Newly Discovered Virus Linked to Neuroendocrine Cancer of the Skin

Researchers are unveiling a new virus in a report published online January 17 in Science. Dubbed the Merkel cell polyomavirus, it is the first to be strongly associated with a human tumor. Polyomaviruses have been shown to cause cancers in animals, but it is unclear what role, if any, they play in human cancer development. Although the important finding does not prove that the polyomavirus causes neuroendocrine cancer of the skin — also known as Merkel cell carcinoma — if confirmed, it might offer clues for future cancer treatment and prevention options.

Merkel cell carcinoma is a rare but extremely aggressive cancer that tends to spread rapidly. The incidence of this skin cancer has reportedly tripled over the past 20 years, to about 1500 cases a year. It tends to be seen in the elderly and in those with compromised immune systems, such as those with AIDS or patients taking transplant-related immunosuppressant drugs. About half of those with advanced Merkel cell carcinoma live 9 months or less.

“If these findings are confirmed, we can look at how this new virus contributes to a very bad cancer with high mortality and, just as important, use it as a model to understand how cancers occur and the cell pathways that are targeted,” senior author Patrick Moore, MD, from the University of Pittsburgh School of Medicine, in Pennsylvania, said in a news release. “Information that we gain could possibly lead to a blood test or vaccine that improves disease management and aids in prevention.”

Dr. Moore and his wife also discovered the cause of Kaposi’s sarcoma. In 1993, the couple identified Kaposi’s sarcoma–associated herpesvirus, the most common malignancy in AIDS patients and the most prevalent cancer in Africa.

During an interview with Medscape Oncology, Dr. Moore said his team was surprised by this latest finding. “We were certainly taken aback,” he said. “I think anyone uncovering what could be a cause of cancer would be surprised by the finding,” he laughed. A lot of work remains, but the Merkel cell polyomavirus might be an exciting clue.

Possible Cause of Rare Cancer Identified

Vaccines are now available against other causes of cancer, such as the human papillomavirus linked to cervical cancer. “The Merkel cell polyomavirus is another model that may increase our understanding of how cancers arise, with possibly important implications for nonviral cancers like prostate or breast cancer,” coauthor Yuan Chang, MD, also from the University of Pittsburgh, pointed out in a news release.

Merkel cell polyomavirus, like the human papillomavirus, is said to integrate into the tumor cell genome, but not the genome of healthy cells. This integration destroys the virus’s ability to replicate normally and might be the first step toward cancer.

Using a technique called digital transcriptome subtraction, the investigators looked at close to 400,000 messenger ribonucleic acid genetic sequences from 4 samples of Merkel cell carcinoma tumor tissue. They compared the sequences expressed by the tumor genome to gene sequences mapped by the Human Genome Project and systematically subtracted known human sequences to identify a group of genetic transcripts that might be from a foreign organism.

They found that 1 sequence was similar to, but distinct from, all known viruses. The team went on to show that this sequence belonged to a new polyomavirus present in 8 of 10 Merkel cell tumors they tested, but only 5 of 59 (8%) control tissues from various body sites and 4 of 25 (16%) control skin tissues.

“This is a rare cancer so it’s hard to get enough tissue samples for large studies from just 1 center,” Dr. Moore told Medscape Oncology. The group plans to continue collecting samples and will partner with others.

Even if the Merkel cell polyomavirus is proven to play a role in neuroendocrine cancer of the skin, Dr. Chang cautions that the virus is likely to be just part of a much larger picture.

“Now we need to find out how it works,” she explained in a news release. “Once the virus integrates, it could express an oncoprotein, or it could knock out a gene that suppresses tumor growth. Either way, the results are bound to be interesting.”

The researchers have disclosed no relevant financial relationships.

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Survival After Dementia Diagnosis Depends on Age, Sex, Disability

A new study by British researchers finds that on average, people who are diagnosed with incident dementia survive for a median of 4.5 years, but survival varied between 10.7 and 3.8 years for those diagnosed in their 60s vs their 90s. Sex and disability prior to dementia onset also affected survival times.

“Our analyses provide robust population-based estimated survival for incident dementia by age, sex, and setting,” the researchers, with senior author Carole Brayne, MD, from the Institute of Public Health, University of Cambridge, United Kingdom, conclude. While some of these findings may seem “self-evident,” the authors write, “they answer questions asked by those caring for and advising people with dementia. We hope the estimates will be valuable to patients, clinicians, carers, service providers, and policy makers.”

The findings, from the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS), were published January 10 in the BMJ.

Doubling Dementia

Life expectancy is increasing globally, with 1 consequence being increasing numbers of people affected by dementia, the authors write. It is estimated that the numbers of those with dementia will double every 20 years, to some 81.1 million by 2040, they note.

One question asked frequently in both clinical and policy settings is the impact of dementia on life expectancy, they write. In the present study, the authors examined overall survival for people with dementia, as well as the association between factors that could affect survival in incident cases of dementia over a 14-year follow-up.

MRC CFAS is a multicenter, longitudinal, prospective population-based epidemiological study of cognitive function and disability in England and Wales, including 2 urban and 3 rural centers. The study included 13,004 individuals aged 65 years or older who were drawn from primary care population registers; at each study visit, information on sociodemographic factors, cognitive function, health conditions, and self-reported health were recorded. Participants were enrolled and followed over time for dementia status and mortality.

Of 438 subjects who developed dementia between 1991 and 2003, 356, or 81%, had died by December 2005.

The estimated median survival time from the onset of dementia to death was 4.5 years for the overall population but slightly longer for women than men, with a median survival of 4.6 vs 4.1 years.

Age at onset of dementia had a significant effect on survival times; “There was a difference of nearly 7 years in survival between the younger old and the oldest people with dementia,” the authors write.

Estimated Median Survival by Age at Dementia Onset

Age at Dementia Onset (y)	Survival (y)
65 – 69	10.7
70 – 79	5.4
80 – 89	4.3
> 90	3.8

Disability with dementia was also associated with shorter survival even after other factors were taken into account, the authors note, with an absolute reduction in survival of about 3 years between the most and least disabled. “This does suggest that the frailer individuals are at higher risk even after age is considered,” they write.

Consider Human Worth

In an editorial accompanying the paper, Murna Downs, PhD, from the Bradford Dementia Group, University of Bradford, United Kingdom, and Barbara Bowers, PhD, from the University of Wisconsin School of Nursing, in Madison, point out that this study shows that dementia “is a terminal condition, the course of which unfolds with coexisting age, related impairment, and ill health.”

The present study provides clear evidence that people with dementia need coordinated care and support from a range of professionals and practitioners “from diagnosis to death” to ensure maximum quality of life and prevent unnecessary disability and suffering, they write. Doctors should also be aware of a “growing evidence base for therapeutic intervention and effective support” in achieving those goals.

“In planning care and support, doctors need to pay as much attention to the essential human worth of a person with dementia and their retained capacity for relationships, pleasure, communication, and coping as they do to deficits and dysfunction,” they conclude.

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Gene Linked to Increased Risk for Cerebral Venous Thrombosis

A new study by British researchers finds that on average, people who are diagnosed with incident dementia survive for a median of 4.5 years, but survival varied between 10.7 and 3.8 years for those diagnosed in their 60s vs their 90s. Sex and disability prior to dementia onset also affected survival times.

“Our analyses provide robust population-based estimated survival for incident dementia by age, sex, and setting,” the researchers, with senior author Carole Brayne, MD, from the Institute of Public Health, University of Cambridge, United Kingdom, conclude. While some of these findings may seem “self-evident,” the authors write, “they answer questions asked by those caring for and advising people with dementia. We hope the estimates will be valuable to patients, clinicians, carers, service providers, and policy makers.”

The findings, from the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS), were published January 10 in the BMJ.

Doubling Dementia

Life expectancy is increasing globally, with 1 consequence being increasing numbers of people affected by dementia, the authors write. It is estimated that the numbers of those with dementia will double every 20 years, to some 81.1 million by 2040, they note.

One question asked frequently in both clinical and policy settings is the impact of dementia on life expectancy, they write. In the present study, the authors examined overall survival for people with dementia, as well as the association between factors that could affect survival in incident cases of dementia over a 14-year follow-up.

MRC CFAS is a multicenter, longitudinal, prospective population-based epidemiological study of cognitive function and disability in England and Wales, including 2 urban and 3 rural centers. The study included 13,004 individuals aged 65 years or older who were drawn from primary care population registers; at each study visit, information on sociodemographic factors, cognitive function, health conditions, and self-reported health were recorded. Participants were enrolled and followed over time for dementia status and mortality.

Of 438 subjects who developed dementia between 1991 and 2003, 356, or 81%, had died by December 2005.

The estimated median survival time from the onset of dementia to death was 4.5 years for the overall population but slightly longer for women than men, with a median survival of 4.6 vs 4.1 years.

Age at onset of dementia had a significant effect on survival times; “There was a difference of nearly 7 years in survival between the younger old and the oldest people with dementia,” the authors write.

Estimated Median Survival by Age at Dementia Onset

Age at Dementia Onset (y)	Survival (y)
65 – 69	10.7
70 – 79	5.4
80 – 89	4.3
> 90	3.8

Disability with dementia was also associated with shorter survival even after other factors were taken into account, the authors note, with an absolute reduction in survival of about 3 years between the most and least disabled. “This does suggest that the frailer individuals are at higher risk even after age is considered,” they write.

Consider Human Worth

In an editorial accompanying the paper, Murna Downs, PhD, from the Bradford Dementia Group, University of Bradford, United Kingdom, and Barbara Bowers, PhD, from the University of Wisconsin School of Nursing, in Madison, point out that this study shows that dementia “is a terminal condition, the course of which unfolds with coexisting age, related impairment, and ill health.”

The present study provides clear evidence that people with dementia need coordinated care and support from a range of professionals and practitioners “from diagnosis to death” to ensure maximum quality of life and prevent unnecessary disability and suffering, they write. Doctors should also be aware of a “growing evidence base for therapeutic intervention and effective support” in achieving those goals.

“In planning care and support, doctors need to pay as much attention to the essential human worth of a person with dementia and their retained capacity for relationships, pleasure, communication, and coping as they do to deficits and dysfunction,” they conclude.

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Safety of Heparin "Bridge" Questioned When Warfarin Is Stopped for Minor Procedures

Patients on chronic warfarin who go off the drug for up to five days while they undergo a minor invasive procedure appear to have a The findings speak to the dilemma providers face when taking patients off oral anticoagulation while they undergo a colonoscopy, dental procedures, or other such outpatient procedures, according to lead author Dr David A Garcia (University of New Mexico Health Sciences Center, Albuquerque). Many want to give short-acting parenteral anticoagulation during such procedures, accepting a potential for more bleeding complications in exchange for a reduced risk of potentially devastating thromboembolic events, he observed for heartwire. But prospective data for guiding such decisions have been in short supply.

“If there’s an overriding message from our study, it’s perhaps that the hemorrhagic risk associated with heparinlike perioperative anticoagulation is greater than previously appreciated, and that it needs to be considered carefully in any risk/benefit analysis that one is doing around an interruption of warfarin for an elective procedure,” Garcia said. “We don’t have good data about the benefit of perioperative heparin, whereas we are getting increasingly more evidence that perioperative heparin certainly comes with a risk.”

Anyway, he observed, the risk of thromboembolic complications during warfarin interruption appears to be quite low, at least in populations like the one his group studied: “outpatients undergoing elective, relatively minor invasive procedures, most of whom had their warfarin interrupted for only brief intervals, three to five days.” Less than one-tenth of the study’s > 1000 patients had received bridge anticoagulation.

The group’s findings, published in the January 14, 2008 issue of Archives of Internal Medicine, are consistent with those of other studies and with current guidelines “proposed by the American College of Chest Physicians, suggesting that low-risk patients may undergo four to five days of warfarin-therapy interruption without bridging therapy.”

Their analysis covered 1293 instances of warfarin interruption in 1024 patients who underwent such outpatient procedures as colonoscopy, oral or dental surgery, or ophthalmic surgery. The patients averaged 72 years in age, and most had been on warfarin due to atrial fibrillation or mechanical heart valves or for management of venous thromboembolism. Only 8.3% of cases of warfarin interruption involved bridge anticoagulation therapy, which was nearly always with a low-molecular-weight heparin, according to the authors. Outcomes included the following:

• There were only seven instances of thromboembolism (0.7%) within 30 days of the procedure. The rate was the same after exclusion of patients who received bridge therapy.
• The rate of thromboembolism was 0.4% when the warfarin interruption lasted five days or less and 2.2% for those of seven or more days.
• Six patients (0.6%), including four who had received bridge therapy, suffered a major bleeding complication, defined as hemorrhage that led to death or to hospitalization with a transfusion ≥ 2 U red packed cells or at a “critical” site (including, for example, intracranial or retroperitoneal bleeding).
• Another 17 patients (1.7%), including 10 who had received bridge therapy, experienced “clinically significant, nonmajor bleeding.”

Bleeding complication risk among patients who received or did not receive bridge anticoagulation therapy

Complication	Bridge anticoagulation (%)	No bridge anticoagulation (%)
Major hemorrhage	3.7	0.2
Significant nonmajor hemorrhage	9	0.6

“Although our paper doesn’t provide any definitive answers, it questions whether the risk of bridging therapy, even in outpatients, can be justified by the potential benefit,” Garcia said, cautioning that it doesn’t apply to patients undergoing major surgery or are hospitalized for an invasive procedure, whose thrombotic and bleeding risks would likely be higher. Randomized, placebo-controlled trials are now needed, he added, to settle the issue.

The study was funded by Bristol-Myers Squibb. Dr. Garcia has disclosed receiving consulting honoraria and research support from Bristol-Myers Squibb, AstraZeneca, and sanofi-aventis. Coauthor Dr. Elaine M. Hylek (Boston University School of Medicine, Massachusetts) has disclosed having served on advisory boards for Bristol-Myers Squibb and receiving research support from AstraZeneca and Bristol-Myers Squibb.

Clinical Context

Significant uncertainty surrounds the treatment of patients who must discontinue warfarin sodium therapy before an invasive procedure. In part, the uncertainty results from the lack of published information about the risk for thromboembolism associated with short-term interruption of warfarin therapy. The patient and clinician have 3 options: (1) continue warfarin therapy, (2) withhold therapy for some time before (and after) the procedure, or (3) temporarily withhold warfarin therapy while also providing a short-acting (bridging) anticoagulant during the perioperative period. The current guidelines from the American College of Chest Physicians suggest that if the annual risk for thromboembolism is low, warfarin therapy may be held for 4 to 5 days before the procedure without bridging and may be restarted shortly thereafter.

The aim of this study was to assess the frequency of thromboembolism and bleeding in patients whose warfarin therapy was temporarily withheld for an outpatient invasive procedure.

Study Highlights

• In this prospective, observational cohort study, enrollment was conducted from April 4, 2000, to March 6, 2002, and was performed at 101 sites (primarily community-based physician office practices) in the United States.
• A total of 1293 episodes of interruption of warfarin therapy in 1024 low- to intermediate-risk individuals were included.
• The mean (SD) age of the patients was 71.9 (10.6) years; 438 (42.8%) were women.
• The most common indications for anticoagulant therapy were atrial fibrillation (n = 550), venous thromboembolism (n = 144), and mechanical heart valve (n = 132).
• The most common procedures were colonoscopy and oral and ophthalmic surgery. Other reasons for withholding warfarin therapy were epidural injection, prostate biopsy, breast biopsy, and dermatologic procedures.
• The main outcome measures were thromboembolism or clinically significant hemorrhage within 30 days of interruption of warfarin therapy.
• Perioperative heparin or low-molecular-weight heparin was used in 8.3% of cases overall.
• Results demonstrated that 7 (0.7%) patients (95% confidence interval [CI], 0.3% – 1.4%) experienced postprocedure thromboembolism within 30 days; 4 of the thromboembolisms were arterial and 3 were venous.
• Among patients whose warfarin therapy was interrupted for 5 days or less, the proportion experiencing thromboembolism was 0.4% vs 2.2% for those with an interruption interval of 7 days or more.
• None of the 7 patients who experienced thromboembolism received periprocedural bridging therapy.
• 6 (0.6%) patients (95% CI, 0.2% – 1.3%) experienced major bleeding, whereas an additional 17 (1.7%) patients (95% CI, 1.0% – 2.6%) experienced a clinically significant, nonmajor bleeding episode.
• Of these 23 patients who had bleeding episodes, 14 received periprocedural heparin or low-molecular-weight heparin.

Pearls for Practice

• According to the American College of Chest Physicians, current recommendations suggest that if the annual risk for thromboembolism is low, warfarin therapy may be held for 4 to 5 days before the procedure without bridging.
• For many patients receiving long-term anticoagulation who need to undergo a minor outpatient intervention, a brief (≤ 5 days) periprocedural interruption of warfarin therapy is associated with a low risk for thromboembolism and bleeding.

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ACE Inhibitors or ARBs in Hypertension? In Chronic Kidney Disease?

A pair of articles in the January 1, 2008 Annals of Internal Medicine brings together the existing literature to address issues that have persisted since the introduction of angiotensin-receptor blockers (ARBs): namely, when and how these drugs might be advantageous in conditions long served by angiotensin-converting enzyme (ACE) inhibitors.

A meticulous survey of studies found that the two drug classes are about equally safe and effective at managing high blood pressure and have similar effects on other risk factors and clinical outcomes in patients with essential hypertension [1]. It also confirmed that ARBs are less likely to cause coughing, but suggested that the side effect might be less common with ACE inhibitors than randomized trials indicate.

In the setting of chronic kidney disease (CKD), concludes the other study, which is a meta-analysis, ACE inhibitor and ARB monotherapy are similarly effective at reducing proteinuria, but a combination of the two angiotensin-2-suppressing drugs works better than either agent individually [2]. But a blanket recommendation to combine them would be premature, according to the authors, because there is little evidence that the combination would improve clinical outcomes over monotherapy, and the safety of such combination therapy is largely undefined.

The authors of both analyses acknowledge that they have major limitations, particularly the heterogeneity of the combined studies, their limited follow-up times, and spotty data on adverse effects.

“The most important contribution of these systematic reviews is that they tell us what we do not know,” notes an accompanying editorial [3]. They suggest that the two drug classes are comparably effective as antihypertensive and antiproteinuric agents, writes Dr Patrick S Parfrey (Memorial University of Newfoundland, St John’s), but “we know far too little about their long-term safety, especially with combination therapy of ACE inhibitors plus ARBs in stage 3 or 4 chronic kidney disease.”

No “clinically meaningful difference” in hypertension

“With the exception of rates of cough, the available evidence does not strongly support the hypothesis that ACE inhibitors and ARBs have clinically meaningful differences in benefits or harms for individuals with essential hypertension,” according to the report’s authors, led by Dr David B Matchar (Duke Center for Clinical Health Policy Research, Durham, NC).

He and his colleagues analyzed 69 reports based on 61 randomized and observational studies that lasted at least three months and directly compared an ACE inhibitor and an ARB in adults with essential hypertension and evaluated meaningful end points like blood pressure control, treatment compliance, and adverse events.

The strength of evidence was considered high for the observation that the two drug classes are similarly effective at controlling blood pressure. They were comparable in 37 of the 50 studies evaluated for that outcome; 47 of those 50 studies were randomized controlled trials (RCTs).

Also similar were the associated rates of death and cardiovascular (CV) events, quality-of-life measures, successful use of the ACE inhibitor or ARB as the only antihypertensive agent, effects on lipid levels and left ventricular (LV) mass, and risk of dysglycemia or renal dysfunction.

Mortality and CV-event outcomes were available for only nine studies, most of which excluded patients with clinically significant CV disease or comorbidities, the group reported. Few of the studies followed patients for even as long as a year, and “there were really very limited data about major events, such as heart attack and stroke,” Matchar told heartwire.

The two drug classes showed similar risks of headache and dizziness, but ACE inhibitors were about three times more likely to have cough as a side effect, regardless of whether the study was cohort-based or an RCT. But the rates of cough were “dramatically higher” in the RCTs, probably because in RCTs, in contrast to cohort-based studies, patients are more likely to be queried specifically for that side effect, Matchar said.

Rate of cough as a side effect of ACE inhibitor and ARB therapy

Research setting	ACE inhibitor (%)	ARB (%)
Randomized controlled trials	9.9	3.2
Cohort-based studies	1.7	0.6

ARB = angiotensin receptor blocker

Other evidence suggested that patients are more likely to stick with ARBs than with ACE inhibitors when each were given as initial therapy, but “the magnitude of this difference is difficult to quantify,” according to the report.

Although any differences in efficacy between the two drug classes are likely to be small, according to Matchar et al, pinning down such small differences might be worth the challenge of mounting a large long-term randomized study, given that small changes in blood pressure are known to have a substantial outcomes effect.

To heartwire Matchar said, “if there really is a marginal benefit to be had from, say, greater tolerability of ARBs compared with ACE inhibitors, then we really do need some [more definitive] head-to-head studies to show it.”

“Encouraging” support for combination therapy in CKD

The other reported study provided “high-quality evidence” that monotherapy with ACE inhibitors or ARBs reduces proteinuria to comparable degrees in patients with CKD, regardless of the underlying cause of renal dysfunction. And, write the authors, led by Dr Regina Kunz (University Hospital, Basel, Switzerland), “evidence is encouraging that the combination of the two drugs is more effective, at usual doses, than either drug alone.”

The group analyzed 49 RCTs that compared ARBs with ACE inhibitors, a combination of the two drug classes, placebo, or calcium-channel blockers and tracked microalbuminuria and proteinuria over at least four weeks in patients with CKD.

ARBs and ACE inhibitors were similarly effective at lowering proteinuria, ARBs were more effective than calcium-channel blockers, and a combination of ARBs and ACE inhibitors was more effective than either agent alone.

Ratio of means (95% CI)* for change in proteinuria, by randomized therapy, over two follow-up intervals

Randomized therapy	Over 1 – 4 mo	Over 5 – 12 mo
ARBs vs placebo	0.57 (0.47 – 0.68)	0.66 (0.63 – 0.69)
ARBs vs ACE-I	0.99 (0.92 – 1.05)	1.08 (0.96 – 1.22)
ARBs vs CCBs	0.69 (0.62 – 0.77)	0.62 (0.55 – 0.70)
ARB+ACE-I vs ARBs	0.76 (0.68 – 0.85)	0.75 (0.61 – 0.92)
ARB+ACE-I vs ACE-I	0.78 (0.72 – 0.84)	0.82 (0.67 – 1.01)

ACE-I = angiotensin-converting-enzyme inhibitor; ARB = angiotensin-receptor blocker; CCB = calcium-channel blocker
*Ratio of means = ratio of the average treatment effect in the intervention group (either ARBs alone or in combination with ACE inhibitors) relative to the control group (placebo or single-drug comparator), with 95% CI

Only one-third of the reports included details on how adverse drug effects were assessed in the studies; according to the authors, few “presented adverse drug reactions in a structured manner that allowed us to make causal inferences,” and 45 of the 49 studies “lacked quantitative data even on more common but less severe adverse drug reactions, prohibiting a reliable estimate of their incidence.”

According to Parfrey, the editorialist, the findings from Kunz et al, along with those of the recent Irbesartan in the Management of PROteinuric patients at high risk for Vascular Events (IMPROVE) trial [4], suggest that “monotherapy with inhibitors of the renin-angiotensin system is sufficient for patients with early-stage renal disease and relatively low albumin excretion and that combination therapy is effective for patients with heavier proteinuria.” However, he cautions, “for combination therapy, we have no safety data in chronic kidney disease, and we do not know the rates of progression of chronic kidney disease. . . . We need a large-scale, long-term, head-to-head, three-group RCT comparing monotherapy with ARBs or ACE inhibitors and with combination therapy involving both ARBs and ACE inhibitors.”

The report by Matchar et al notes that coauthor Dr Douglas C McCrory (Duke Center for Clinical Health Policy Research) has received honoraria from AstraZeneca and coauthor Dr Gregory P Samsa (Duke Center for Clinical Health Policy Research) holds Pfizer stock or stock options. The article by Kunz et al says that “meetings, literature search, and statistical analysis were supported in part by Novartis” and that coauthor Dr Johannes F E Mann (Munich General Hospital, Germany) has received honoraria from Boehringer-Ingelheim, Novartis, and Aventis and grants from Aventis and Novartis.

Clinical Context

More than 65 million Americans have hypertension, and it is the leading attributable risk factor for death throughout the world. According to the editorialist of the 2 studies reviewed, drugs affecting the rennin-angiotensin system are effective in several important diseases including essential hypertension and chronic renal disease, and ACE inhibitors and ARBs both affect angiotensin II, with potential for efficacy alone or in combination in both diseases.

The 2 studies comprise a meta-analysis of 61 studies comparing the effectiveness of ACE inhibitors and ARBs in adults with essential hypertension, and a systematic review of 49 RCTs examining short-term and longer-term outcomes of ACE inhibitors and ARBs for proteinuria in patients with chronic renal disease.

Study Highlights

• Matchar and colleagues (essential hypertension)
  • Included were studies that directly compared ACE inhibitors and ARBs of any design (RCTs, controlled trials, nonrandomized trials, cohort and case control studies) lasting at least 12 weeks and enrolling at least 20 patients, which provided direct comparison of ACE inhibitors and ARBs.
  • Outcomes examined were blood pressure control, adherence, quality of life, intermediate outcomes, and harms.
  • Of 61 studies analyzed, 47 were RCTs, 9 were retrospective cohort studies, 1 cross-sectional, 1 case control cohort, and 1 nonrandomized trial.
  • Rates of use as monotherapy were similar for the 2 classes of drugs.
  • ACE inhibitors and ARBs had similar efficacy for blood pressure control, with no significant differences in benefits or harms (strength of evidence: high).
  • Quality-of-life measures and adherence were similar for ACE inhibitors and ARBs.
  • There were no consistent differential effects seen for death and cardiovascular events.
  • Both classes of medication had similar effects on lipid levels, left ventricular mass, and risk for dysglycemia or renal dysfunction.
  • Adverse effects of headache and dizziness were similar for the 2 classes.
  • Cough as an adverse effect was 3 times more common with ACE inhibitors, with overall rates much higher in randomized trials (9.9% vs 3.2%) vs cohort-based studies (1.7% vs 0.6%).
  • The number needed to treat to cause 1 case of chronic cough for ACE inhibitors was 15.
  • The average duration of follow-up exceeded 6 months in only one third of the head-to-head studies, and there was a lack of long-term studies.
  • There was a lack of adequate studies reporting adverse effect profile of both medication classes.
• Kunz and colleagues (chronic renal disease)
  • Included were RCTs of short-term (1 to 4 months) and longer-term (5 to 12 months) studies involving a total of 6181 patients with microalbuminuria and proteinuria of diabetic origin and other causes and reported changes in proteinuria during follow-up.
  • Trials were at least 4 weeks in duration with parallel group or crossover designs.
  • Excluded were studies of patients who had renal transplantation and those with less than 10 participants.
  • Of 49 RCTs, 12 compared ARBs with placebo, 9 with calcium-channel blockers, 23 with ACE inhibitors, and 16 with the combination of ACE inhibitors and ARBs.
  • 23 trials compared combination ARBs and ACE inhibitors with an ACE inhibitor alone.
  • Monotherapy with ACE inhibitors or ARBs reduced proteinuria to a similar degree but less than combination therapy.
  • Mean reduction in proteinuria with combination vs ARB monotherapy in 5- to 12-month studies was 0.75 vs 0.82 (ratio of means) with ACE inhibitors.
  • Monotherapy with ARBs reduced proteinuria vs placebo, with a ratio of means of 0.57 in 1 to 4 months and 0.69 in 5 to 12 months.
  • Results were similar for ACE inhibitors and ARBs vs calcium-channel blockers.
  • 92% of studies lacked quantitative data on adverse drug reactions.
  • In the absence of safety data on long-term combination therapy with ACE inhibitors and ARBs, therapy should be limited to those with stage 3 or 4 disease with close monitoring of potassium levels.
  • The editorialist concluded that monotherapy with ACE inhibitors or ARBs was sufficient treatment for early-stage renal disease with relatively low albumin exertion, and combination therapy was effective for patients with heavier proteinuria when monotherapy failed to decrease 24-hour urinary protein excretion to less than 0.5 g.

Pearls for Practice

• ACE inhibitors and ARBs are equivalent in efficacy for the treatment of essential hypertension, and ACE inhibitors are associated with a 3 times higher rate of chronic cough.
• ACE inhibitors and ARBs are similar in efficacy for the treatment of proteinuria of chronic renal disease, with the combination being more effective than monotherapy with either drug, but long-term adverse effects are not well documented.

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Mediterranean Diet During Pregnancy Protects Against Asthma in Children

Pregnant women who followed a Mediterranean diet experienced a protective effect against asthma-like symptoms and atopy in their children, according to the results of a prospective cohort study reported in the January 15 Online First issue of Thorax.

“Dietary intake of specific nutrients or food groups during pregnancy could play a role in the risk of asthma and atopy in offspring, but specific dietary patterns have not been implicated,” write Leda Chatzi, MD, PhD, from the University of Crete in Heraklion, Greece, and colleagues. “In general, the Mediterranean diet is characterised by elevated intake of plant foods such as fruits and vegetables, bread and cereals (primarily wholegrain), legumes and nuts. Low to moderate amounts of dairy products and eggs, and only little amounts of red meat are included in the diet. This dietary pattern is low in saturated fatty acids, rich in carbohydrates, fibre and antioxidants, and has a high content of monounsaturated fatty acids and n-3 polyunsaturated fatty acids, which are primarily derived from olive oil and fish intake.”

The investigators recruited women presenting for antenatal care at all general practices in Menorca, a Mediterranean island in Spain, during a 12-month period beginning in mid-1997. After 6.5 years of follow-up, 460 children were included in the analysis. Food frequency questionnaires were used to evaluate maternal dietary intake during pregnancy and children’s dietary intake at age 6.5 years, and a priori defined scores evaluated adherence to a Mediterranean diet. Follow-up included parental questionnaires on the child’s respiratory tract and allergic symptoms, as well as skin prick tests, with 6 common aeroallergens, for the children.

At age 6.5 years, prevalence rates were 13.2% for persistent wheeze, 5.8% for atopic wheeze, and 17.0% for atopy. According to the Mediterranean Diet Score during pregnancy, one third (36.1%) of mothers had a low-quality Mediterranean diet, and the rest had a high-quality Mediterranean diet.

After adjustment for potential confounders and use of the “low” score as the reference, a high Mediterranean Diet Score during pregnancy was found to be protective for persistent wheeze (odds ratio [OR], 0.22; 95% confidence interval [CI], 0.08 – 0.58), atopic wheeze (OR, 0.30; 95% CI, 0.10 – 0.90), and atopy (OR, 0.55; 95% CI, 0.31 – 0.97) at age 6.5 years.

Adherence to a Mediterranean diet during childhood was negatively associated with persistent wheeze and atopy, but this did not reach statistical significance.

“Our results support a protective effect of a high level of adherence to a Mediterranean diet during pregnancy against asthma-like symptoms and atopy in childhood,” the study authors write.

Limitations of the study include no information on maternal food allergy, and parental reports on children’s diet and symptoms creating possible information bias.

“Further studies are needed to better understand the mechanisms of this protective effect and the most relevant window of exposure,” the study authors conclude. “Further follow-up of this cohort will allow determining if this protective effect persists in older children.”

This study was supported by the Instituto de Salud Carlos III red de Grupos Infancia y Media Ambiente, the Fundacio “La Caixa,” the Instituto de Salud Carlos III, red de Centros de Investigacion en Epidemiologia y Salud Publica and EU grant NewGeneris. One of the study authors has received support in part from the National Center for Environmental Health – Centers for Disease Control and Prevention, Atlanta, Georgia; the GA2LEN project; and the Ministry of Education and Science, Spain. Another study author has received support from the Oficina de Ciencia y Tecnología, Generalitat Valenciana.

Thorax. Published online January 15, 2008.

Clinical Context

Dietary habits seem to play a role in the risk for wheezing and atopy. According to Romieu and colleagues in the April 2007 issue of Clinical and Experimental Allergy, fish intake during pregnancy was linked to a lower risk for eczema, atopy, and atopic wheeze in the offspring. In the June 2007 issue of Thorax, Garcia-Marcos reported that a Mediterranean diet in female children seemed to protect against severe asthma.

In the November 1997 issue of Nutrition Reviews, Trichopoulou described a Mediterranean diet: high intake of fruits, vegetables, wholegrain bread and cereals, legumes, and nuts; low to moderate dairy products and eggs; and low intake of red meat. Overall, there is low intake of saturated fatty acids and high intake of fiber, antioxidants, monounsaturated fatty acids, and n-3 polyunsaturated fatty acids (from fish and olive oil).

This cohort study of pregnant women and their offspring from Menorca, a Mediterranean island in Spain, evaluates whether adherence to a Mediterranean diet during pregnancy and childhood affects the prevalence of asthma-like symptoms and atopy in the children.

Study Highlights

• 507 pregnant women in a Mediterranean region were recruited in a 12-month period.
• Data were available for 468 of their offspring at age 6.5 years.
• 8 children were excluded because of total energy intake values less than 800 kcal/day or more than 3000 kcal/day.
• Parents were interviewed every year about the child’s medical conditions in the previous 12 months.
• Demographic data were obtained during pregnancy and at the child’s age of 6.5 years.
• 415 (90.2%) children had height and weight data at age 6.5 years.
• For assessment of childhood dietary intake at age 6.5 years, a 96-item food frequency questionnaire and point values for Mediterranean-related foods (vegetables, legumes, fruits, nuts, cereal, fish, dairy products, olive oil) and non–Mediterranean-type foods (sweets, fast foods) were used to categorize diet as optimal, medium-quality, or low-quality Mediterranean.
• For assessment of maternal dietary intake during pregnancy, a 42-item food frequency questionnaire and point system for Mediterranean-type foods were used to categorize diet as high or low in Mediterranean diet quality.
• Primary outcome measures at age 6.5 years were persistent wheeze (defined by at least 1 episode of “whistling or wheezing from chest, but not noisy breathing from nose” in the previous 12 months and preceding years), atopic wheeze (current wheeze and atopy), and atopy (skin prick test).
• Skin prick testing was conducted on 412 (89.6%) children at age 6.5 years.
• Adjustment was made for possible confounding factors: sex, parental asthma, maternal factors (atopy, age at pregnancy, social class, education, smoking during pregnancy, supplement use during pregnancy), breast-feeding, lower respiratory tract infections at age 1 year, birth weight, gestational age, birth order, number of siblings, and body mass index at age 6.5 years.
• Childhood adherence to a Mediterranean diet was low quality for 9.3%, intermediate for 53.7%, and high for 37.0%.
• Maternal adherence to a Mediterranean diet was low quality for 36.1%.
• At age 6.5 years, 13.2% of children had persistent wheeze, 5.8% had atopic wheeze, and 17.0% had atopy.
• High level of childhood adherence to a Mediterranean diet was not significantly associated with wheeze, atopic wheeze, and atopy at age 6.5 years.
• High level of maternal adherence to a Mediterranean diet during pregnancy was protective for all outcome measures in children at age 6.5 years:
  
  • Persistent wheeze (OR, 0.23; 95% CI, 0.09 – 0.60)
  • Atopic wheeze (OR, 0.34; 95% CI, 0.12 – 0.97)
  • Atopy (OR, 0.55; 95% CI, 0.32 – 0.97)
• Lower risk for childhood wheeze was associated with maternal intake of certain foods:
  
  • Vegetables more than 8 times per week (OR, 0.36; 95% CI, 0.14 – 0.92)
  • Fish more than 2.5 times per week (OR, 0.34; 95% CI, 0.13 – 0.84)
  • Legumes more than once per week (OR, 0.36; 95% CI, 0.13 – 1.01)
• Lower risk for childhood atopy was associated with maternal intake of vegetables more than 8 times per week.
• Maternal adherence to a Mediterranean diet was linked with childhood adherence to a Mediterranean diet.

Pearls for Practice

• Maternal adherence to a Mediterranean diet during pregnancy is linked to a lower risk for persistent wheeze, atopic wheeze, and atopy in the offspring during childhood.
• Adherence to a Mediterranean diet during childhood does not significantly affect the risk for persistent wheeze, atopic wheeze, and atopy in childhood.

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Modified-Release Prednisone May Be Well-Tolerated, Effective in Rheumatoid Arthritis

Modified-release prednisone was well tolerated and reduced morning stiffness of joints in patients with rheumatoid arthritis (RA), according to the results of a double-blind, randomized controlled trial reported in the January 19 issue of The Lancet.

“Circadian rhythms are changed in patients with rheumatoid arthritis,” write Frank Buttgereit, MD from the Charité University Medicine in Berlin, Germany, and colleagues. “A new modified-release delivery system has been developed which adapts the release of the administered glucocorticoid to the circadian rhythms of endogenous cortisol and disease symptoms to improve the benefit–risk ratio of glucocorticoid therapy in rheumatoid arthritis. . . . The Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA-1) study (EMR 62 215-003) assessed the efficacy and safety of a new modified-release prednisone tablet compared with immediate-release prednisone in patients with rheumatoid arthritis.”

In this 12-week, multicenter trial, 288 patients with active RA were randomized to receive either a modified-release prednisone tablet at bedtime or an immediate-release prednisone tablet in the morning. With the modified-release tablet, prednisone was released 4 hours after ingestion. The main endpoint was duration of morning stiffness of the joints, and analysis was by intent-to-treat.

From baseline to end of treatment, the mean relative change in duration of morning stiffness of the joints was higher with modified-release prednisone than with immediate-release prednisone (–22.7% vs –0.4%; difference, 22·4%; 95% confidence interval [CI], 0.49 – 44.30; P = .045). In the prednisone modified-release group, mean reduction from baseline in duration of morning stiffness was 44.0 ± 136.6 minutes. The absolute difference between the groups was 29.2 minutes (95% CI –2.59 to 61.9) favoring modified-release prednisone (P = .072).

Both treatments had a similar safety profile.

“Modified-release prednisone is well tolerated, convenient to administer, and produces a clinically relevant reduction of morning stiffness of the joints in addition to all known therapeutic effects of immediate-release prednisone,” the study authors write. “Interleukin 6 serum concentrations were also significantly reduced by modified-release prednisone after 3 months but were unchanged by immediate-release prednisone.”

Study limitations include that it was not designed to evaluate IL-6 in statistical confirmatory tests.

“Modified-release prednisone provides an improvement with respect to conventional glucocorticoids for the treatment of rheumatoid arthritis,” the authors conclude. “We should stress that patients need to be carefully advised with regard to the correct timing of this evening drug to achieve this beneficial effect in clinical practice. This new prednisone tablet might also be an option for the treatment of other diseases such as polymyalgia rheumatica or even asthma.”

Merck KGaA supported the study and employs one of its authors. Two of the authors have disclosed relevant financial relationships with Abbott, Bristol-Myers Squibb, Merck Pharma GmbH, Organon, Pfizer, Wyeth, Amgen, Roche, the Deutsche Forschungsgemeinschaft, the Federal Ministry of Education and Research Germany, and/or Schering-Plough. Nitec Pharma GmbH employs two of the authors.

In an accompanying editorial, Johannes W.J. Bijlsma, MD, PhD, and Johannes W.G. Jacobs, MD, PhD, from University Medical Centre Utrecht in the Netherlands, call these results “clearly relevant for daily clinical practice,” despite remaining questions regarding long-term efficacy, the effect on radiologic joint destruction, and long-term adverse events.

“Additional and more long-term data on the modified-release formulation are therefore needed, although Buttgereit’s study provides proof-of-principle for this chronotherapy,” Drs. Bijlsma and Jacobs write.

Dr. Bijlsma has disclosed receiving consultancy fees from Nitec, and Dr. Jacobs has disclosed no relevant financial relationships.

Clinical Context

Glucocorticoids have considerable benefits for inflammatory conditions, but there are potential serious adverse effects that lead to recommendations to use the lowest dose necessary. To optimize treatment outcomes, a modified-release system was developed that releases prednisone about 4 hours after ingestion to allow adaptation to the circadian rhythm of endogenous cortisol and symptoms of RA by preventing the proinflammatory impulse of cytokines in the morning. Early morning stiffness is a disabling and common symptom in patients with RA.

This study is a multicenter, double-blind, randomized controlled trial to compare the effect of modified-release vs standard prednisone on morning stiffness in patients with RA with significant morning stiffness, conducted at 17 centers in Germany and 12 centers in Poland.

Study Highlights

• Included were 288 patients with RA by the American College of Rheumatology criteria; active inflammatory component with 45 minutes or longer average duration of morning stiffness; maximum pain intensity of 30 mm or more on a 0- to 100-mm visual analog scale (VAS; 0 = no pain; 100 = maximal pain); and erythrocyte sedimentation rate (ESR) of 28 mm or higher or C-reactive protein 1.5 times or higher than normal.
• Patients had to have received prednisone for at least 3 months with stable dose of 2.5 to 10 mg daily for at least 1 month and disease-modifying rheumatic drugs for at least 3 months.
• Excluded were those taking biological agents within 4 months or who had renal or hepatic impairment or other significant diseases.
• 144 were randomized to modified-release and 144 to standard prednisone for 12 weeks after a run-in of 2 weeks, using a double-dummy technique. A dose of usual prednisone was maintained.
• Doses were given at 0600 to 0800 hours and once at bedtime at 2200 hours.
• Visits were conducted at weeks 0 (baseline), 2, 6, and 12, and patients completed a daily diary.
• The diary documented time of awakening, medication intake, joint stiffness duration, sleep quality, intensity on VAS (0 mm = very good to 100 mm = very bad), use of analgesics in the prior 24 hours, and recurrence of stiffness in the daytime.
• The 28-joint disease activity score (DAS28) was assessed at each visit for 28 joints with the global patient assessment of disease activity, short-form 36, health status using the health assessment questionnaire, ESR, C-reactive protein, and IL-6 levels.
• Primary outcome was relative change in duration of morning stiffness.
• Secondary outcomes were recurrence of joint stiffness, pain intensity, sleep quality, and DAS28.
• Mean age was 55 years, 86% were women, 99% were white, mean duration of morning stiffness at baseline was 164 minutes, mean pain score was 58 mm on VAS, 61% had duration of 5 or more years of RA, and the mean stable daily dose of prednisone was 6.5 mg.
• 87% completed the study with the most common reason for dropout being adverse events.
• Mean duration of therapy was 83 days in both groups.
• Modified-release prednisone was linked with significantly greater reduction in duration of morning stiffness vs immediate-release prednisone (reduction of 44 minutes vs baseline).
• The absolute difference between treatment groups was 29.2 minutes.
• Improvement in morning stiffness duration was evident after 2 weeks with 10% difference and increased to 38% difference from week 7 to 12.
• Other secondary variables were similar between the groups with no difference seen for ESR and C-reactive protein but significantly lower IL-6 level for the modified-release group at week 12 (P = .02).
• Adverse events were reported in 41% of both groups with one third attributable to the medications.
• Worsening of RA was the most common, followed by upper abdominal pain, nasopharyngitis, headache, flushing, and nausea.
• 8% and 7% of those in the modified- and immediate-release groups, respectively, experienced premature discontinuation.
• Only 1 serious adverse effect (depressed consciousness) was attributable to medication and occurred in a patient taking the immediate-release prednisone.

Pearls for Practice

• Modified-release prednisone vs immediate-release prednisone therapy for 12 weeks is associated with shorter duration of morning stiffness in patients with RA.
• Adverse effect profile is similar for modified-release compared with immediate-release prednisone for 12 weeks.

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