Office protocols: Vitamin D – one physician’s experience

Greg Hood, MD, Internal Medicine, 10:21PM Jan 15, 2011

Office protocols can significantly streamline and ease the work which needs to get done in the day's work. Having a protocol for evaluation and management of vitamin D deficiency and vitamin D insufficiency is an excellent example of individualizing management of a medical issue for your office.

Vitamin D has been discussed in a number of recent articles on Medscape. My particular interest in vitamin D goes back 8-10 years. Having received the traditional education in medical school about vitamin D I managed it just as everyone did during my residency and years in practice in San Diego. However, within a couple years of practicing in Kentucky I had noticed that some conditions, notably osteoporosis, did not respond as favorably to treatment in Kentucky as they had in southern California. The only logical conclusion when treatment outcomes for patients of the same demographics and treatment recommendations were significantly different was that there was a difference based in the geography. In this case latitude and average temperature differences make a significant difference in the amount of ambient Sunlight to which patients were being exposed.

As a number of studies and reports have stated over the last several years there are many indications that the level of vitamin D reported to be "normal" and the amount of vitamin D required to achieve this from supplementation have been woefully inadequate.

I also think the recent calls for a reduction in calcium supplementation appear prudent. From my reading, a patient who is vitamin D deficient absorbs roughly 15% of their ingested calcium. As the vitamin D levels improve the corresponding increases in calcium absorption should mitigate what may have been excessive calcium recommendations, in essence putting the milk cart before the horse.

Recently, there have been recommendations to increase the RDA of vitamin D. The proposed increases are conservative to say the least. The lower limit of normal, 32 from our lab, and the new recommendations for intake are merely sufficient to avert rickets and osteomalacia, hardly the harbingers of good health.

As implied by the seminal NEJM article I have seen between a third and forty percent of my patients who came to me thinking that they had fibromyalgia resolve their symptoms when treated to vitamin D levels in the 70s, and another third report their symptoms lessen in intensity. Over 85% of the MS patients I see have been vitamin D deficient.

I agree that there is not concrete, double blind validated proof of many of the assertions about correcting vitamin D levels. However, when one considers the potential that something as simple as this may move the needle on the incidences of pancreatic cancer, breast and ovarian cancer it is hard to argue against working more robustly in the normal range. One study out of Canada, a low vitamin D/Sun exposure area, stating that vitamin D deficient women were more likely to get breast cancer, that their cancers were more aggressive, and responded less well to treatment certainly begs the question of why to not treat this problem more rigorously.

Yet the degree of increase is not my biggest gripe with the recommendations. To date I have yet to see sufficient attention paid in the guidelines to customizing the RDA for latitude. Patients in Key West are given the same advice that patients in Bangor, Maine receive. It deserves mentioning that simply living in a latitude south of Atlanta doesn't mean one will have Sun exposure. I have seen patients from Miami who avoided the Sun who had undetectable levels of vitamin D. Colleagues from San Diego have told me that they have seen a progressive frequency of vitamin D deficiency as sunscreen use has escalated.

It is for all the above reasons that I believe vitamin D protocols are something useful for you to consider in your office. If you haven't been already, test at least the at risk patients including those with dark skin, those with low bone density, fibromyalgia, osteomalacia, multiple sclerosis, and those whom are heavy users of sunscreen or whom avoid the Sun by virtue of their jobs or schedules. As you get a sense of your own practice's frequency of deficiency you may wish to expand the circles of patients you test.

This testing will give you an idea of how much vitamin D supplementation is needed for your area. As you see patients who come back with very good levels and review how much they've been taking it may help guide you to preferred replacement levels at your latitude. Many of my patients are taking between 2000 and 5000 units of over the counter vitamin D a day. Some do better with the size of the prescription vitamin D and do better keeping up with one pill on a scheduled basis than daily vitamins. In either case it is important to continue to monitor their levels and response to therapy, especially if they are taking 4000IU a day or more, or prescription capsules. Once you get familiar with how vitamin D responds in your area you may be able to move the monitoring on this somewhat expensive blood test to a less frequent interval, every two years in some cases of maintenance therapy, for example.

It is important to build into your protocol exceptions of patients with whom you will wish to avoid vitamin D supplementation, or at least will proceed with more caution, and more intensive monitoring, such as patients with sarcoidosis and other granulomatous conditions, those with cancer or undiagnosed/uncorrected hypercalcemia.

It typically takes 10-12 weeks for patients to note symptomatic relief. Serum levels of vitamin D should be stable within 3-4 months from initiating therapy so this can be a good time frame in which to retest, at least as you get used to supplementing and in higher risk patients. As a goal target blood level, +/- 75nmol/L is appearing appropriate at the time of this writing. Targeting this range I have yet to make a patient vitamin D toxic. If you are using the prescription vitamin D it is helpful to ask patients when they took their last capsule prior to testing, because if you check the day or so after the last capsule you may not see a steady-state result. It is also helpful to build into your protocol monitoring of serum calcium, and at times PTH and ionized calcium levels.

Those hoping for a cookbook protocol to be laid out in this entry are surely disappointed. Unfortunately, this issue underscores the importance of using one's brain, training and observational skills in optimizing the delivery of healthcare. However, this issue equally underscores how using these skills can optimize and streamline management within your practice of health issues. Once you've worked out the details monitoring protocols, refills, and patient recalls can be customized and benefit your patients and your office flow.

Disclaimer: This article is general discussion of information and opinions on the part of one internist. Derivation of protocols or individual treatment decisions by health professionals who read this are their own choices from their own clinical judgment. Lay persons who read this should consult with their healthcare provider prior to embarking on, or adjusting their health approach. Nothing discussed should be considered a substitute for a personal interaction with your own physician or healthcare provider. Author accepts no risk or responsibility for decisions others make based upon the opinion(s) as stated above.

This is the Medscape Neurology Minute. I'm Dr. Alan Jacobs. Compared with epidemiologic data, controlled trials have yielded mixed results on the effect of therapeutic homocysteine lowering on stroke prevention. Now, researchers at the UCLA Stroke Center in Los Angeles California have performed a meta-analysis of randomized controlled trials to assess the efficacy of folic acid supplementation in the prevention of stroke. Their study consisted of 13 trials with 39,000 participants enrolled for folic acid therapy to reduce homocysteine, in which stroke was reported as an outcome measure. Across all trials, folic acid supplementation was associated with a trend toward mild benefit that did not reach statistical significance in reducing the risk for stroke. The relative risk for non-secondary-prevention trials was significant at 0.89. In stratified analyses, a greater beneficial effect was seen in the trials testing combination therapy of folic acid plus vitamins B₆ and B₁₂, and in the trials that disproportionately enrolled men. The investigators concluded that although folic acid supplementation did not demonstrate a major effect in averting stroke, potential mild benefits in primary stroke prevention, especially when folate is combined with B vitamins and in men, does merit further investigation. This article was selected from Medscape Best Evidence. I'm Dr. Alan Jacobs.

This is the Medscape Neurology Minute. I'm Dr. Alan Jacobs. Compared with epidemiologic data, controlled trials have yielded mixed results on the effect of therapeutic homocysteine lowering on stroke prevention. Now, researchers at the UCLA Stroke Center in Los Angeles California have performed a meta-analysis of randomized controlled trials to assess the efficacy of folic acid supplementation in the prevention of stroke. Their study consisted of 13 trials with 39,000 participants enrolled for folic acid therapy to reduce homocysteine, in which stroke was reported as an outcome measure. Across all trials, folic acid supplementation was associated with a trend toward mild benefit that did not reach statistical significance in reducing the risk for stroke. The relative risk for non-secondary-prevention trials was significant at 0.89. In stratified analyses, a greater beneficial effect was seen in the trials testing combination therapy of folic acid plus vitamins B₆ and B₁₂, and in the trials that disproportionately enrolled men. The investigators concluded that although folic acid supplementation did not demonstrate a major effect in averting stroke, potential mild benefits in primary stroke prevention, especially when folate is combined with B vitamins and in men, does merit further investigation. This article was selected from Medscape Best Evidence. I'm Dr. Alan Jacobs.

Abstract

Objective To investigate whether dietary supplementation with B vitamins or omega 3 fatty acids, or both, could prevent major cardiovascular events in patients with a history of ischaemic heart disease or stroke.
Design Double blind, randomised, placebo controlled trial; factorial design.
Setting Recruitment throughout France via a network of 417 cardiologists, neurologists, and other physicians.
Participants 2501 patients with a history of myocardial infarction, unstable angina, or ischaemic stroke.
Intervention Daily dietary supplement containing 5-methyltetrahydrofolate (560 μg), vitamin B-6 (3 mg), and vitamin B-12 (20 μg) or placebo; and containing omega 3 fatty acids (600 mg of eicosapentanoic acid and docosahexaenoic acid at a ratio of 2:1) or placebo. Median duration of supplementation was 4.7 years.
Main outcome measures Major cardiovascular events, defined as a composite of non-fatal myocardial infarction, stroke, or death from cardiovascular disease.
Results Allocation to B vitamins lowered plasma homocysteine concentrations by 19% compared with placebo, but had no significant effects on major vascular events (75 v 82 patients, hazard ratio, 0.90 (95% confidence interval 0.66 to 1.23, P=0.50)). Allocation to omega 3 fatty acids increased plasma concentrations of omega 3 fatty acids by 37% compared with placebo, but also had no significant effect on major vascular events (81 v 76 patients, hazard ratio 1.08 (0.79 to 1.47, P=0.64)).
Conclusion This study does not support the routine use of dietary supplements containing B vitamins or omega 3 fatty acids for prevention of cardiovascular disease in people with a history of ischaemic heart disease or ischaemic stroke, at least when supplementation is introduced after the acute phase of the initial event.
Trial registration Current Controlled Trials ISRCTN41926726.

B Vitamins and -3 Fatty Acids for Preventing Cardiovascular Disease

Supplementation did not prevent major CV events in patients with previous myocardial infarction, unstable angina, or stroke.

Preventive Effects of Mindfulness in Recurrent Depression

A potentially valuable approach, especially for patients with unstable remissions who wish to discontinue their medication after successful acute treatment.

Discontinuation of antidepressants after successful treatment of recurrent depression causes relapse in many patients. In a randomized, controlled trial, researchers evaluated the 18-month effectiveness of three maintenance approaches — mindfulness-based cognitive therapy (MBCT), continued antidepressant monotherapy, and pill placebo plus clinical management. Of 160 patients with recurrent depression who received open-label, two-step antidepressant monotherapy, 84 achieved remission in at least 7 months and entered the maintenance phase. Remission before randomization was labeled as stable (n=41 patients) or unstable (i.e., patients had frequent symptom flurries before finally remitting; n=43).

Mindfulness skills, taught in eight weekly 2-hour group meetings and a daylong retreat after session six, helped patients substitute nonjudgmental awareness and acceptance for automatic modes of thinking that promote rumination and avoidance. Treatment effects of MBCT were significant only in unstable remitters; relapse rates in this subgroup were significantly lower with continuation pharmacotherapy (27%) and MBCT (28%) than with placebo (71%), in contrast to the relapse rates in patients who had achieved stable remission before randomization (59%, 62%, and 50%, respectively).

Comment: This study shows that medication and MBCT had prophylactic effects only in patients with an unstable pattern of remission. The small effect of prophylactic pharmacotherapy in stable remitters is puzzling; the authors speculate that these patients might have been responding to nonspecific supportive aspects of the intervention. Nonetheless, the equivalent effect of mindfulness and continuation medication in unstable remitted patients is noteworthy and suggests the value of this approach for patients wishing to discontinue their medication after successful acute treatment.

— Peter Roy-Byrne, MD

Published in Journal Watch Psychiatry January 14, 2011

January 10, 2011 — New findings point to a robust relationship between depression, stress, and the serotonin transporter promoter polymorphism 5-HTTLPR, according to the authors of a meta-analysis in the January 3 online issue of the Archives of General Psychiatry.

In an analysis of 54 studies of more than 40,000 patients, lead author Katja Karg, BSc, of the University of Wuerzburg, Wuerzburg, Germany, and colleagues found "strong evidence that 5-HTTLPR moderates the relationship between stress and depression, with the s allele associated with an increased risk of developing depression under stress (P=.00002)."

The new study contradicts findings of 2 smaller meta-analyses by different authors, both showing no evidence of an interaction. Although 56 studies have examined the interaction among stress, depression, and 5-HTTLPR, the earlier meta-analyses included only 5 and 14 of those studies, respectively, the current authors say. Reasons for the omissions included the inability to obtain primary data for many of the studies, and inclusion only of studies that looked at stressful life events (SLEs), and not other stressors such as childhood maltreatment. Rather than limiting their examination to a specific category of studies, "we sought to perform a meta-analysis on the entire body of work assessing the relationship between 5-HTTLPR, stress, and depression," Ms. Karg and her colleagues write. To overcome the problems in comparing data from different study designs, they used the Liptak-Stouffer z score to combine and compare P values across the studies.

All in all, 54 studies involving 40,749 patients met the inclusion criteria. When the authors stratified the patients into subgroups according to specific types of stressors, they found strong relationships between the s allele of 5-HTTLPR and increased stress sensitivity in the childhood maltreatment group (P = .00007) and the specific medical condition group (P = .0004), and marginal evidence of an association between the allele and the SLE group (P = .03).

The studies looking at depression and childhood maltreatment or specific conditions had similar designs, unlike the studies involving SLEs in general, which varied widely in design, Ms. Karg and her colleagues say. This may account for their finding of a more robust relationship between depression and childhood maltreatment or medical conditions vs SLEs.

The method of stress assessment used in the various studies also emerged as an important variable. "In particular, we found that the evidence of genetic moderation was stronger among studies that used objective measures or in-person interviews to assess stress than among studies that used self-report questionnaires," the study authors write.

One drawback to this study is that, by basing their analysis on P values rather than the primary data, the authors may have incorporated any errors or bias in the original data into their own study. Another drawback to the meta-analytic method, they write, is that they could not estimate the magnitude of the genetic effect "and, in particular, how the interaction effect size compares with any genetic main effect."

Despite these limitations, the study authors conclude that "the present study suggests that there is cumulative and replicable evidence that 5-HTTLPR moderates the relationship between stress and depression. Our evidence, particularly the identification of important study characteristics that influence study outcome (stressor type and stress assessment method), can provide guidance for the design of future gene x environment interaction studies."

The study authors have disclosed no relevant financial relationships.

Arch Gen Psychiatry. Published online January 3, 2011. Abstract

Arch Gen Psychiatry. 2011 Jan 3. [Epub ahead of print]

The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-analysis Revisited: Evidence of Genetic Moderation.

Karg K, Burmeister M, Shedden K, Sen S.

University of Wuerzburg, Wuerzburg, Germany (Ms Karg); and Departments of Psychiatry (Ms Karg and Drs Burmeister and Sen), Human Genetics (Dr Burmeister), and Statistics (Dr Shedden), University of Michigan, Ann Arbor.

Abstract

CONTEXT: Two recent meta-analyses assessed the set of studies exploring the interaction between a serotonin transporter promoter polymorphism (5-HTTLPR) and stress in the development of depression and concluded that the evidence did not support the presence of the interaction. However, even the larger of the meta-analyses included only 14 of the 56 studies that have assessed the relationship between 5-HTTLPR, stress, and depression.

OBJECTIVE: To perform a meta-analysis including all relevant studies exploring the interaction.

DATA SOURCES: We identified studies published through November 2009 in PubMed.

STUDY SELECTION: We excluded 2 studies presenting data that were included in other larger studies.

DATA EXTRACTION: To perform a more inclusive meta-analysis, we used the Liptak-Stouffer z score method to combine findings of primary studies at the level of significance tests rather than the level of raw data.

DATA SYNTHESIS: We included 54 studies and found strong evidence that 5-HTTLPR moderates the relationship between stress and depression, with the 5-HTTLPR s allele associated with an increased risk of developing depression under stress (P = .00002). When stratifying our analysis by the type of stressor studied, we found strong evidence for an association between the s allele and increased stress sensitivity in the childhood maltreatment (P = .00007) and the specific medical condition (P = .0004) groups of studies but only marginal evidence for an association in the stressful life events group (P = .03). When restricting our analysis to the studies included in the previous meta-analyses, we found no evidence of association (Munafò et al studies, P = .16; Risch et al studies, P = .11). This suggests that the difference in results between meta-analyses was due to the different set of included studies rather than the meta-analytic technique.

CONCLUSION: Contrary to the results of the smaller earlier meta-analyses, we find strong evidence that the studies published to date support the hypothesis that 5-HTTLPR moderates the relationship between stress and depression

Perspective

The Age-Old Struggle against the Antivaccinationists

Gregory A. Poland, M.D., and Robert M. Jacobson, M.D.

N Engl J Med 2011; 364:97-99January 13, 2011

Article

References

Since the introduction of the first vaccine, there has been opposition to vaccination. In the 19th century, despite clear evidence of benefit, routine inoculation with cowpox to protect people against smallpox was hindered by a burgeoning antivaccination movement. The result was ongoing smallpox outbreaks and needless deaths. In 1910, Sir William Osler publicly expressed his frustration with the irrationality of the antivaccinationists by offering to take 10 vaccinated and 10 unvaccinated people with him into the next severe smallpox epidemic, to care for the latter when they inevitably succumbed to the disease, and ultimately to arrange for the funerals of those among them who would die (see the Medical Notes section of the Dec. 22, 1910, issue of the Journal). A century later, smallpox has been eradicated through vaccination, but we are still contending with antivaccinationists.

The Cow Pock — or — the Wonderful Effects of the New Inoculation.

Since the 18th century, fear and mistrust have arisen every time a new vaccine has been introduced. Antivaccine thinking receded in importance between the 1940s and the early 1980s because of three trends: a boom in vaccine science, discovery, and manufacture; public awareness of widespread outbreaks of infectious diseases (measles, mumps, rubella, pertussis, polio, and others) and the desire to protect children from these highly prevalent ills; and a baby boom, accompanied by increasing levels of education and wealth. These events led to public acceptance of vaccines and their use, which resulted in significant decreases in disease outbreaks, illnesses, and deaths. This golden age was relatively short-lived, however. With fewer highly visible outbreaks of infectious disease threatening the public, more vaccines being developed and added to the vaccine schedule, and the media permitting widespread dissemination of poor science and anecdotal claims of harm from vaccines, antivaccine thinking began flourishing once again in the 1970s.1

Little has changed since that time, although now the antivaccinationists' media of choice are typically television and the Internet, including its social media outlets, which are used to sway public opinion and distract attention from scientific evidence. A 1982 television program on diphtheria–pertussis–tetanus (DPT) vaccination entitled “DPT: Vaccine Roulette” led to a national debate on the use of the vaccine, focused on a litany of unproven claims against it. Many countries dropped their programs of universal DPT vaccination in the face of public protests after a period in which pertussis had been well controlled through vaccination2 — the public had become complacent about the risks of the disease and focused on adverse events purportedly associated with vaccination. Countries that dropped routine pertussis vaccination in the 1970s and 1980s then suffered 10 to 100 times the pertussis incidence of countries that maintained high immunization rates; ultimately, the countries that had eliminated their pertussis vaccination programs reinstated them.2 In the United States, vaccine manufacturers faced an onslaught of lawsuits, which led the majority of them to cease vaccine production. These losses prompted the development of new programs, such as the Vaccine Injury Compensation Program (VICP), in an attempt to keep manufacturers in the U.S. market.

The 1998 publication of an article, recently retracted by the Lancet, by Wakefield et al.3 created a worldwide controversy over the measles–mumps–rubella (MMR) vaccine by claiming that it played a causative role in autism. This claim led to decreased use of MMR vaccine in Britain, Ireland, the United States, and other countries. Ireland, in particular, experienced measles outbreaks in which there were more than 300 cases, 100 hospitalizations, and 3 deaths.4

Today, the spectrum of antivaccinationists ranges from people who are simply ignorant about science (or “innumerate” — unable to understand and incorporate concepts of risk and probability into science-grounded decision making) to a radical fringe element who use deliberate mistruths, intimidation, falsified data, and threats of violence in efforts to prevent the use of vaccines and to silence critics. Antivaccinationists tend toward complete mistrust of government and manufacturers, conspiratorial thinking, denialism, low cognitive complexity in thinking patterns, reasoning flaws, and a habit of substituting emotional anecdotes for data.5 Their efforts have had disruptive and costly effects, including damage to individual and community well-being from outbreaks of previously controlled diseases, withdrawal of vaccine manufacturers from the market, compromising of national security (in the case of anthrax and smallpox vaccines), and lost productivity.2

The H1N1 influenza pandemic of 2009 and 2010 revealed a strong public fear of vaccination, stoked by antivaccinationists. In the United States, 70 million doses of vaccine were wasted, although there was no evidence of harm from vaccination. Meanwhile, even though more than a dozen studies have demonstrated an absence of harm from MMR vaccination, Wakefield and his supporters continue to steer the public away from the vaccine. As a result, a generation of parents and their children have grown up afraid of vaccines, and the resulting outbreaks of measles and mumps have damaged and destroyed young lives. The reemergence of other previously controlled diseases has led to hospitalizations, missed days of school and work, medical complications, societal disruptions, and deaths. The worst pertussis outbreaks in the past 50 years are now occurring in California, where 10 deaths have already been reported among infants and young children.

In the face of such a legacy, what can we do to hasten the funeral of antivaccination campaigns? First, we must continue to fund and publish high-quality studies to investigate concerns about vaccine safety. Second, we must maintain, if not improve, monitoring programs, such as the Vaccine Adverse Events Reporting System (VAERS) and the Clinical Immunization Safety Assessment Network, to ensure coverage of real but rare adverse events that may be related to vaccination, and we should expand the VAERS to make compensation available to anyone, regardless of age, who is legitimately injured by a vaccine. Third, we must teach health care professionals, parents, and patients how to counter antivaccinationists' false and injurious claims. The scientific method must inform evidence-based decision making and a numerate society if good public policy decisions are to be made and the public health held safe. Syncretism between the scientific method and unorthodox medicine can be dangerous.

Fourth, we must enhance public education and public persuasion. Patients and parents are seeking to balance risks and benefits. This process must start with increasing scientific literacy at all levels of education. In addition, public–private partnerships of scientists and physicians could be developed to make accurate vaccine information accessible to the public in multiple languages, on a range of reading levels, and through various media. We must counter misinformation where it is transmitted and consider using legal remedies when appropriate.

The diseases that we now seek to prevent with vaccination pose far less risk to antivaccinationists than smallpox did through the early 1900s. Unfortunately, this means that they can continue to disseminate false science without much personal risk, while putting children, the elderly, and the frail in harm's way. We can propose no Oslerian challenge to demonstrate our point but have instead a story of science and contrasting worldviews: on the one hand, a long history of stunning triumphs, such as the eradication of smallpox and control of many epidemic diseases that had previously maimed and killed millions of people; on the other hand, the reality that none of the antivaccinationists' claims of widespread injury from vaccines have withstood the tests of time and science. We believe that antivaccinationists have done significant harm to the public health. Ultimately, society must recognize that science is not a democracy in which the side with the most votes or the loudest voices gets to decide what is right.

Cardioprotective ‘polypill’ trial begins

7 January 2011

MedWire News: A phase III trial to assess the effect of a four-component “polypill” on primary prevention of ischemic heart disease (IHD) and stroke in individuals aged 50 years and older begins in the UK this week, the investigators have announced.

If taken daily, the single tablet containing a statin and three different antihypertensives “could reduce cardiovascular (CV) disease by about 75%,” say Professor Nicholas Wald and Dr David Wald, both from Barts and the London School of Medicine and Dentistry.

Writing in the journal Heart, they explain that the findings from an earlier meta-analysis led by Professor Wald demonstrated that “about one in three people taking the polypill would directly benefit from doing so, and each of these would, on average, gain 11 years of life without a heart attack or stroke.”

At the time of the meta-analysis, the researchers reported that aspirin would be a component of the polypill. However, this decision has since been reversed due to uncertainty over whether the benefits of aspirin outweigh the bleeding risk in patients who are considered healthy.

The researchers are aiming to enrol 100 men and women aged 50 years or older with no history of CV disease.

The participants will be randomly assigned to receive the polypill or placebo for 12 weeks, followed by a cross over to the alternative treatment for a further 12 weeks. The final stage of the trial will be conducted as a 2-year open-label period during which all participants will take the polypill.

The researchers say that participants’ blood pressure and cholesterol levels will be closely monitored throughout, and long-term efficacy and safety outcomes assessed.

Speaking to MedWire News, Dr Wald said that the relatively small study size would not prevent valid conclusions from being drawn from the study’s findings.

“Although the study is small in size, the crossover design means that relatively few participants are required to demonstrate statistically significant effects on cholesterol and blood pressure,” he explained.

Dr Wald added that favorable trial findings could pave the way for the polypill to enter the market.

He said: “One cannot be certain how soon the polypill will enter the market, however we would hope to achieve this within the next 2 years.”

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; 2011

Heart 2010; 96: 1–4

Summary and Comment Vitamin D in Health and Disease: More Questions Than Answers Insufficient data (specifically from randomized controlled trials) exist to support dose-response relations between vitamin D levels — and other health outcomes other than bone health. While there is still much we need to learn about the role of vitamin D in health and disease, we do know that many children and adolescents in the U.S. have suboptimal levels. A U.S. study of 559 adolescents (mean age, 16 years; 45% black) showed that 29% had deficient serum 25-hydroxyvitamin D (25[OH]D) levels (deficiency, <20 src="http://www.jwatch.org/math/le.gif" alt="≤" border="0">10 ng/mL); regardless of season, black adolescents were significantly more likely than whites to have deficient levels, with severe deficiency in 11% of blacks versus 0% of whites (JW Pediatr Adolesc Med Jun 16 2010). Data from the National Health and Nutrition Examination Survey (NHANES) suggest that nearly 51 million children and adolescents have insufficient vitamin D levels (15–29 ng/mL) and 7.6 million have deficient levels (<15 href="http://pediatrics.jwatch.org/cgi/content/full/2009/1104/1">JW Pediatr Adolesc Med Nov 4 2009). Vitamin D levels have been reported to be inversely associated with several diseases or adverse physiologic attributes. In a recently published longitudinal study, suboptimal vitamin D levels were associated with greater increases in body-mass index (BMI), waist circumference, and subscapular-to-triceps skinfold-thickness ratio over time, compared with sufficient vitamin D levels (JW Pediatr Adolesc Med Dec 8 2010). In a study of 92 black children with physician-verified asthma, 54% had serum 25(OH)D levels <20 href="http://pediatrics.jwatch.org/cgi/content/full/2010/616/5">JW Pediatr Adolesc Med Jun 16 2010). Low vitamin D levels have also been correlated with higher parathyroid hormone levels and systolic blood pressure and with lower levels of calcium and HDL cholesterol. Children with the lowest vitamin D levels (<15 href="http://pediatrics.jwatch.org/cgi/content/full/2009/1104/1">JW Pediatr Adolesc Med Nov 4 2009). Apparently, most of us cannot "tan" our way out of this problem, at least not during seasons other than summer. After 2 PM in Boston during the winter, not even individuals with the fairest of skin (Fitzpatrick type I) could spend enough time in the sun to synthesize adequate vitamin D. In Miami, people with type V skin (brown skin that rarely burns) would need 15 minutes of sun exposure at noon in the summer and 29 minutes of sun exposure at noon in the winter to make 1000 IU of vitamin D (JW Dermatol Jun 4 2010). Although consumption of milk at least once per week and vitamin D supplements reduce the risk for vitamin D deficiency (JW Pediatr Adolesc Med Nov 4 2009), precious few data show that vitamin D supplementation can ameliorate or prevent any of the disease states described above. In a randomized controlled trial of vitamin D supplementation (400 IU) in 164 healthy Finnish army conscripts, the supplemented group was no less likely to develop respiratory infections, report cold or flu symptoms, or miss days of work than the placebo group, even though vitamin D levels fell 30% in the control group and remained stable in the supplemented group (JW Gen Med Sep 14 2010). This lack of data on the relation between health outcomes other than bone health and vitamin D status is reflected in a newly released Institute of Medicine (IOM) report on dietary reference intakes for calcium and vitamin D (JW Dermatology 2010 Dec 17). The IOM concluded that bone health is the only health outcome that satisfies criteria for use as an "indicator" in developing recommended dietary intakes. Insufficient data (specifically, those from randomized controlled trials) exist to support dose-response relations between vitamin D levels and other health outcomes. On the basis of the existing evidence regarding vitamin D and bone health, the IOM established 600 IU as the recommended daily allowance (RDA) for all infants, children, and adolescents (age range, 1–19 years) and e stimated that this level would result in a 25(OH)D concentration 20 ng/mL in at least 97.5% of children. This RDA is 50% higher than the intake of 400 IU currently recommended by the American Academy of Pediatrics. The report also reiterated that children and adolescents, especially girls, should consume at least 1300 mg of calcium per day. Additional commentary on the IOM recommendations is available here. — Alain Joffe, MD, MPH, FAAP Published in Journal Watch Pediatrics and Adolescent Medicine January 5, 2011

Year in Review Here Come the Alternatives to Warfarin! Dabigatran or other oral clotting inhibitors might be better choices for some patients. FDA approval of a drug is not usually sufficient impetus for a Journal Watch Top Story of the year. An exception to this informal policy is the recent approval of dabigatran (Pradaxa) for stroke prophylaxis in patients with atrial fibrillation, because it portends the eventual decline of warfarin, a notoriously frustrating drug to manage. Dabigatran is an oral thrombin inhibitor that does not require international normalized ratio (INR) monitoring (JW Gen Med Oct 28 2010). FDA approval was based on the RE-LY trial, in which 18,000 participants were randomized to one of two twice-daily doses of dabigatran (110 or 150 mg) or dose-adjusted warfarin and were followed for a median of 2 years. Annual risk for systemic embolism or stroke was 1.7% in the warfarin group, 1.5% in the 110-mg group, and 1.1% (significantly lower) in the 150-mg group. The incidence of major bleeding was similar to that of warfarin in the 150-mg dabigatran group and was significantly lower in the 110-mg group. Dyspepsia was almost twice as common with dabigatran, and rates of myocardial infarction (MI) also were higher in both dabigatran groups than in the warfarin group (by about 2 cases per 1000 patients treated annually; JW Cardiol Sep 1 2009). In a subgroup analysis of 3623 patients with prior (but not very recent) stroke or transient ischemic attack, rates of stroke or systemic embolism were similar in all treatment groups. However, hemorrhagic stroke was significantly less common with either dose of dabigatran, and incidence of major bleeding was significantly lower in the 110-mg dabigatran group than in the warfarin group (relative risk, 0.66; JW Gen Med Dec 14 2010). Concerns about the relative costs of these two agents and associated monitoring were addressed recently in a cost-effectiveness model using data from the trial. Assuming dabigatran costs US$13 daily (an estimate provided by the manufacturer) and is associated with slightly lower stroke and bleeding risks, the cost per quality-adjusted life-year for dabigatran is $45,000 — a value many experts consider to be cost-effective (JW Gen Med Dec 2 2010). Dabigatran is not the only oral alternative to warfarin being touted right now. At the 2010 American Heart Association meeting, researchers presented results from a large study of rivaroxaban (a direct factor Xa inhibitor) to prevent stroke in patients with atrial fibrillation unrelated to valve disease. In the primary analysis, rivaroxaban was noninferior to warfarin, although not significantly superior to warfarin in the full intent-to-treat analysis. Major bleeding incidence was similar (ROCKET-AF trial preliminary report). These data and the FDA's approval of dabigatran give physicians an alternative to warfarin in patients with atrial fibrillation who are at high risk for stroke. Some experts have suggested that in patients with stable INRs who are doing well on warfarin, there is little reason to switch, but the case for dabigatran has been bolstered recently by both the favorable subgroup analysis and the new cost-effectiveness analysis (as of this writing, national chain pharmacies were charging between $230 and $280 for a 1-month supply of dabigatran). Many unanswered questions remain, including how the data on MI risk will develop, and how oral warfarin alternatives will perform for other indications. — Kirsten E. Fleischmann, MD, MPH Published in Journal Watch General Medicine December 30, 2010

The hills are alive with discussion of the most exciting development in cardiovascular medicine this year: the emergence of novel anticoagulants that may well replace the "gold standard" that has been in place for 50 years. In the coming year as many as 3 new agents may be available to consider as alternatives to warfarin and aspirin for the prevention of stroke in patients who have atrial fibrillation. The implications for anticoagulation therapy are enormous. Drs. Garcia, Alexander, Mahaffey, and Wallentin discuss aspects of RE-LY, AVERROES, ROCKET AF, and ARISTOLE, all pivotal trials either completed or soon to be completed in the quest for a better and easier to use anticoagulant for preventing stroke in patients who have atrial fibrillation.

Marcus SC, Olfson M.
Arch Gen Psychiatry. 2010;67:1265-1273.

Summary

This is a report of service utilization data from 2 large nationally representative surveys of the US population. The authors measured rates of depression treatment, use of antidepressant medication and psychotherapy, and the number of outpatient treatment visits and expenditures. The authors found that the rate of outpatient treatment for depression increased from 2.37 per 100 persons in 1998 to 2.88 per 100 persons in 2007. The percentage of treated patients who used antidepressants changed little -- from 73.8% in 1998 to 75.3% in 2007 -- but the percentage of those receiving psychotherapy declined from 53.6% to 43.1%. National expenditure for outpatient treatment of depression increased from $10.05 billion to $12.45 billion, primarily due to an increase in medication expenditures from $4.59 billion to $6.60 billion but also because of an increase in Medicare expenditures for depression treatment from $0.52 billion to $2.25 billion.

Abstract and Introduction

Abstract

Purpose of review The aim of this systematic review was to examine the efficacy and safety of second-generation antipsychotics (SGAs) in nonpsychotic major depressive disorder (MDD).
Recent findings In MDD, SGA monotherapy or adjunctive therapy to conventional antidepressants showed rapid onset of antidepressant efficacy. Although maintenance data are limited, quetiapine monotherapy, risperidone adjunctive therapy, and amisulpride adjunctive therapy significantly delayed the time to relapse as compared with placebo. In general, extrapyramidal symptoms appeared to be low with SGAs, but a higher incidence of akathisia was observed with aripiprazole. An elevated risk of weight gain was observed with olanzapine–fluoxetine combination, risperidone, aripiprazole, and quetiapine compared with placebo. At present, there are insufficient data to confidently distinguish between different SGAs in the treatment of MDD. A recent meta-analysis found that adjunctive SGAs were significantly more effective than placebo, but differences in efficacy were not identified among the studied agents, nor were outcomes affected by trial duration or the method of establishing treatment resistance.
Summary Both SGA monotherapy and adjunctive therapy showed greater efficacy in the treatment of MDD than placebo, but augmentation is more widely utilized in treatment-resistant depression. Clinicians should routinely monitor for cardiometabolic side-effects and extrapyramidal symptoms during SGA therapy.

Introduction

Major depressive disorder (MDD) is an impairing, common and costly mental disorder, representing one of the most prevalent psychiatric conditions in the USA.^[1] Affecting approximately 16% of individuals over their lifetime, MDD frequently assumes a recurrent course and is associated with substantial disability and role impairment. MDD ranks fourth worldwide as the leading cause of total disease burden according to a World Health Organization report and is associated with an earlier mortality both from suicide and natural causes, including cardiovascular disease.^[2]

Over the past several decades, there has been a substantial growth in the number of medications approved by the US Food and Drug Administration for the treatment of acute MDD. Nevertheless, results from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, one of the largest 'real-world' clinical studies conducted to date, suggest that only one-third of patients will achieve remission after an adequate course of antidepressant treatment.^[3] Among patients who did not remit after two treatment strategies in the STAR*D study, the likelihood of achieving remission significantly declined. As a consequence, several treatment strategies have evolved for difficult-to-treat forms of depression,^[4] including switching to another class of antidepressants or augmenting with agents such as thyroid hormone, lithium, and second-generation antipsychotics (SGAs). In addition, some traditional antidepressants are limited by their slower onset of action.

The evidence base for SGAs in the treatment of MDD has grown at a rapid pace. Given the expansion of clinical trials in this area, the aim of the present systematic review was to examine the efficacy and safety of SGAs in the treatment of patients with MDD and to provide an updated clinical perspective to guide prescribers.

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Off orbit? ROCKET AF: Rivaroxaban noninferior to warfarin, but superiority analyses at odds

November 15, 2010 | Michael O'Riordan

Time to retire warfarin from stroke prevention in atrial fibrillation?

Freek Verheugt
Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands

21 December 2010

Oral anticoagulation with warfarin remains the cornerstone of stroke prevention in patients with atrial fibrillation (AF). But warfarin can be difficult to manage, and around half of AF patients at risk for stroke are either unable or unwilling to take it.

Evidence is now emerging that some novel antithrombotic agents may offer effective alternatives to warfarin. Two recent trials of oral factor Xa inhibitors in AF patients, the AVERROES trial evaluating apixaban and ROCKET-AF trial studying rivaroxaban, have produced promising results.

MedWire spoke to Professor Freek Verheugt at the recent American Heart Association (AHA) Scientific Sessions 2010 in Chicago, Illinois, to hear his thoughts on AVERROES (Apixaban versus Acetysalicylic Acid to Prevent Strokes) and ROCKET-AF (Rivaroxaban in Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), what they mean for patients, and how to interpret them in the light of other recently reported and ongoing trials of novel antithrombotics in AF.

Addressing a major unmet need
Patients with atrial fibrillation (AF) are at very high risk for stroke, with a five times greater risk than people without the arrhythmia. Vitamin K antagonists, such as warfarin, reduce the risk for stroke by two-thirds compared with placebo [1], and by one-third when compared with aspirin or the combination of aspirin and clopidogrel [2,3].

However, Verheugt explains, only half of patients with AF are diagnosed with the arrhythmia in the first place. Of these, only half receive treatment with an anticoagulant, and in turn, only half are adequately anticoagulated.

“So only one out of eight patients with AF is properly anticoagulated, which I think shows there is a huge unmet need,” he stresses.

Part of the problem is that warfarin increases the risk for severe bleeding complications, the most dangerous being cerebral bleeding (intracranial hemorrhage [ICH]) [4]. Furthermore, response to warfarin is unpredictable, and patients need careful monitoring to make sure they remain within the therapeutic international normalized ratio (INR) range.

Doctors are therefore often reluctant to prescribe warfarin, particularly if the patient is unlikely to comply with monitoring because of dementia or alcohol misuse, or is at risk of falls or head trauma. And patients themselves may fear the bleeding complications and prefer not to have to go through monitoring. As a consequence, an estimated 40–50% of AF patients who are at moderate or high risk for stroke and would benefit from warfarin treatment do not receive it [5,6].

The standard of care for AF patients at risk for stroke but considered unsuitable for a vitamin K antagonist has been aspirin [7], or more recently, the combination of aspirin and clopidogrel [8]. But these drugs offer relatively weak antithrombotic protection against stroke, and are also associated with increased bleeding risks. The AVERROES trial sought to address the unmet need in this group of patients, aiming to demonstrate that apixaban is superior to aspirin for stroke prevention. Most trials evaluating alternative anticoagulants for stroke prevention in AF focus on demonstrating noninferiority to warfarin, however, and this was the approach adopted in the ROCKET-AF trial.

AVERROES – an alternative solution
The AVERROES trial included 5600 AF patients, aged an average of 70 years, at moderate or high risk for stroke (mean CHADS2 score 2.1) who were randomly assigned to receive apixaban 5 mg twice daily or aspirin 81–324 mg once daily for up to 3 years.

The trial was halted early after interim analysis showed a significant 54% reduction in the relative risk for stroke or systemic embolism, the primary endpoint. Importantly, this benefit was seen without an increase in bleeding risk. The relative risk for the primary safety endpoint of major bleeding was 14% higher in the apixaban compared with the aspirin group, a statistically nonsignificant difference. And, although there was a moderate increase in minor bleeding, there was no difference in the most feared bleeding complication, ICH.

“The outcome was smashingly positive – a 50% reduction of stroke and systemic embolism. A little bit as expected, because aspirin as we know is not a very effective drug for stroke prevention,” says Verheugt.

“What was unexpected was the low rate of bleeding with apixaban – particularly because doctors felt in about half of cases the patients were unsuitable for a vitamin K antagonist because of falling. Yet cerebral bleeding [ICH] was similar in each group – which is amazing.”

Table 1: AVERROES outcomes – annual event rates

	Apixaban (n=2809)	Aspirin (n=2791)	Relative risk (95% confidence interval)	p-value
Primary endpoint Stroke or systemic embolism	1.6	3.6	0.46(0.33–0.64)	<0.001
Primary safety endpoint Major bleeding	1.4	1.2	1.14 (0.74–1.75)	0.56
Other safety endpoints Minor bleeding ICH Fatal bleeding	5.2 0.4 0.1	4.1 0.3 0.1	1.27 (1.01–1.61) 1.09 (0.50–2.39) 0.84 (0.26–2.75)	0.04 0.83 0.77

Abbreviations: ICH, intracranial hemorrhage.

VERROES have yet to be published, but should yield important information on the risk-benefit ratio of apixaban according to stroke risk, age, and reason for warfarin contraindication. They should also address the wide dosing range in the aspirin arm.

Verheugt explains: “That was one of the criticisms of the trial – that the only really effective dose for stroke prevention in AF is 325 mg. But it’s so uncommonly prescribed in Europe, because of the associated gastrointestinal bleeding at higher doses.”

Some critics also queried the rationale behind AVERROES. Verheugt himself questions how many patients are truly unsuitable for warfarin therapy [9], and other commentators asked whether it was ethical to test an attractive anticoagulant against aspirin, which is considered rather ineffective. But he points out that in practice, these patients would not have been given anything more than aspirin.

How apixaban compares with warfarin should become clearer with the results of the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation) trial, due to be reported at the European Society of Cardiology Annual Conference in 2011 [10]. In the meantime, top-line results of the ROCKET-AF trial comparing rivaroxaban with warfarin that were released last month underlined the potential of this class of drugs.

ROCKET-AF – rivaroxaban has lift off
The ROCKET-AF trial included over 14,000 AF patients aged an average of 73 years at moderate or high risk for stroke (mean CHADS2 score 3.5). Patients were randomly assigned to rivaroxaban 20 mg once daily or warfarin (target INR of 2.0–3.0) in a double-blind, double-dummy design, and followed-up for 1.9 years.

Patients who received rivaroxaban had a significant 21% reduction in risk for stroke or non-central nervous system (CNS) embolism relative to those taking warfarin, by per-protocol analysis, meaning that rivaroxaban met criteria for non-inferiority to warfarin.

Table 2: ROCKET-AF outcomes – event rates per 100 patient-years

	Rivaroxaban (n=7081)	Warfarin (n=7090)	Hazard ratio (95% confidence interval)	p-value
Primary efficacy endpoint Stroke, non-CNS embolism	1.71	2.16	0.79 (0.66–0.96)	<0.001>
Primary safety endpoint Major or non-major clinically relevant bleeding	14.91	14.52	1.03 (0.96–1.11)	0.442
Other safety endpoints ICH Fatal bleeding	0.49 0.24	0.74 0.48	0.67 (0.47–0.94) 0.50 (0.31–0.79)	0.019 0.003

Importantly, there was no increased risk for bleeding events with rivaroxaban compared with warfarin. In fact, there was a significant reduction in the risk for ICH with rivaroxaban, which Verheugt says is “very reassuring,” as well as for fatal bleeding.

Although the results demonstrated noninferiority to warfarin, the primary efficacy endpoint did not differ significantly between groups by “gold standard” intention-to-treat analysis. So how does this leave rivaroxaban relative to the direct thrombin inhibitor dabigatran, which was found to be superior to warfarin in the RE-LY (Randomized Evaluation of Long-term anticoagulant therapY) trial? [11].

Verheugt says: “The RE-LY study showed superiority, but it was in an open-label trial – simpler to do but more difficult to interpret because when doctors and patients know their treatment allocation you get a lot of bias in reporting events, even efficacy endpoints as well as safety events. So I have my doubts whether dabigatran is really superior to warfarin.”

In addition, the study population in ROCKET-AF represented a much more high-risk, complex group of patients than that in RE-LY. On the other hand, the time in therapeutic range in the warfarin group in ROCKET-AF was considered low, at 57.8%, suggesting that the performance of warfarin was not quite what it could be.

Despite this, Verheugt emphasizes: “To even come close to warfarin, which is extremely effective, is very good. And to show equivalence really is a major finding.”

From rags to riches
Guidelines and regulatory bodies will take some time to catch up with these latest developments. But Verheugt says that after decades of returning to the “old workhorse” warfarin, doctors could soon have as many as four alternative new antithrombotics to choose from.

Apixaban is unique in having data to support its use in the large group of AF patients deemed unsuitable for warfarin. Dabigatran is already approved for AF in the USA, and has entered Canadian guidelines, but Verheugt emphasizes that it has not been tested in this group of patients specifically and that the dosing remains uncertain.

Verheugt also believes that the increased rate of myocardial infarctions (MIs) with dabigatran seen in RE-LY could be an Achilles heel, noting that “the consequences of MI are much worse in the elderly.” This risk was seen with another univalent direct thrombin inhibitor, ximelagatran, development of which was abandoned because of associated liver toxicity.

There was no evidence of excess MIs with rivaroxaban in ROCKET-AF, Verheugt notes, although the study duration was short and the overall MI rate low. “So we have to wait for ARISTOTLE – if that study also finds no increase in MIs I think that it’s quite possible there is a class effect of the direct thrombin blockers, which you would like to avoid in the elderly.”

In addition, another promising oral factor Xa inhibitor, edoxaban, is being tested against warfarin in a similar population to that of RE-LY in the ENGAGE AF-TIMI 48 (Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation) trial, which is due to report in 2012 [12].

The ‘old workhorse’ to retire?
Despite the potential of these newer drugs, Verheugt remains a strong proponent of warfarin. He believes that with proper monitoring systems and improved awareness and patient information, many patients deemed unsuitable for warfarin therapy could, in fact, take it [9].

“I have my severe doubts that this is a distinct group of patients. Yes, sometimes, people really are not suitable, but most of the patients could be given warfarin,” he says.

The monitoring process also provides a useful way of ensuring compliance as well as checking up on patients’ general health, he explains. In addition, many healthcare systems will have to establish whether the increased cost of the newer drugs can be justified. Some European and Scandinavian countries have such well established networks of warfarin monitoring clinics that the cost of warfarin is negligible, Verheugt points out. In these countries there may be considerable resistance to paying for the newer alternatives. Despite these caveats, however, Verheugt concedes that warfarin may finally be on its way out.

“I have to admit we now have two big trials that show an effective alternative, probably with a better safety profile, compared with warfarin,” he says. “Doctors love to hate warfarin, especially in the USA. And for simplicity, of course, doctors like these new drugs, to be able to just give a prescription.

“So in the end I think warfarin, the ‘old workhorse’, will take honorable retirement.”

Op de deur van de Heiligen Kerk in Alexandrië kleven nog stukjes menselijk vlees. Overblijfselen van de aanslag van afgelopen Nieuwjaarsnacht. Schoonmakers die de resten willen verwijderen, worden weggejaagd door jonge koptische christenen. "Laat het zitten, dit is martelarenbloed", roept één van hen.

Iets meer dan een dag na de aanslag, waarbij 21 gelovigen om het leven kwamen en tientallen gewond raakten, herdachten de kopten de aanslag, in dezelfde Heiligen Kerk van Alexandrië. Een zondagsdienst vol verdriet, maar ook woede.

Kopten

De Kopten zijn een minderheid in het overwegend islamitische Egypte: van de tachtig miljoen Egyptenaren is ongeveer tien procent christelijk, de meesten aanhangers van de Koptische Orthodoxe Kerk. Dat is één van de oudste kerken van het christendom, met een eigen 'paus' aan het hoofd, de aartsconservatieve Shenouda de Derde. De laatste jaren zijn er steeds meer spanningen tussen moslims en kopten.

Die toegenomen spanningen zijn onder meer het gevolg van overheidsbeleid. President Hosni Mubarak vreest de groeiende invloed van de fundamentalistische islam, de grootste oppositiebeweging in Egypte. Om de populariteit van de fundamentalisten in te dammen, stelt Mubarak zich op als voorvechter van de islam. Zo mag iedereen die dat wil een moskee beginnen, maar moeten christenen tal van vergunningen aanvragen om een kerk te kunnen bouwen.

Een andere omstreden maatregel heeft te maken met de mogelijkheid om te kunnen scheiden. Burgerlijke huwelijken bestaan niet in Egypte, trouwen en scheiden kan alleen in een kerk of moskee. Scheiden kan bij de moslims wel, maar binnen de Koptische Kerk niet. Tot voor kort was het gebruikelijk dat een kopt die toch wilde scheiden, zich liet bekeren tot een ander christelijk geloof waar scheiden wel is toegestaan. Dat mag niet meer: kopten die toch willen scheiden kunnen dat alleen nog voor elkaar krijgen door moslim te worden.

Dreigementen

Het verhaal van de 25-jarige Camilla Shehata, vrouw van een koptische priester, illustreert deze spanningen. Ze zou vrijwillig moslim zijn geworden om te kunnen scheiden van haar man. Kopten brachten haar daarop naar een klooster, waar ze tot op de dag van vandaag tegen haar zin wordt vastgehouden. Net als een andere vrouw van een koptische priester, die al sinds 2004 om dezelfde reden in een klooster zou zitten.

Het verhaal van Camilla Shehata inspireerde al-Qaida in Irak tot dreigementen aan het adres van de kopten in Egypte. De terreurbeweging dreigde met aanslagen, als de twee vrouwen niet snel zouden worden vrijlaten.

Buitenlanders

Ook al is het onduidelijk of al-Qaida daadwerkelijk achter de aanslag van Nieuwjaarsnacht zat, president Mubarak suggereert alvast dat "buitenlanders" verantwoordelijk zijn voor de bloedigste aanslag op christenen in Egypte in jaren.

Buitenlanders, geen Egyptenaren: het zou de president goed uitkomen. Want zolang de terroristen van buiten komen, kan Mubarak blijven ontkennen dat er sprake is van oplopende spanningen tussen bevolkingsgroepen. En hoeft er niets te veranderen.

Current and Emerging Treatment Options

Although warfarin has been used in AF thromboprophylaxis for many years, its limitations have contributed to underuse. For long-term use, there is a need for safer and more effective oral anticoagulants that do not require routine monitoring of coagulation. A new generation of anticoagulants, oral direct antithrombin inhibitors and oral factor Xa inhibitors, are in clinical development. These agents can be orally administered and directly target specific factors in the coagulation cascade. Efficacy and safety of perioperative prophylaxis for venous thromboembolism after hip and knee surgery has been shown with the direct thrombin inhibitor dabigatran as well as for the oral factor Xa inhibitors rivaroxaban and apixaban, compared with low-molecular-weight heparins.^[89-92]

Dabigatran was recently approved by the US Food and Drug Administration (FDA) for the prevention of stroke in patients with AF. The Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial compared warfarin (with target INR 2-3) with 2 doses of dabigatran in 18,000 patients with AF with a CHADS₂ score ≥ 1.^[93] Dabigatran 150 mg twice daily was superior to warfarin in efficacy (thromboembolism prevention) and similar to warfarin in safety (bleeding rates), whereas dabigatran 110 mg twice daily was noninferior to warfarin in efficacy and appeared to be safer.

Similar trials have been conducted for rivaroxaban (Rivaroxaban – Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation [ROCKET-AF]) and apixaban (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE]). In fact, findings from ROCKET-AF were reported on November 15, 2010 at a late-breaking clinical trials session at the AHA Scientific Sessions.^[94] In this trial, 14,264 patients with nonvalvular AF (average CHADS₂ score ≈3.47; 55% with previous embolic event) were randomly assigned to rivaroxaban (20 mg daily) or warfarin (with target INR 2-3). Rivaroxaban was found to be as effective as warfarin in preventing stroke. In the primary analysis, the rate of stroke and embolization was 1.71 per 100 patient-years in the rivaroxaban group and 2.16 per 100 patient-years in the warfarin group (hazard ratio, 0.79; 95% CI, 0.66-0.96; P < .001 for noninferiority; P = .018 for superiority). The incidence of major bleeding complications was comparable in the 2 groups. The trial investigators also reported that the median time spent within the therapeutic range was only 57.8% in the warfarin group.

Data from A Phase III Study of Apixaban in Patients With Atrial Fibrillation (AVERROES), presented at the 2010 ESC meeting, indicated that patients with AF unable to take warfarin had a significantly lower risk for stroke and systemic embolic events with apixaban 5 mg twice daily than with aspirin (81-324 mg/day).^[95] AVERROES was stopped early after a predefined interim analysis "revealed clear evidence of a clinically important reduction in stroke and systemic embolism." These new oral agents represent alternative therapies to stroke prevention in AF that is substantially different from the current agents, and potentially alters the current benefit-risk ratio associated with long-term anticoagulant treatment.

Left atrial appendage is considered the thromboembolic source in > 80% of AF-related thromboembolism. Consequently, percutaneous or surgical appendage closure is being evaluated as an alternative strategy for stroke prevention in AF. A few devices for left atrial appendage occlusion have been subject to clinical evaluation. The WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients with Atrial Fibrillation (PROTECT AF) Trial is evaluating the Watchman® Left Atrial Appendage Occluder (Atritech, Inc.; Plymouth, Massachusetts) compared with conventional warfarin therapy. After approximately 3 years' follow-up, the device appears to be noninferior in efficacy, but is associated with higher rate of adverse safety events compared with warfarin.

Cost-Effectiveness of Dabigatran for Stroke Prevention

Dabigatran, at the right price, is an attractive option for many atrial fibrillation patients.

Dabigatran (Pradaxa), a direct thrombin inhibitor that recently received FDA approval (JW Gen Med Oct 28 2010), is at least as effective and safe as warfarin for preventing strokes in patients with atrial fibrillation. However, is dabigatran cost-effective? Using a simulated population of patients with atrial fibrillation and CHADS₂ scores 1, researchers developed a mathematical model to compare outcomes and costs for warfarin (targeted international normalized ratio [INR], 2–3) and for twice-daily 150-mg dabigatran. The model was based on annual rates of ischemic stroke of 1.20% for warfarin and 0.92% for dabigatran. Rates of hemorrhage in the model were 0.74% for warfarin and 0.30% for dabigatran. Cost for dabigatran was estimated at US$13 daily.

Projected lifetime patient costs were $143,000 for treatment with warfarin and $168,000 with dabigatran. Compared with warfarin, dabigatran had an incremental cost-effectiveness ratio of $45,000 per quality-adjusted life-year (QALY).

Comment: Many consider QALY costs of $50,000 to be cost-effective. In this computer model, dabigatran costs would remain under this ceiling, assuming that the authors' estimated price of $13 daily is realistic. As of December 2010, the price at several national pharmacy chains was substantial but lower than $13 daily (range, $232–$280 for a 1-month supply of sixty 150-mg tablets). I suspect that most atrial fibrillation patients would gladly switch to dabigatran if a considerable portion of the cost was covered by insurance.

— Jamaluddin Moloo, MD, MPH

Published in Journal Watch General Medicine December 2, 2010