidence of CDI was 18.4 per 10,000 patient-days; after the intervention was initiated, the incidence was 3.76 per 10,000 patient-days, "far exceeding" their goal of a reduction in incidence of 30%, Dr. Orenstein said.

According to the authors, patients tolerated the cleaning well, and although environmental services "employees initially had concerns regarding odor and irritation, these were resolved." The cost of the intervention was estimated at $18,671 per year.

"I am struck by the fact that our highest-risk unit has gone 6 months without a hospital-acquired case attributable to their unit, despite the fact that the overall incidence (i.e., cases admitted with this infection) continues to rise," Dr. Orenstein said. "This suggests what we did really had a great impact," he added. "This is especially gratifying knowing the impact that C difficile disease can have on our patients lives."

"C difficile has been in the news for the last decade," said Carlene A. Muto, MD, medical director for infection control at the University of Pittsburgh School of Medicine in Pennsylvania. "What has taken focus this year is that the environment matters," she said.

According to Dr. Muto, an analysis by their group presented in the late-breaking session described the undetected reservoir in patients who asymptomatically carry C difficile (~6% of the patients tested).

"Many studies have described noncompliance with cleaning patient rooms and how a focused effort can change this behavior," Dr. Muto told Medscape Infectious Disease. "Our group implemented a bleach/detergent cleaning program years ago, but since June 2009, we have used this product on every surface, every time, not just in the rooms of patients known to be positive."

She noted that "patients not known to be colonized/infected one day may be so the next. We did see a decrease in C difficile healthcare-associated infections using this approach."

Neither study was commercially funded. Dr. Miller, Dr. Orenstein, and Dr. Muto have disclosed no relevant financial relationships.

Fifth Decennial International Conference on Healthcare-Associated Infections (ICHAI) 2010: Abstract 386, presented March 20, 2010; Abstract 142, presented March 19, 2010.

March 12, 2010 (New Orleans, Louisiana) — An unusual type of bone fracture has been reported in women who have taken bisphosphonates for osteopenia and osteoporosis for more than 4 years, according to 2 studies reported here at the American Association of Orthopaedic Surgeons 2010 Annual Meeting.

"Bisphosphonates are wonderful drugs. They've cut the vertebral fracture rate by 70% and the hip fracture rate by 50%. People die from hip fractures. There has been great enthusiasm for these drugs, and clearly the rate of hip fractures is decreasing," said Joseph Lane, MD, chief of the Metabolic Bone Service at the Hospital for Special Surgery and professor of orthopedic surgery at Weill Cornell Medical College in New York CIty.

But concern is mounting that long-term use might adversely affect bone quality, he added.

There is significant morbidity and mortality associated with osteoporotic fractures. Vertebral fractures can result in chronic disabling pain, and 1 in 5 patients who have a hip fracture die within 1 year, researchers told meeting attendees.

Bisphosphonates have been shown to prevent the rapid loss of bone that occurs during the first years of menopause and to reduce the incidence of fracture in postmenopausal women.

However, there have been reports of "peculiar" fractures — that is, low-energy femur fractures that are typically transverse or slightly oblique, diaphyseal, or subtrochanteric, with thickened cortices and a unicortical beak — in patients who have been on long-term bisphosphonate treatment. The first report was published in 2005 in a "semi-obscure" journal, Dr. Lane told Medscape Orthopaedics.

In a small prospective study, Dr. Lane and his colleagues obtained bone biopsies from the lateral femurs of 21 postmenopausal women with femoral fractures. Twelve of the women had been on bisphosphonate therapy for an average duration of 8.5 years, and 9 had no history of bisphosphonate use.

They found that the heterogeneities of the mineral/matrix ratio were significantly reduced in the bisphosphonate group by 28%, and the crystallinity of the bone was significantly reduced by 33% (P < .05).

"The biopsies showed that the bone was very, very old," Dr. Lane said. "This suggests to us that suppression of bone turnover, which is what bisphosphonates do [over the] long term, results in a loss of heterogeneity of the tissue properties, and this may be a contributing factor to the risk of atypical fractures that we are starting to see."

In a second unrelated study, Melvin P. Rosenwasser, MD, Robert E. Carroll Professor of Hand Surgery at Columbia University in New York City, and colleagues evaluated the bone structure of 112 postmenopausal women with primary osteoporosis, 62 of whom had been taking bisphosphonates for at least 4 years, and 50 control subjects who were taking only calcium and vitamin D supplements.

They found that bisphosphonate use improved structural integrity early in the course of treatment, but that these gains were diminished as treatment extended beyond 4 years.

"It seems as if there is a plateau of benefit at 4 or 5 years and, after that, the benefit is negated. In the early treatment period, patients using bisphosphonates experienced improvements in all parameters, including decreased buckling ratio and increased cross-sectional area," he said in an interview with Medscape Orthopaedics. "But after 4 years of use, these trends reversed."

Women who are being treated with bisphosphonates should take a drug holiday if they have been on them for 5 years, both investigators told Medscape Orthopaedics.

"These drugs are excellent," Dr. Rosenwasser said. "But women should take some time off of them. Exercise caution. Don't throw them away, but don't stay on them for long periods."

Dr. Lane added that "bisphosphonates are wonderful for preventing fractures. At 5 years, however, go back and talk to your doctor and ask if you should continue the drug or take a rest period. This is what I would tell my patients. Nobody in my field would ever treat a patient past 5 years. We're never going to do that again because our information suggests that you need a rest period."

It would also be a good idea for women who have been on bisphosphonates for more than 5 years to have a test to measure their bone turnover, Dr. Lane said.

However, this can be problematic for a number of reasons. Many physicians do not know how to interpret tests for bone turnover. The tests are controversial, and most insurance companies will not pay for them, "so it's a real problem right now," he said.

The American Society of Bone and Mineral Research has struck a task force on these atypical fractures and is in the process of developing a consensus statement to warn the public, Dr. Lane added. "The goal is to have this available by the fall of 2010, at least to give some guidelines to the public."

Approached for independent comment about these 2 studies, Thomas Moore, MD, director of trauma at Emory University in Atlanta, Georgia, agreed that there is increasing evidence that the long-term use of bisphosphonates can cause spontaneous transverse fractures, particularly in the femur in women.

"The question is whether or not the [US Food and Drug Administration] should put out some warnings about this particular clinical entity. I myself have seen this occur. Women are taking these bisphosphonates for osteoporosis, and in fact they do decrease hip fractures, but these new types of fractures represent a catastrophic complication that really needs to be looked at statistically, and appropriate warnings [need to] be put out."

Dr. Lane, Dr. Rosenwasser, and Dr. Moore have disclosed no relevant financial relationships.

American Association of Orthopaedic Surgeons (AAOS) 2010 Annual Meeting: Abstract 241, presented March 10, 2010; Abstract 339, presented March 11, 2010.

SUMMARY AND COMMENT

Preventing Recurrence of Aspirin-Related Peptic Ulcers

• March 5, 2010
• David J. Bjorkman, MD, MSPH (HSA), SM (Epid.)

Famotidine, a histamine-2–receptor antagonist, was less effective than pantoprazole, a proton-pump inhibitor.

• Reviewing:
• Ng F-H et al. Gastroenterology 2010 Jan; 138:82

Introduction

Hand osteoarthritis (OA) has an estimated prevalence of 20% to 30% [1,2], making the hand the second most frequent site of OA pain [1,3]. The prevalence of hand OA increases with age, surpassing 50% after patients reach the age of 60 years [4-6]. Symptoms include not only pain but also functional impairment in the form of stiffness, reduced grip strength, reduced hand mobility, and difficulty performing dexterous tasks [2,4,7,8].

Function is irreversibly compromised in OA of the hand as articular surfaces are eroded and deformed. In OA of the knee and hip, a definitive improvement in function can be obtained with surgical replacement of the joint, but prosthetic joints have been less successful for hand OA [9]. More often, surgery for hand OA may be performed for cosmetic reasons rather than to provide functional improvement (for example, patients self-conscious of and eager to remove Heberden nodes).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended for the management of pain in patients with hand OA who do not respond to physical measures and acetaminophen [10]. Though effective for the treatment of mild to moderate OA pain [11], NSAIDs have been associated with an increase in the risk of serious gastrointestinal adverse events, including ulcers, perforations, and bleeding related to dose and duration of use [12,13]. The potential risk of cardiovascular [14-16] and renal [17,18] adverse events with NSAIDs is also considered exposure-related and generally observed during long-term NSAID therapy.

Treatment guidelines recommend topical NSAIDs as effective monotherapy for relief of OA pain in superficial joints, such as those in the hands [10], with the potential to mitigate the risk of NSAID-related adverse events by reducing systemic NSAID exposure. Topical diclofenac sodium 1% gel provided safe and effective pain relief compared with placebo in a large clinical trial in patients with hand OA [19]. Administration of diclofenac sodium 1% gel results in substantially lower systemic diclofenac concentrations than occur following oral administration [20].

NSAIDs relieve OA pain but are not believed to alter the underlying changes that produce biomechanical limitations of physical function in OA. However, other interventions that provide symptomatic relief without altering underlying structural changes, such as opioids, have been associated with improvement of physical function in OA of the knee and hip [21]. This finding suggests that in addition to the biomechanical limitations caused by hypertrophic changes in OA, it is possible that pain or the anticipation of pain leads to voluntary and involuntary restriction of activity [22]. If this is true, relief of pain alone may improve physical function in OA although no biomechanical improvement has occurred. In the present analysis, we tested the hypothesis that pain relief is associated with improved physical function in patients with hand OA.

RACE II: Lenient heart rate control in AF not inferior to strict control

Watch our Video Highlights interview on RACE II

MedWire News: Less rigorous control of heart rate in patients with permanent atrial fibrillation (AF) appears to be as effective as strict rate control at preventing serious adverse events, including death from all causes, reported investigators from the RACE II study at the 59th annual Scientific Sessions of the American College of Cardiology (ACC), in Atlanta, GA, USA, and online in the New England Journal of Medicine.

“Lenient rate control may be adopted as the first-choice rate control strategy in patients with permanent atrial fibrillation,” said Isabelle C. Van Gelder (University Medical Center Groningen and the Interuniversity Cardiology Institute in Utrecht, The Netherlands).This recommendation applies to patients both at high risk (CHADS 2 [congestive heart failure, hypertension, age >75 years, diabetes, and prior stroke] score 2-6).and low risk (CHADS 2 score 0-1) for complications from permanent AF.

The RACE II trial compared event rates for 311 patients randomized to lenient control (resting heart rate <110 beats per minute [bpm]) and 303 assigned to strict control (resting rate <80 bpm, exercise rate <110 bpm). The primary endpoint was a composite of cardiovascular mortality, heart failure (HF) hospitalization, stroke, systemic emboli, major bleeding, syncope, sustained venous thromboembolism, cardiac arrest, life-threatening adverse effects of rate-control drugs, and implantation of a pacemaker for bradycardia or of an implantable cardioverter defibrillator for ventricular arrhythmias.

Patients were treated with negative dromotropic agents, including beta-blockers, non-dihydropyridine calcium-channel blockers (verapamil or diltiazem), and digoxin, alone or in combination. Dosages were adjusted until the heart-rate target was achieved.

After 3 years of follow-up, the estimated cumulative incidence of adverse events was 12.9% in the lenient control group, vs 14.9% in patients on strict control (absolute difference of -2.0%, hazard ratio 0.84; neither difference was statistically significant). Deaths from any cause occurred in 5.6% of patients on lenient control and 6.6% on strict control.

At the end of follow-up, about 46% of patients in each group had symptoms associated with AF (including dyspnea, fatigue, and/or palpitations). About 70% in each group were in New York Heart Association functional class I, 23% were in class II, and 6.5% were in class III (p=0.74 for all comparisons). There were no significant differences in the frequency of hospitalization or of adverse drug-related events between the two groups.

Rates of individual adverse events within the primary composite endpoint were similar, although Van Gelder noted that the study was not powered to detect significant differences among the various components.

In a sub-group analysis by CHADS 2 score, fatal and nonfatal endpoints occurred in 4.5% of lenient group patients and 3.5% of strict group patients with CHADS 2 scores of <2. Among patients with scores of 2 or greater, 5.1% of lenient group patients and 10.0% of strict group patients had an event (p=0.02 for non-inferiority).

Free full text http://content.nejm.org/cgi/content/full/NEJMoa1001337v1

Lipid-Lowering Therapy and Risk for Bleeding Among Warfarin Users

March 2, 2010 | Jamaluddin Moloo, MD, MPH | General Medicine

Bleeding risk was elevated after cytochrome P₄₅₀ enzyme inhibitors were added to warfarin regimens.

Reviewing: Schelleman H et al. Am J Med 2010 Feb 123:151

PERINDOPRIL

Als je een beta-blpcker gebruikt zoals perindopril dan geen kalium sparende plas tablet gebruiken. In de gebruiksaanwijzing staat ook, vertel uw dokter als U plas-middelen of kalium-sparende plas-middelen gebruikt.
kalium-sparende plas-middelen zoals triamteree,sirolactonof amiloride
Ook geen zouten met extra kalium.

Freek Verheugt on EXPLORE-Xa

"Nearly 500 patients with atrial fibrillation were randomized to three doses of the novel oral direct factor Xa blocker betrixaban for 5 months, or to warfarin. Bleeding and side effects were the lowest with low-dose (40 mg) betrixaban. Betrixaban is cleared completely by the liver and seems to be a promising once-daily Xa blocker. Larger trials are warranted, though."

Freek Verheugt on the study

“In South Korea, 2701 patients on clopidogrel and aspirin after drug-eluting stent (DES) implantation were randomized 12 months later to either continue with double antiplatelet therapy or stop receiving clopidogrel and continue with aspirin alone. At 19 months after randomization, there was no benefit to continuing double therapy compared with aspirin. Dual antiplatelet therapy beyond 12 months after DES implantation is not shown to be beneficial.”

Wat is het verschil tussen marcoumar (phenprocoumon) en sintrom (acenocoumarol) en waarom kiest de ene arts voor het ene medicijn en een andere arts voor een ander medicijn?

Beide middelen zijn antistollingsmiddelen van de coumarine-groep. Dit betekent dat ze dezelfde werking hebben. Het grote verschil tussen deze medicijnen zit in de werkingsduur die bij Marcoumar ontzettend lang is en bij sintrom heel kort. Bij marcoumar duurt het 140 uur (ongeveer 7 dagen) voor de helft van het medicijn uit het bloed is verdwenen. Bij Sintrom is dat maar 11 uur.

Wat zijn de voor- en nadelen van beide medicijnen?

Phenprocoumon (Marcoumar)

• betere kwaliteit van antistolling: door zijn lange werkingsduur heeft phenprocoumon het voordeel minder te schommelen op lange termijn dan acenocoumarol. De patiënten zijn een groter deel van de tijd binnen hun INR-streefwaarden.

• tijdstippen van inname en INR-meting zijn minder belangrijk: door de werkingsduur die veel langer is dan een dag, is het verband tussen het innemen van de phenproumon en de INR op die dag beperkt. Verschuivingen in de tijdstippen van inname en meting zullen dan ook weinig effect hebben op de gemeten INR.

• het eenmalig vergeten van een inname heeft minder gevolgen: door de lange werkingsduur is de INR bij phenprocoumon niet alleen afhankelijk van de ingenomen medicatie van die dag, maar ook van de laatste 14 dagen. Dit betekent dat als men een dag vergeet in te nemen, dit niet veel effect zal hebben op de INR behalve een lichte daling in de daarop volgende dagen.

• bij lichte bloedingen of een te hoge INR zal het onderbreken van de medicatie weinig effect hebben: door de lange werkingsduur heeft het een dag overslaan van phenprocoumon enkel een trage daling van de INR als gevolg. Als een sneller effect moet geraliseerd worden, zal vitamine K nodig zijn
  bij lagere INR-waarden dan wat het geval is bij acenocoumarol. Indien onmiddellijke correctie van de stolling noodzakelijk is, dient 4-Factorenconcentraat te worden toegediend.

• het beredeneren van de doserering is wat moeilijker en wat meer abstract: door de lange werkingsduur is de INR bij phenprocoumon afhankelijk van de inname van de laatste 14 dagen en moet om de dosering te beredeneren dus rekening worden gehouden met de voorafgaande inname. Het effect van phenprocoumon kan een hele tijd doorwerken. Als de inname een aantal dagen is gestopt of vitamine K is gegeven, zal de INR toch nog verhoogd zijn, en dient niet opnieuw (volledig) te worden opgestart met de medicatie. Bij phenprocoumon wordt vaak gezien dat na toediening van vitamine K de INR normaal wordt maar nadien weer stijgt nadat het vitamine K effect is uitgewerkt. Het effect van phenprocoumon duurt langer dan dat van vitamine K.
  

Acenocoumarol (Sintrom)

• mindere kwaliteit van antistolling: door zijn korte werkingsduur heeft acenocoumarol het nadeel meer te schommelen op korte en lange termijn dan acenocoumarol. De patiënten zijn een kleiner deel van de tijd binnen hun INR-streefwaarden dan bij phenproucomon.

• tijdstippen van inname en INR-meting zijn heel belangrijk: door de korte werkingsduur die niet veel langer is dan een dag, is het verband tussen het innemen van de acenocoumarol en de INR op die dag heel duidelijk. Verschuivingen in de tijdstippen van inname en meting zullen dan ook potentieel belangrijke effect hebben op de gemeten INR.

• het eenmalig vergeten van een inname heeft duidelijke gevolgen: door de korte werkingsduur is de INR bij acenocoumarol sterk afhankelijk van de ingenomen medicatie van die dag, en in mindere mate van de voorgaande 2 dagen. Dit betekent dat als men een dag vergeet in te nemen, dit onmiddellijk een duidelijk effect zal hebben op de INR. Twee dagen vergeten en de INR zal bijna normaal zijn.

• bij lichte bloedingen of een te hoge INR zal het onderbreken van de medicatie een vlug effect hebben: door de korte werkingsduur heeft het een dag overslaan van acenocoumarol een snelle daling van de INR als gevolg. Dit betekent dat gemakkelijk tegen de patiënt kan worden gezegd een dagje over te slaan. Vitamine K zal enkel nodig zijn om hogere INR-waarden te laten dalen, hogere waarden dan bij phenprocoumon. Indien onmiddellijke correctie van de stolling noodzakelijk is, dient 4-Factorenconcentraat te worden toegediend.

• het beredeneren van de doserering is wat gemakkelijker en duidelijker: door de korte werkingsduur is de INR bij acenocoumarol vooral afhankelijk van de inname van de voorgaande dag. Het is dus gemakkelijker om de dosis te
  beredeneren. Wat men vandaag doet, heeft morgen effect en in principe is er bijna geen uitgesteld effect zoals bij pheprocoumon. Als de inname een aantal dagen is gestopt of vitamine K is gegeven, zal de INR normaal zijn, en dient opnieuw te worden opgestart met de medicatie.
  

Samenvattend is het voordeel van phenprocoumon (Marcoumar) dus zijn betere kwaliteit van antistolling door zijn lange werkingsduur, en betekent dit dat er wat losser met het tijdstip van inname en meting kan worden omgegaan. Het moet bekeken worden als een wat "log" medicijn: het reageert wat trager maar wat je doet heeft een langdurig effect. Een beetje als het sturen van een grote olietanker; het duurt even voor het schip op koers is, en overdreven bewegingen geven lange afwijkingen van de koers, maar als het schip op koers ligt, zal het moeilijker van die koers afwijken. Sleepboten (vitamine K) kunnen nodig zijn om snelle correcties te doen. Acenocoumarol (Sintrom) is als een zeiljacht: makkelijk wendbaar; kleine bewegingen geven onmiddellijk koersafwijkingen die weer snel kunnen corrigeren maar de koers is moeilijk houdbaar. Sleepboten zijn enkel nodig is bijzondere gevallen.

Waarom kiest de ene arts of trombosedienst voor phenprocoumon en de andere voor acenocoumarol?
Kort gezegd: de ene vaart liever met een olietanker en de andere met een zeiljacht. De ene heeft meer oog op de stabiliteit en de andere op de wendbaarheid. En hoewel er genoeg aanwijzingen waren voor het voordeel van phenprocoumon, is het pas recent dat drie grote studies (Gadisseur et al, Penning-van Beest et al, Fihn et al) zijn uitgevoerd om de twee medicijnen te vergelijken. Alledrie geven ze hetzelfde resultaat, namelijk dat het langwerkende phenprocoumon een beter kwaliteit van antistolling geeft. In Italie is een vergelijking gedaan tussen acenocoumarol (Sintrom) en warfarine (werkingsduur 40 uur) en ook daar kwam het langer werkende warfarine als beter uit de bus dan het kortwerkende acenocoumarol.

Deze pagina is geschreven door Dr. A.P.A. Gadisseur, toen werkzaam als internist - hemeatoloog bij het LUMC en de Trombosedienst Leiden. Meer informatie over anti-stolling treft u aan op de site van de