Gene Linked To Increased Risk Of Developing Inflammatory Arthritis May Also Increase Patients' Risk Of Dying From Cardiovascular Disease

Medical News Today News Article: "Gene Linked To Increased Risk Of Developing Inflammatory Arthritis May Also Increase Patients' Risk Of Dying From Cardiovascular Disease
01 Feb 2008

People with rheumatoid arthritis (RA), an inflammatory autoimmune disease, tend to die younger and, largely from cardiovascular disease (CVD). One explanation for this increasingly recognized fact is that inflammation promotes atherosclerosis. A marker of inflammation, elevation of the C-reactive protein (CRP) level has been shown to predict CVD in the general population. However, other highly inflammatory diseases - Crohn's, for example - do not carry the same high risk of premature death from heart disease.

To identify other possible suspects, researchers in the United Kingdom investigated whether genetic variants linked to the likelihood of developing RA might also make patients more likely to die from CVD. Led by Dr. Tracey M. Farragher at the University of Manchester and funded by the Arthritis Research Campaign (arc), the study focused on two genes - HLA-DRB1and PTPN22 - and their interactions with known RA risk factors. The evidence, presented in the February 2008 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), implicates HLA-DRB1 genotypes, already associated with RA susceptibility and severity, as a predictor of premature death from CVD for inflammatory arthritis patients. For RA patients in particular, having the shared epitope (SE) - a group of HLA-DRB1 alleles with kindred amino acid traits - plus anti-cyclic citrullinated peptide (anti-CCP) antibodies and current smoking is an especially deadly combination."

Aspirin 'resistance' linked to increased CV morbidity

Aspirin 'resistance' linked to increased CV morbidity

By Caroline Price

18 January 2008

Br Med J 2008; Advance online publication

MedWire News: Patients who do not respond to aspirin therapy are at increased long-term risk for cardiovascular (CV) morbidity, the results of a systematic review and meta-analysis show.

Such patients, labeled "aspirin resistant," had an approximately four-fold increased risk for nonfatal and fatal cardiovascular, cerebrovascular, or vascular events when taking aspirin compared with those classified as sensitive to aspirin.

"Not only did aspirin resistance have an effect on clinical outcome but this risk was not ameliorated by currently used adjunct antiplatelet therapies," the study authors note.

It is not clear why a significant number of CV disease patients derive no benefit from aspirin therapy, nor how these patients may be identified, explain Michael Buchanan (McMaster University, Hamilton, Ontario, Canada) and colleagues.

Such patients have been termed aspirin resistant because their platelets are not affected in the same way as platelets from individuals who seem to benefit from aspirin therapy. Yet it remains unknown whether these patients simply receive too low an aspirin dose, are not compliant, have differing abilities to absorb aspirin, or have an underlying genetic disposition that makes aspirin ineffective. Furthermore, few studies have addressed the impact of aspirin resistance on clinical outcomes.

To look for any relationship between aspirin resistance and clinical outcomes, Buchanan and team reviewed the literature and conducted a meta-analysis on 20 studies involving 2930 patients with CV disease who were receiving aspirin as an antithrombotic. Patients were classified as aspirin resistant if their platelet response was not inhibited in vitro by aspirin.

Overall, 810 (28%) patients were classified as aspirin resistant. These patients, regardless of underlying clinical symptoms, had a greater risk for death, acute coronary syndrome, failure in vascular intervention, or a new cerebrovascular event.

Indeed, 39% of aspirin-resistant compared with 16% of aspirin-sensitive patients had any cardiovascular event, giving an odds ratio of 3.85 (p<0.001).

The odds ratios for acute coronary syndrome, graft failure, and new cerebrovascular event in aspirin resistant compared with aspirin sensitive patients were 4.06, 4.35, and 3.78, respectively.

Moreover, the odds ratio for mortality for aspirin resistant patients was 5.99 (p<0.003).

A planned sensitivity analysis revealed no evidence of a dose-response relationship between aspirin resistance and any cardiovascular outcome among patients who received aspirin alone or who received a second antiplatelet. Furthermore, patients who were aspirin resistant had no benefit from concomitant therapy with clopidogrel or tirofiban, or both.

Italian cardiologists Giuseppe Biondi-Zoccai (University of Turin) and Marzia Lotrionte (Catholic University, Rome) commented in an accompanying editorial that further trials are needed to clarify whether aspirin resistance is just a nonmodifiable risk factor, or whether more aggressive antithrombotic regimens will benefit patients with aspirin resistance.

However, they cautioned that although clinical trials will help "fill in the gaps," there may be another factor generating interest in aspirin resistance.

"Drug companies may be keen to downgrade aspirin from its leading role as an effective drug in CV disease so that they can substitute it with much more expensive but marginally more effective alternatives," they stated.

Journal

Physical Activity, Moderate Alcohol Intake Associated with Improved Survival

Physical Activity, Moderate Alcohol Intake Associated with Improved Survival

Physical activity and moderate alcohol consumption may help reduce fatal ischemic heart disease (IHD) and all-cause mortality, reports the European Heart Journal.

Nearly 12,000 Danish adults without previous IHD reported their alcohol intake and physical activity level and then were followed for about 20 years. Overall, about half died, with IHD accounting for 20% of the deaths.

After adjustment for confounders such as age and smoking status, active subjects had lower risks for fatal IHD and all-cause mortality than inactive subjects, and moderate drinkers (1 to 14 drinks a week) had lower mortality risks than nondrinkers. A combination of physical activity and moderate drinking appeared most beneficial — active subjects who consumed at least one drink weekly had up to a 50% lower risk for fatal IHD and up to a 33% lower all-cause mortality risk.

European Heart Journal article (Free PDF)

Abstract:

The combined influence of leisure-time physical activity and weekly alcohol intake on fatal ischaemic heart disease and all-cause mortality


Aims

To determine the combined influence of leisure-time physical activity and weekly alcohol intake on the risk of subsequent fatal ischaemic heart disease (IHD) and all-cause mortality.


Methods and results

Prospective cohort study of 11 914 Danes aged 20 years or older and without pre-existing IHD. During _20 years of follow-up, 1242 cases of fatal IHD occurred and 5901 died from all causes. Within both genders, being physically active was associated with lower hazard ratios (HR) of both fatal IHD and all-cause mortality than being physically inactive. Further, weekly alcohol intake was inversely associated with fatal IHD and had a U-shaped association with all-cause mortality. Within level of physical activity, non-drinkers had the highest HR of fatal IHD, whereas both non-drinkers and heavy drinkers had the highest HR of all-cause mortality. Further, the physically inactive had the highest HR of both fatal IHD and all-cause mortality within each category of weekly alcohol intake. Thus, the HR of both fatal IHD and all-cause mortality were low among the physically active who had a moderate alcohol intake.

Conclusion

Leisure-time physical activity and a moderate weekly alcohol intake are both important to lower the risk of fatal IHD and all-cause mortality.

Combined Impact of Health Behaviours and Mortality in Men and Women: The EPIC-Norfolk Prospective Population Study

Combined Impact of Health Behaviours and Mortality in Men and Women: The EPIC-Norfolk Prospective Population Study

Kay-Tee Khaw, Nicholas Wareham, Sheila Bingham, Ailsa Welch, Robert Luben, Nicholas Day


Background

There is overwhelming evidence that behavioural factors influence health, but their combined impact on the general population is less well documented. We aimed to quantify the potential combined impact of four health behaviours on mortality in men and women living in the general community.


Methods and Findings

We examined the prospective relationship between lifestyle and mortality in a prospective population study of 20,244 men and women aged 45–79 y with no known cardiovascular disease or cancer at baseline survey in 1993–1997, living in the general community in the United Kingdom, and followed up to 2006. Participants scored one point for each health behaviour: current non-smoking, not physically inactive, moderate alcohol intake (1–14 units a week) and plasma vitamin C >50 mmol/l indicating fruit and vegetable intake of at least five servings a day, for a total score ranging from zero to four. After an average 11 y follow-up, the age-, sex-, body mass–, and social class–adjusted relative risks (95% confidence intervals) for all-cause mortality(1,987 deaths) for men and women who had three, two, one, and zero compared to four health behaviours were respectively, 1.39 (1.21–1.60), 1.95 (1.70–-2.25), 2.52 (2.13–3.00), and 4.04 (2.95–5.54)

Conclusions

Four health behaviours combined predict a 4-fold difference in total mortality in men and women, with an estimated impact equivalent to 14 y in chronological age

LINK:

"http://medicine.plosjournals.org/perlserv/?request=index-html&issn=1549-1676

Effect of Antecedent Hypertension and Follow-Up Blood Pressure on Outcomes After High-Risk Myocardial Infarction

Effect of Antecedent Hypertension and Follow-Up Blood Pressure on Outcomes After High-Risk Myocardial Infarction

Hypertension. 2008;51:48-54;

Jens J. Thune; James Signorovitch; Lars Kober; Eric J. Velazquez; John J.V. McMurray; Robert M. Califf; Aldo P. Maggioni; Jean L. Rouleau; Jonathan Howlett; Steven Zelenkofske; Marc A. Pfeffer; Scott D. Solomon


The influence of blood pressure on outcomes after high-risk myocardial infarction is not well characterized. We studied the relationship between blood pressure and the risk of cardiovascular events in 14 703 patients with heart failure, left ventricular systolic dysfunction, or both after acute myocardial infarction in the Valsartan in Myocardial Infarction Trial.

We assessed the relationship between antecedent hypertension and outcomes and the association between elevated (systolic: >140 mm Hg) or low blood pressure (systolic: <100 mm Hg) in 2 of 3 follow-up visits during the first 6 months and subsequent cardiovascular events over a median 24.7 months of follow-up. Antecedent hypertension independently increased the risk of heart failure (hazard ratio [HR]: 1.19; 95% CI: 1.08 to 1.32), stroke (HR: 1.27; 95% CI: 1.02 to 1.58), cardiovascular death (HR: 1.11; 95% CI: 1.01 to 1.22), and the composite of death, myocardial infarction, heart failure, stroke, or cardiac arrest (HR: 1.13; 95% CI: 1.06 to 1.21).

While low blood pressure in the postmyocardial infarction period was associated with increased risk of adverse events, patients with elevated blood pressure (n=1226) were at significantly higher risk of stroke (adjusted HR: 1.64; 95% CI: 1.17 to 2.29) and combined cardiovascular events (adjusted HR: 1.14; 95% CI: 1.00 to 1.31). Six months after a high-risk myocardial infarction, elevated systolic blood pressure, a potentially modifiable risk factor, is associated with an increased risk of subsequent stroke and cardiovascular events. Whether aggressive antihypertensive treatment can reduce this risk remains unknown.

Coronary Artery Calcium Scores and Risk for Cardiovascular Events in Women Classified as "Low Risk" Based on Framingham Risk Score

Coronary Artery Calcium Scores and Risk for Cardiovascular Events in Women Classified as "Low Risk" Based on Framingham Risk Score

The Multi-Ethnic Study of Atherosclerosis (MESA)

Susan G. Lakoski, MD, MS; Philip Greenland, MD; Nathan D. Wong, PhD, MPH; Pamela J. Schreiner, PhD; David M. Herrington, MD, MHS; Richard A. Kronmal, PhD; Kiang Liu, PhD; Roger S. Blumenthal, MD

Arch Intern Med. 2007;167(22):2437-2442.

Objective To assess coronary artery calcium (CAC) score and subsequent risk for coronary heart disease (CHD) and cardiovascular (CVD) events among asymptomatic women judged to be at low risk by the Framingham risk score (FRS), a common approach for determining 10-year absolute risk for CHD. Based on population survey data, 95% of American women are considered at low risk based on FRS.

Methods The Multi-Ethnic Study of Atherosclerosis (MESA) included 3601 women aged 45 to 84 years at baseline. The CAC score was measured by coronary computed tomography. Cox proportional hazard models were used to examine the CHD and CVD risk associated with CAC score among women classified as "low risk" based on FRS.

Results Excluding women with diabetes and those older than 79 years, 90% of women in MESA (mean ± SD age, 60 ± 9 years) were classified as "low risk" based on FRS. The prevalence of CAC (CAC score > 0) in this low-risk subset was 32% (n = 870). Compared with women with no detectable CAC, low-risk women with a CAC score greater than 0 were at increased risk for CHD (hazard ratio, 6.5; 95% confidence interval, 2.6-16.4) and CVD events (hazard ratio, 5.2; 95% confidence interval, 2.5-10.8). In addition, advanced CAC (CAC score 300) was highly predictive of future CHD and CVD events compared with women with nondetectable CAC and identified a group of low-risk women with a 6.7% and 8.6% absolute CHD and CVD risk, respectively, over a 3.75-year period.

Conclusions The presence of CAC in women considered to be at low risk based on FRS was predictive of future CHD and CVD events. Advanced CAC identified a subset of low-risk women at higher risk based on current risk stratification strategies.

Childhood Body-Mass Index and the Risk of Coronary Heart Disease in Adulthood

New England Journal of Medicine

December 6, 2007

Jennifer L. Baker, Ph.D., Lina W. Olsen, Ph.D., and Thorkild I.A. Sørensen, M.D., Dr.Med.Sci.

ABSTRACT

Background The worldwide epidemic of childhood obesity is progressing at an alarming rate. Risk factors for coronary heart disease (CHD) are already identifiable in overweight children. The severity of the long-term effects of excess childhood weight on CHD, however, remains unknown.

Methods We investigated the association between body-mass index (BMI) in childhood (7 through 13 years of age) and CHD in adulthood (25 years of age or older), with and without adjustment for birth weight. The subjects were a cohort of 276,835 Danish schoolchildren for whom measurements of height and weight were available. CHD events were ascertained by linkage to national registers. Cox regression analyses were performed.

Results In 5,063,622 person-years of follow-up, 10,235 men and 4318 women for whom childhood BMI data were available received a diagnosis of CHD or died of CHD as adults. The risk of any CHD event, a nonfatal event, and a fatal event among adults was positively associated with BMI at 7 to 13 years of age for boys and 10 to 13 years of age for girls. The associations were linear for each age, and the risk increased across the entire BMI distribution. Furthermore, the risk increased as the age of the child increased. Adjustment for birth weight strengthened the results.

Conclusions Higher BMI during childhood is associated with an increased risk of CHD in adulthood. The associations are stronger in boys than in girls and increase with the age of the child in both sexes. Our findings suggest that as children are becoming heavier worldwide, greater numbers of them are at risk of having CHD in adulthood

Rethinking a “healthy weight”: New study finds that being overweight is not associated with increased mortality from cardiovascular causes

Rethinking a “healthy weight”: New study finds that being overweight is not associated with increased mortality from cardiovascular causes


November 9, 2007 By Benjamin A. Olenchock, M.D. Ph.D.


Bethesda, MD



A new study has examined disease-specific mortality rates based on body mass index (BMI) using data from the National Health and Nutrition Examination Survey (NHANES) databases.

The findings, published in the Journal of the American Medical Association, suggest that individuals defined as overweight (BMI between 25 and 30) do not have increased cardiovascular mortality. Obesity (BMI > 30), however, was associated with excess cardiovascular mortality, although to a much lesser extent than in previous years. Under-weight (BMI<18.5) was associated with higher non-CVD/non-cancer mortality. This research is a continuation of work published in 2005 that examined all-cause mortality.

The previous study reported that over-weight individuals had decreased all-cause mortality compared to normal weight individuals, while obesity and under-weight were found to have increased all-cause mortality.


The statistical analyses required to do such a study were quite complex. The study used the NHANES databases to gather baseline data in representative cross-sectional samples of the United States population. Cause of death was divided into three categories: cardiovascular, cancer, and all other. They used a Cox proportional hazard model to calculate the relative disease-specific risk for the different BMI classes, separating the analysis by age for statistical reasons. The model included sex, smoking status, race, and alcohol consumptions as other covariates. To estimate the excess disease-specific mortality in 2004 attributable to BMI class, they applied their relative risk data to mortality data from the United States vital statistics in 2004, estimating the current distribution of covariates using the NHANES 1999-2002 cross-sectional data set.


Obesity was associated with 81,072 [CI 51,433 to 110,710] excess deaths from cardiovascular disease but no statistically significant increase in cancer deaths (14,930, [CI -13,721 to 43,582]). Obesity was, however, associated with increased obesity-related cancers, defined as colon, breast, esophageal, uterine, ovarian, kidney and pancreatic (13,839 excess deaths, CI 1920 to 25,758). The authors analyzed longitudinal changes in attributable deaths by using relative risk estimates for individual NHANES databases. They found that using NHANES I (1971-1975) relative risk estimates, obesity was associated with 161,290 excess deaths from cardiovascular causes, much more than the current estimate of 81,072.


Overweight was associated with no excess deaths from cardiovascular causes (-17,074, CI -50,407 to 16,259) or cancer (-13,533, CI -44364 to 17298), but significantly decreased deaths from all-other causes (-107674, CI -148738 to -66610). Underweight, in contrast, was associated with excess deaths from all-other causes (23,455, CI 11,848 to 35,061). Looking closer at the over-weight category, the authors did find that both overweight and obese individuals had excess deaths from kidney disease and diabetes.


This data adds significantly to their previous work, which demonstrated differences in all-cause mortality based on BMI. One interesting finding is that over-weight is associated with less all-cause mortality and no difference in cardiovascular mortality. Also, the data are notable for the apparent change in the excess cardiovascular deaths associated with obesity over time, perhaps reflecting improvements in medical care in recent years. These data are sure to bring commentaries on the statistical methods used, changes in BMI class over time as a consequence rather than cause of disease, concerns about cause of death reporting bias, etc. Nonetheless, this work is an important contribution to our current understanding of healthy body weight and the relationship between cardiovascular disease mortality and excess body weight.

Metformin linked to reduced mortality in diabetic patients with HF

Metformin linked to reduced mortality in diabetic patients with HF

7 September 2007

MedWire News: Metformin is associated with reduced mortality in patients with heart failure (HF) and diabetes, Canadian researchers report in the British Medical Journal.

HF is common in diabetic patients, but few studies have compared the effect of antidiabetic drugs in patients with both conditions, the authors say.

Jeffrey Johnson, from the University of Alberta in Edmonton, and colleagues therefore carried out a meta-analysis of eight studies to evaluate the effects of antidiabetic agents in patients with HF and diabetes.

Four studies evaluated the effect of insulin treatment, three examined metformin, four evaluated thiazolidinediones, and two studies compared sulfonylureas with other agents.

Insulin use was associated with increased risk for all cause mortality in studies that did not adjust for diet and antidiabetic drug treatment (odds ratio [OR]=1.25), and in the studies that accounted for these factors (hazard ratio [HR]=1.66).

• 
  In contrast, all cause mortality was significantly lower in patients treated with metformin, at a HR of 0.86 compared with other antidiabetic drugs and insulin, and at a HR of 0.70 compared with sulfonylureas.

In addition, metformin was not associated with increased hospital admission at 1 year for any cause (HR=0.94) or for HF (HR=0.92). The pooled effect suggested that treatment with metformin might be linked to a reduced all cause hospital admission at 1 year (pooled OR=0.85).
Thiazolidinediones were associated with reduced all cause mortality (pooled OR=0.83), but they were also linked to an increased risk for hospital admission for HF (pooled OR=0.83). The researchers note that this conflicting result might be due to differences in comparator treatments.

Johnson and co-workers conclude: "Our analysis revealed that treatment with metformin may be associated with lower mortality rates."

Nevertheless, they note that the US Food and Drug Administration still recommends cautious use of metformin in this population.

Br Med J 2007; 335: 497

Hormone therapy and thromboembolic disease.

Hormone therapy and thromboembolic disease.

Hemostasis and thrombosis Current Opinion in Hematology. 14(5):488-493, September 2007.

Battaglioli, Tullia; Martinelli, Ida

Abstract:

Purpose of review:

Hormone therapy increases the risk of venous thromboembolism (VTE). To reduce this risk, changes in dosage, composition and route of administration have been made over the years. This review provides a summary of the available evidence and an update on the most recent findings on the issue.

Recent findings:

Contraceptives containing third-generation progestagens confer a higher risk of VTE than second-generation compounds. Little data are available on preparations containing less than 30 [mu]g of estrogen, new progestagens or levonorgestrel-releasing intrauterine devices. Hormone replacement therapy increases the risk of VTE by 2 to 3-fold. Transdermal administration may be less thrombogenic than oral administration, while different estrogens and progestagens may carry a different risk. VTE risk is further increased in carriers of inherited thrombophilia. Despite a similar increase in relative risk of thrombosis associated with hormone therapy, absolute risk is lower in fertile women and higher in postmenopausal ones. Universal screening for thrombophilia before prescribing hormone replacement therapy might be cost-effective.

Summary:

Careful evaluation of individual risk factor is warranted before prescribing hormone therapy. Further investigations are needed to establish whether or not newer compounds are safer than older ones with respect to the risk of thrombosis.

ECG parameters predict prognosis in CABG patients

Quantitative Measures of Electrocardiographic Left Ventricular Mass, Conduction, and Repolarization, and Long-Term Survival After Coronary Artery Bypass Grafting

Michael S. Lauer, MD; Derlis Martino, MD; Hemant Ishwaran, PhD; Eugene H. Blackstone, MD
From the Department of Cardiovascular Medicine (M.S.L.), the Department of Thoracic and Cardiovascular Surgery (D.M., H.I., E.H.B.), and the Department of Quantitative Health Sciences (H.I., E.H.B.), The Cleveland Clinic Foundation, and the Department of Epidemiology and Biostatistics (M.S.L.), Case Western Reserve University School of Medicine, Cleveland, Ohio.

Correspondence to Dr Michael S. Lauer, Division of Prevention and Population Science, National Heart, Lung, and Blood Institute, 6701 Rockledge Dr, Room 10122, Bethesda, Md 20892. E-mail lauer@nhlbi.nih.gov

Received April 12, 2006; accepted June 8, 2007.

Background— Quantitative ECG measures of left ventricular mass and repolarization predict outcome in population-based cohorts and patients with hypertension. We assessed the prognostic value of preoperative quantitative electrocardiography in patients who underwent isolated coronary artery bypass grafting.

Methods and Results— For 6 years we followed 8166 patients who underwent primary isolated coronary artery bypass grafting between 1990 and 2003, all of whom had routine preoperative ECGs. With use of specialized digital software, quantitative measures were recorded on ventricular rate, P duration, PR interval, QRS duration, QT interval, QRS axis, Sokolow-Lyon and Cornell voltages, and ST-segment depression and slope. There were 1516 deaths. After adjustment for age, gender, clinical characteristics, left ventricular ejection fraction, and other confounders, death was independently predicted by ventricular rate (adjusted hazard ratio [AHR] for 90 versus 60 beats per minute, 1.34; 95% confidence interval [CI], 1.21 to 1.50; P<.0001), PR interval (AHR for 200 versus 150 ms, 1.05; 95% CI, 1.00 to 1.10; P<.0001), QRS duration (AHR for 120 versus 80 ms, 1.24; 95% CI, 1.07 to 1.44; P<.0001), Sokolow-Lyon voltage (AHR for 3.5 versus 1.5 mV, 1.18; 95% CI, 1.05 to 1.31; P<.0001), and ST-segment slope (AHR for –0.1 versus 0 mV, 1.16; 95% CI, 1.02 to 1.31; P<.0001). We derived a quantitative ECG score and demonstrated that, with the exception of age, it was the most powerful predictor of long-term death.

Conclusions— Quantitative ECG measures of left ventricular rate, mass, and repolarization are predictive of mortality among patients who underwent isolated coronary artery bypass grafting. These findings suggest that quantitative electrocardiography may be valuable for risk stratification in patients with severe coronary artery disease.

Circulation 2007; 116: 888-893

Routine Pulse Checks Improve Detection of Atrial Fibrillation

Routine Pulse Checks Improve Detection of Atrial Fibrillation

Routine pulse checking in older patients can lead to a substantial increase in the detection of atrial fibrillation, a major risk factor for stroke, according to a study in the British Medical Journal.

The study, conducted in England on nearly 15,000 patients ages 65 and over, compared active screening for atrial fibrillation — in which practice nurses either measured the patients' radial pulses to determine the need for follow-up electrocardiography or simply offered all patients electrocardiography — versus routine care during office visits.

The annual detection rate of new cases was 1.63% during active screening, compared with 1.04% in control practices.

The detection rate for active screening was nearly identical regardless of whether patients were offered electrocardiography routinely or only if they had an irregular pulse.

The authors concluded that routine electrocardiography is unnecessary for finding atrial fibrillation "as long as healthcare professionals are conscientious about feeling the pulse."

Link: BMJ article (Free)

Published in Physician's First Watch August 6, 2007

ADOPT analysis shows rosiglitazone increases risk of fracture in women

ADOPT analysis shows rosiglitazone increases risk of fracture in women

June 29, 2007

Chicago, IL - Not unlike a prizefighter battered and bruised, rosiglitazone (Avandia, GlaxoSmithKline) continued to take it on the chin this week, with a new analysis from A Diabetes Outcome Progression Trial (ADOPT) expanding upon the risks of the thiazolidinedione (TZD) and showing an increase in the risk of fracture in women taking the controversial medication.

"In ADOPT, the increased risk of bone fractures in women with type 2 diabetes was accentuated with rosiglitazone," said lead investigator Dr Steven Kahn (University of Washington, Seattle) during a late-breaking clinical-trials session here at the American Diabetes Association 2007 Scientific Sessions this week. "It appears to increase fractures principally in the upper and lower limbs, and there was no observed increase in spinal fractures with rosiglitazone."

Kahn, however, pointed out that this adverse effect of rosiglitazone is also observed with pioglitazone (Actos, Takeda Pharmaceuticals). Based on these data, the ADOPT investigators say that "special attention should be paid to bone health in women with type 2 diabetes who are receiving thiazolidinediones."

A bad month altogether for rosiglitazone

Previously reported by heartwire, ADOPT was a multicenter, randomized, double-blind clinical trial involving 4360 patients who had not received pharmacologic treatment for recently diagnosed type 2 diabetes. Patients were treated with rosiglitazone, metformin, or glyburide, and investigators showed that initial treatment with rosiglitazone slowed the progression to monotherapy failure more effectively than either metformin or glyburide. Investigators concluded that there was a clinically meaningful difference between rosiglitazone and glyburide, but the difference between rosiglitazone and metformin, based on glucose control, was less significant.

As noted during the trial, however, the side-effect profile differed significantly among the agents, with the risk of congestive heart failure associated with rosiglitazone similar to metformin, a risk that was higher in both drugs compared with glyburide. In addition, investigators also observed an increased risk of fracture in female rosiglitazone-treated patients, and the purpose of this analysis, compiled from adverse- and serious-adverse-events data during follow-up, was to further analyze and quantify that risk.

In terms of the overall fracture risk in men, there was no significant difference when investigators compared those treated with rosiglitazone with those treated with metformin, nor was there a difference in fracture risk in a comparison between rosiglitazone and glyburide. In women, however, there was 81% increase in the incidence of fracture among those treated with rosiglitazone compared with those treated with metformin. The risk of fracture was even higher in a comparison between the rosiglitazone- and glyburide-treated female patients. This increased risk of fracture appears to start after about one year of treatment with the TZD, said Kahn.

In looking to determine when women at increased risk could be identified, Kahn said there were more postmenopausal women included in the study, and those taking metformin and glyburide had less fracture risk than those taking rosiglitazone. Regarding premenopausal women, there was significantly less fracture in the glyburide-treated patients, but only a trend toward less fracture in the metformin-treated patients. Overall, more fractures were observed in the lower and upper limbs, including the hand, humerus, and foot, but no difference in fracture rates in the spine and hip. The baseline characteristics, including medication use, were similar in the three study arms, and there was no observed difference in fracture risk among ADOPT women taking estrogen or calcium supplements. There was a greater risk of fracture among women taking a bisphosphonate, investigators found.

Not to leave pioglitazone out of the mix, Kahn also analyzed existing pioglitazone data involving more than 8000 patients treated with the TZD and compared the risk of fracture with approximately 7400 patients taking a comparator drug. Treated, on average, for 3.5 years, there was no increased fracture risk in men, but a similar risk to rosiglitazone was observed in women treated with pioglitazone.

"It would appear that this is a class effect," said Kahn. At this time, however, no clear recommendations can be made, he said, except for clinicians to continue to monitor their patients. He noted that type 2 diabetes alone increases the risk of fracture, and this risk increases with the duration of disease.

Source:
Kahn S, on behalf of the ADOPT investigators. Increased incidence of fractures in women who received rosiglitazone in ADOPT. American Diabetes Association 2007 Scientific Sessions; June 26, 2007; Chicago, IL.

Related links:

A house divided: No clear answers on rosiglitazone safety or political backstory [HeartWire > Cardiometabolic risk; Jun 07, 2007]
The rosiglitazone aftermath: Legitimate concerns or hype? [HeartWire > Cardiometabolic risk; May 24, 2007]
Rosiglitazone increases MI and CV death in meta-analysis [HeartWire > Cardiometabolic risk; May 21, 2007]
Pioglitazone beneficial in diabetes patients with previous MI? [HeartWire > Acute coronary syndromes; Apr 20, 2007]
ADOPT: Rosiglitazone delays treatment failure in patients with type 2 diabetes [HeartWire > Cardiometabolic risk; Dec 04, 2006]
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Prognostic Value of the New York Heart Association Classification in End-Stage Renal Disease

Prognostic Value of the New York Heart Association Classification in End-Stage Renal Disease

Maurizio Postorino; Carmen Marino; Giovanni Tripepi; Carmine Zoccali; on behalf of the Calabrian Registry of Dialysis and Transplantation*

Nephrol Dial Transplant. 2007;22(5):1377-1382. ©2007 Oxford University Press


Abstract and Introduction

Abstract

Background:

The New York Heart Association (NYHA) classification is a strong predictor of mortality and an established instrument for risk stratification in patients with heart disease but data on the validity of this classification in end-stage renal disease (ESRD) are sparse.

Methods:

In this study, we tested the predictive value of the NYHA in patients with ESRD and compared it with that of two established indexes of disease severity, i.e. the Khan index and the renal disease severity score (RDSS). The study cohort was composed of 1322 incident patients in a dialysis registry (772 male and 550 female, age 61 ± 16 years).

Results:

During the follow-up period (41 ± 27 months) 551 patients died. A multivariate COX model including the NYHA classification explained 39% of the variation in mortality, a figure almost identical to that of a model based on the RDSS (37%) and superior (P < 0.001) to that provided by the Khan index-based model (32%). The area under the receiver operating characteristic curve of NYHA classification, as related to all-cause mortality, was 0.74 (95% CI: 0.71-0.77, P < 0.001). Again, RDSS had a predictive value for mortality (0.74, 95% CI: 0.72-0.77) identical to that of NYHA and higher than that of the Khan index (0.70, 95% CI: 0.67-0.72).

Conclusion:

The NYHA is a powerful predictor of mortality in ESRD and provides prognostic information equal or superior to that given by other established indexes of disease severity. Given the pervasive nature of cardiovascular disease in ESRD, this classification may be recommended for risk stratification in this population.

More:

Link: http://www.medscape.com/viewarticle/557267_print

Antioxidant vitamins increase mortality

Qual o impacto que um trabalho como esse poderá trazer à prática médica brasileira?

Antioxidant vitamins increase mortality

http://www.theheart.org/article/773375.do

Copenhagen, Denmark - The largest analysis of data on antioxidant vitamins ever conducted has shown that beta-carotene, vitamin A, and vitamin E probably increase mortality [1]. Two other antioxidant substances—vitamin C and selenium—had no effect on mortality.

The meta-analysis of 68 randomized trials with a total of 232 606 participants, published in the February 28, 2007 issue of the Journal of the American Medical Association, was conducted by a group led by Dr Goran Bjelakovic (Copenhagen University Hospital, Denmark).

Coauthor Dr Christian Gluud (Copenhagen University Hospital) commented to heartwire: "This is the most comprehensive collection of data on antioxidant vitamins ever conducted, and we have shown that on the whole these agents have no benefit. Indeed, vitamin A, vitamin E, and beta-carotene are associated with an increase in mortality at the doses studied. Vitamin A and beta-carotene seem to have a dose-related effect, with mortality increasing as doses increase, whereas vitamin E does not appear to have a dose-related effect, with all doses associated with increased mortality."

Jury still out on vitamin C and selenium

Gluud added that the jury is still out on vitamin C and selenium. "Vitamin C does not appear to be detrimental, but it is not beneficial either, and all the trials of selenium together suggest a small benefit, but when only the well-conducted trials are included, there appears to be neither benefit nor harm.

"Our data show that antioxidant vitamins should not be taken in an effort to prevent illness. People should instead eat a balanced diet and take regular exercise," he said.

In the paper, the authors note that many people are taking antioxidant supplements in the belief that they improve health and prevent diseases. Many primary- or secondary-prevention trials of antioxidant supplements have been conducted to investigate the prevention of several diseases—mainly cardiovascular disease and cancer—but results have generally not been positive, with some trials showing increases in mortality.

To find out more, they conducted the current systematic review to analyze the effects of antioxidant supplements on all-cause mortality of adults included in primary- and secondary-prevention trials. They included all primary- and secondary-prevention published trials in adults randomized to receive beta-carotene, vitamin A, vitamin C, vitamin E, or selenium vs placebo or no intervention.

Results showed that when all trials of antioxidant supplements were pooled together, there was no significant effect on mortality, but when the 47 trials said to have a low risk of bias (in a total of 180 938 participants) were analyzed alone, the antioxidant supplements as a whole significantly increased mortality, and beta-carotene, vitamin A, and vitamin E were all associated with increased mortality when given alone or in combination. Vitamin C and selenium had no significant effect on mortality.

The researchers note that more than two thirds of the included trials fell into the category of those with a low risk of bias, which they say highlights the validity of their results. "Antioxidant supplements not only seem to be one of the most researched topics in the world, they also seem to be one of the most adequately researched clinical questions," they say.

They point out that a large number of unpublished trials on supplements may exist, but as unpublished trials are more likely to have been either neutral or negative than to have shown beneficial effects, this suggests their estimate of a 5% increase in mortality is likely to be conservative.

Substantial public-health consequences

Noting that 10% to 20% of the adult population (80 million-160 million people) in North America and Europe may consume these supplements, Bjelakovic et al say the public-health consequences may be substantial.

Speculating on possible mechanisms, they point out that although oxidative stress has a hypothesized role in the pathogenesis of many chronic diseases, it may be the consequence of pathological conditions, and that eliminating free radicals may interfere with some essential defensive mechanisms.

In an interview with heartwire, Gluud also suggested that the antioxidant vitamins could actually also have pro-oxidant effects. "We don't know exactly how they are doing harm, but rather than preventing cardiovascular disease and cancer, they actually seem to be accelerating these conditions."

Lessons learned

He said these observations were "a huge disappointment" but added that at least it has been discovered. "We must see the positives in this. The question has been thoroughly addressed and we now know the answer—these agents are harmful. The companies selling these antioxidant vitamins have been able to dodge the issue for a long time, saying that any negative data have not been comprehensive. They cannot do this any longer. There are lessons to be learned here— for example, the importance of conducting trials with these agents and publishing the results."

Gluud added that food supplements should be regulated in the same way as medical products. "The governments of the world now have the responsibility to inform people of these results. They have been too slow in the past in requesting that health supplements be properly evaluated before allowing these products to be added to foods. People have been buying these supplements and foods advertised as having these supplements added under the impression that they are good for them, when in actual fact they are harmful. Any potential health supplements should not be allowed to be added to foods unless they have been shown to be beneficial or at least proven not to be harmful."