Thursday, May 31, 2007

American Society of Hypertension 22nd Annual Meeting and Exposition (ASH)

American Society of Hypertension 22nd Annual Meeting and Exposition (ASH)

Conference News

Impaired Glycemic Control Reversible When Switching Off Diuretic-Based TherapyResults from a six-month extension study have shown that impairment in glycemic control after one year of diuretic-based combination treatment is reversible by switching to treatment not involving a diuretic, in this case, an ACE inhibitor and calcium-channel blocker.
Heartwire, May 25, 2007

Combination Therapy With ARB and Amlodipine Effectively Reduces Blood PressureTwo new studies presented this week suggest that fixed-dose combination therapy with amlodipine and an angiotensin receptor blocker, either valsartan or olmesartan, can achieve significant reductions of blood pressure without an increase in serious adverse events.
Heartwire, May 24, 2007

ACCOMPLISH at 18 Months: Better Blood-Pressure Control With Single-Tablet Combination TherapyInterim data from the ACCOMPLISH study has shown that a single-tablet dual-mechanism therapy initiated in high-risk hypertensive patients is highly effective in reducing blood pressure and significantly better in getting more patients to treatment goals. While some see combination drugs as the wave of the future, others are concerned about going too fast in some patients.
Heartwire, May 22, 2007

Novel ARB Provides Greater Reductions in Proteinuria in Diabetics With Overt NephropathyOne year of treatment with telmisartan provided greater reductions in proteinuria when compared with losartan. The greater protection was not attributed to differences in blood pressure, and the antiproteinuric effects were sustained with telmisartan two months after therapy was stopped.
Heartwire, May 22, 2007

CAMELOT: Obese Patients Benefit the Most From Intensive Antihypertensive Drug TherapyAn analysis of the CAMELOT study has shown that the clinical benefits of intensive antihypertensive therapy in CAD patients is greatest in those considered obese, despite the fact that blood-pressure reductions were lower for obese patients than for lean or overweight patients.
Heartwire, May 21, 2007

Diet of Hypertensive Adults Is Getting Worse: Just 22% Following the DASH DietMore and more Americans are losing out in their mad DASH to good eating habits. A new study reveals that the dietary quality of hypertensive adults has deteriorated since the DASH diet became part of the national guidelines.
Heartwire, May 21, 2007

BAFTA: Warfarin bests aspirin for stroke prevention in elderly AF patients

BAFTA: Warfarin bests aspirin for stroke prevention in elderly AF patients

Glasgow, Scotland - Results of the Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) trial show that even among elderly patients with atrial fibrillation (AF), anticoagulation with warfarin was superior to aspirin for primary stroke prevention [1].
The benefit of treatment was not at the cost of more major hemorrhage, the rates of which were similar between groups. The results were presented here at the 16th European Stroke Conference.
"Use of anticoagulation rather than aspirin in over-75s in our study will prevent one primary event for every 50 patients treated for a year, or 25 treated for two years," Dr Jonathan W Mant (University of Birmingham, UK) told attendees here. "Our conclusion is that warfarin could be safely used much more widely in the elderly than it is at the moment, and age itself should not be regarded as a contraindication to warfarin therapy."

Wednesday, May 30, 2007

Linear risk scores needed in HCM

Cardiovascular News

Linear risk scores needed in HCM

30 May 2007

MedWire News: Experts in hypertrophic cardiomyopathy (HCM) are conducting population-based studies to develop improved risk stratification methods for management of the disease.
Speaking at the UK Cardiomyopathy Association Conference, held in London, UK, Perry Elliott (The Heart Hospital, University College London) noted that current risk stratification relies on relatively crude ways of assessing risk, based on a small number of simple, non-linear risk factors.

“We need to start modeling risk in a slightly more sophisticated way,” he said, emphasizing that there is a continuum of risk, with complex interactions between risk factors and variations over time.

Elliott explained that determining risk in HCM is particularly challenging because, although HCM affects 1 in 500 of the general population, it remains relatively uncommon in everyday clinical practice.

Another problem is that although sudden unexplained death (SUD) is the best known complication of HCM, it is actually quite rare, now occurring in less than 1% of the HCM population per year. Finally, there is a great degree of heterogeneity in symptoms, even within families with the same underlying genetic defect.

Elliott outlined the main risk factors on which risk stratification in HCM is currently based, namely unexplained syncope, a family history of sudden unexplained death (SUD), the severity of left ventricular hypertrophy (LVH), presence of an abnormal BP response on exercise, and the presence of arrhythmia on 24-hour ECG monitoring.

The problem with each of these risk factors is that there caveats to their interpretation.

For example, Elliott noted, a family history of SUD is emotively the most powerful risk factor. Yet if the logic of this is followed too stringently, it might lead to implanting defibrillators in multiple family members even though, statistically, a family history of SUD is no more or less predictive than other risk factors. There are some families in whom such a history is very bad, and so taking this into account may be enough. But for other families – perhaps where a more distant relative has been affected and the cause remains uncertain – it is not so powerful.

Similarly, caveats apply to all the other risk factors. Fainting does not necessarily carry an adverse prognostic significance, and measures of LVH can only be semi-quantitative - while the threshold of ≥30 mmHg in heart muscle thickness is considered a risk factor, there is always a gradation of risk around this measure.

Elliott noted that left ventricular outflow tract obstruction (LVTOTO), a defining feature of HCM, has recently been established as a risk factor.

Unlike most of the other risk factors it is modifiable, since the outflow tract obstruction can be relieved by surgery or alcohol ablation. But owing to the risk associated with any type of surgery, the decision to operate has to be taken on the basis of gradient severity and in conjunction with other risk factors.

In practice, clinicians have to look at the global risk burden, since the more severe the disease, the more likely patient is to have multiple risk factors.

Speaking to MedWire News, Elliott said that developments in two key areas will lead to improved risk stratification that will help to aid decision-making in borderline cases of HCM.
The first involves doing a much larger study, “looking at other variables that tell you about the severity of the disease,” he said.

“When you’re trying to construct risk scores it’s always much better to have thousands of patients because then the scores have more predictive power,” he explained. “So for cholesterol and blood pressure there are now some very well trusted risk algorithms.

“By contrast, historically we’ve only had relatively small numbers of HCM patients to study.”
But over the past decade this has changed quite rapidly and most are centers now following several thousand patients, he said.

“I think if we study 10,000 patients this should be able to generate more meaningful risk scores.”

Elliott noted that such studies are now underway at The Heart Hospital.

“The second thing is that we’re always looking out for new techniques that tell you about the vulnerability of the heart to rhythm disturbance,” he added.

These include non-invasive techniques, such as the T-wave alternans test, that in conjunction with clinical markers will help to focus on those individuals who are at the greatest risk.

“So it’s a case of taking a more population-based approach as well as technical advances,” Elliott summarized.

Link: UK Cardiomyopathy Association Annual Conference; London, UK: 25 May 2007

Obstructive Sleep Apnea Wearies the Heart

AAPA: Obstructive Sleep Apnea Wearies the Heart

A lecture delivered at the American Academy of Physician Assistants conference, Philadelphia, Pa., May 26-31.


PHILADELPHIA, May 29 -- The most obvious clinical feature of obstructive sleep apnea may be weariness of mind, but this breathing disorder also slowly and silently wears down the heart, according to researchers.

Recent evidence suggests that 60% of people hospitalized for myocardial infarction also have obstructive sleep apnea. Yet occurrence among the general population is only about 9%, said Jose R. Marquina, M.D., of the Collier County Medical Society in Naples, Fla., at the American Academy of Physician Assistants meeting here.

In addition, recent research also suggests that as many as 70% of patients hospitalized for stroke have obstructive sleep apnea as a comorbid condition, Dr. Marquina said.

During the night, severe sleep apnea sufferers stop breathing anywhere from 30 to 120 times per hour, and the resulting lack of oxygen in the body strains and stupefies the cardiovascular system, Dr. Marquina said.

Over the years, hypoxemia in patients with obstructive sleep apnea can damage the sinus node, the group of specialized heart cells that govern cardiac rhythm, he said. This hypoxic damage causes a variety of cardiac arrhythmias including bradycardia, atrial fibrillation, and sinus arrest.

In addition, he said, the stress of hypoxemia causes the body to release catecholines, a group of hormones linked to hypertension.

Oxygen levels in the blood are also involved in controlling pulmonary artery pressure, Dr. Marquina said, and chronic hypoxemia can, therefore, also lead to pulmonary hypertension. In fact, recent evidence suggests that 12% to 17% of patients with obstructive sleep apnea also have pulmonary hypertension, he said.

These cardiovascular effects of obstructive sleep apnea occur in addition to the more well known neurological effects, which include cerebral anoxia, cerebrovascular disease, and impaired memory and concentration, Dr. Marquina said.

Obstructive sleep apnea can also severely reduce a person's overall quality of life. The condition has been associated with poor performance at work or school, depression, and marital problems, he said.

Men are affected twice as often as women: occurrence is 4% among men versus 2% among women, Dr. Marquina said. The risk for obstructive sleep apnea also increases among those who are overweight. Among overweight men the occurrence rises to 24%, and it reaches 9% for overweight women, he said.

As many as 90% of cases of obstructive sleep apnea go undiagnosed, Dr. Marquina said. Clinicians should be more aware of the symptoms, which include excessive daytime sleepiness or tiredness upon waking. "The typical patient will say they slept for eight hours but woke up still feeling tired," he said.

Another symptom is loud snoring, although snoring also occurs normally in about 70% of individuals age 35 and older, Dr. Marquina said. Patients will often deny snoring, so it may be more useful to ask a bed partner about this condition, he added.

Up to five episodes of apnea per hour while sleeping is also normal for healthy individuals, Dr. Marquina said. But five to 15 episodes identified by polysomnography indicate mild obstructive sleep apnea, 15 to 30 are defined as a moderate condition, and 30 or more are defined as severe obstructive sleep apnea, he said.

In addition, obstructive sleep apnea tends to be associated with a neck circumference of 18 inches or more, he said.

"Obstructive sleep apnea must be treated not only to improve the symptoms of fatigue and overall quality of life but to prevent the development of cardiovascular problems," Dr. Marquina concluded.

Dr. Marquina is a speaker for Cephalon.

Primary source: American Academy of Physician Assistants conference

Source reference:

Marquina J. "The consequences of sleep: snoring, obstructive sleep apnea, and cardiovascular disease." A lecture delivered at the American Academy of Physician Assistants conference, Philadelphia, Pa., May 26-31.

A meta-analysis of trials of pulmonary hypertension

American Heart Journal, 153:6:e33-e45,889-1132

A meta-analysis of trials of pulmonary hypertension: A clinical condition looking for drugs and research methodology

Alejandro Macchia, MDa, Roberto Marchioli, MDa, RosaMaria Marfisi, MSa, Marco Scarano, MSa, Giacomo Levantesi, MDa, Luigi Tavazzi, MDb, Gianni Tognoni, MDa

Received 21 October 2006; accepted 9 February 2007 published online 13 April 2007.


Various innovative pharmacologic strategies for the treatment of patients with pulmonary hypertension have been tested in recent years. Neither their comparative efficacy on surrogate end points nor the overall impact on mortality have been formally reviewed.


We did a systematic overview of all randomized trials on the therapeutic yield of prostacyclin and analogues, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors in patients with pulmonary hypertension searched in EMBASE, MEDLINE, and CINAHL databases from January 1985 to December 2005.


Sixteen trials involving 1962 patients met the inclusion criteria. Up to 80% of the patients were in functional class III/IV with a median walking distance of 330 m at baseline. Overall, experimental treatments were associated with (1) a nonsignificant reduction in all-cause mortality (relative risk 0.70, 95% CI 0.41-1.22), (2) a minor but statistically significant improvement in exercise capacity of 42.8 m (95% CI 27.8-57.8), and (3) an improved dyspnea status by at least one functional class (relative risk 1.83, 95% CI 1.26-2.66). Changes in exercise capacity were not found to be predictive of a survival benefit.


Although confirming the limited benefits in clinical end points documented by each trial, the overview fails to support a significant survival advantage and does not support the predictive power of surrogate end points.


Tolvaptan has no effect on left ventricular (LV) remodeling

Cardiovascular News

Tolvaptan fails to affect LV remodeling

30 May 2007

MedWire News: A year of treatment with the vasopressin V2 receptor antagonist tolvaptan has no effect on left ventricular (LV) remodeling in patients with chronic systolic heart failure (HF) receiving evidence-based medical therapy, results of a small randomized trial show.

However, the investigators note that tolvaptan use was associated with a significant reduction in the combined endpoint of time to mortality or HF hospitalization in a non-prespecified analysis.

Tolvaptan has previously been shown to reduce body weight in HF patients, consistent with improved volume homeostasis, and to normalize serum sodium in hyponatremic HF patients, explain James Udelson (Tufts University School of Medicine, Boston, Massachusetts, USA) and colleagues.

For the current study, the researchers looked at the effects of tolvaptan on changes in LV volumes that are driven by LV remodeling.

They randomly assigned 120 patients with New York Heart Association class II-III HF and LV ejection fraction ≤30% to either tolvaptan 30 mg/day or placebo, on top of standard background medical therapy.

Quantitative radionuclide ventriculography at baseline and at 1-year follow-up showed that there was a small reduction of 1.8 ml/m2 in the LV end-diastolic volume index with tolvaptan and no reduction with placebo. The between-group difference was nonsignificant.

Six (5%) deaths and 21 (18%) hospitalizations for HF occurred in the tolvaptan group compared with 11 (9%) and 34 (28%) deaths and HF hospitalizations, respectively, in the placebo group.

“In a time-to-event analysis there was a significant favorable effect of tolvaptan on the composite of mortality or HF hospitalization (p<0.03),” the authors report in the Journal of the American College of Cardiology.

There were no significant differences between groups in measures of quality of life using standardized questionnaires, but patients’ assessments of their global status, categorized as “better,” “worse,” or “unchanged” revealed that more patients who received tolvaptan reported a score of “better” than did patients in the placebo group at both 28-week and 1-year visits.

“In a well-treated population of stable HF patients, there was no significant effect of tolvaptan therapy on LV volumes observed during 1 year of therapy,” Udelson and colleagues conclude.

Link: J Am Coll Cardiol 2007; 49: 2151-2159

Gene therapy reverses heart failure

PHILADELPHIA, May 29 (UPI) -- U.S. heart researchers at Thomas Jefferson University Medical College have used gene therapy to reverse heart failure in animals.

The scientists also report they have found such a gene therapy strategy has "unique and additive effects" to standard heart failure drugs called beta-blockers.

Researchers led by Walter Koch, director of the university's Center for Translational Medicine, used a virus to carry the gene for a protein, S100A1, into the heart cells of rats with heart failure. The researchers said they virus expressed the S100A1 gene only in heart cells and not in other organs, essentially making it a tailored therapy. After 18 weeks, those animals that received the gene therapy had significantly improved heart function compared with non-treated animals.

The researchers also discovered that the S100A1 gene therapy changed the geometry of the heart. In heart failure, the heart tends to increase in size. The added S100A1 slowed that process and actually reversed it. Koch said the added S100A1 appears to improve calcium signaling in heart cells, which is critical to the force of contraction of individual cells.

The study is reported in the journal Circulation.

Sunday, May 27, 2007

Sleep apnea increases risk of heart attack

Sleep apnea increases risk of heart attack (from Heart Watch)

The nighttime breathing disorder known as obstructive sleep apnea increases a persons risk of having a heart attack or dying by 30% over a period of four to five years, as per a research studypresented at the American Thoracic Society 2007 International Conference, on Monday, May 21.

The more severe the sleep apnea at the beginning of the study, the greater the risk of developing heart disease or dying, the study found.

While prior studies have shown an association between sleep apnea and heart disease, ours is a large study that allowed us to not only follow patients for five years and look at the association between sleep apnea and the combined outcome of heart attack and death, but also adjust for other traditional risk factors for heart disease, says researcher Neomi Shah, M.D., of Yale University.

We recommend that patients who experience symptoms of obstructive sleep apneaexcessive daytime sleepiness, or snoring along with breathing pausesconsult their physician, Dr. Shah says. There is some evidence to make us think that when sleep apnea is appropriately treated, the risk of heart disease can be lowered.

In obstructive sleep apnea, the upper airway narrows, or collapses, during sleep. Periods of apnea end with a brief partial arousal that may disrupt sleep hundreds of times a night. Obesity is a major risk factor for sleep apnea.

The most effective therapy for sleep apnea is a technique called nasal CPAP, for continuous positive airway pressure, which delivers air through a mask while the patient sleeps, keeping the airway open. It has proved successful in a number of cases in providing a good nights sleep, preventing daytime accidents due to sleepiness and improving quality of life.

The study included 1,123 patients referred for sleep apnea evaluation. They underwent an overnight sleep study to determine if they had sleep apnea. Over the next four to five years, they were followed to see how a number of had any heart disease events (heart attack, coronary angiography or bypass surgery) or died.

Sleep apnea triggers the bodys fight or flight mechanism, which decreases the amount of blood pumped to the heart. Repeated episodes every night for a few years can starve the heart of enough oxygen when it is combined with the bodys decreased oxygen intake due to the frequent breathing stoppages during the night, Dr. Shah says.

Chronic Inflammation And Atherosclerosis

Insights Into Chronic Inflammation And Atherosclerosis

Rheumatoid arthritis, lupus, and other inflammatory rheumatic diseases are linked to a high rate of death from heart disease. One explanation is a greater susceptibility to atherosclerosis. Eventhough atherosclerosis is associated with inflammation in healthy individuals as well, the mechanism of inflammation and the reason for accelerated atherosclerosis in patients with inflammatory rheumatic disease remain unclear. Does atherosclerosis result from systemic inflammation, a hallmark of these rheumatic diseases, or from local inflammation of vessels?

To shed light on the link between chronic inflammation and atherosclerosis, a team of scientists in Norway and the United States, affiliated with the Cleveland Clinic Foundation and Brigham and Women's Hospital in Boston, focused on the aortas of recent recipients of coronary artery bypass graft (CABG) surgery, comparing biopsy specimens from patients with inflammatory rheumatic disease to those from patients without it. Their study, presented in the June 2007 issue of Arthritis & Rheumatism (, affirms inflammatory rheumatic disease and smoking as independent predictors of vessel wall inflammation. The vascular inflammation might be a factor that promotes atherosclerosis and the formation of aneurysms.

Aortic samples were obtained during CABG surgery, performed at two cardiac centers in Norway, from 66 patients with inflammatory rheumatic disease and 51 control patients. The inflammatory rheumatic disease group included patients with rheumatoid arthritis, psoriatic arthritis, lupus, ankylosing spondylitis, polymyalgia and other diseases. Age, body mass index, family history of heart disease, and other traditional cardiovascular risk factors were similar in both groups. All specimens were reviewed, by light microscope, for evidence of chronic inflammatory cell infiltration in the aortic wall. This was achieved by counting and measuring the mononuclear cell infiltrates (MCI) in the aorta, with particular attention to the adventitia, the deepest layer of vascular tissue. Using statistical analysis, the relationship between these inflammatory infiltrates and established lifestyle risk factors for heart disease was also assessed.
In the adventitia, MCIs occurred more frequently in patients with inflammatory rheumatic disease -- 47 percent of this group, compared with 20 percent of the control group. Along with greater prevalence, these inflammatory cells were larger in size. In the middle layer of the vessel wall (the media), MCIs were detected only in patients with inflammatory rheumatic disease. What's more, MCIs were observed in 6 of 7 patients with a history of aortic aneurysm.

In addition to inflammatory rheumatic disease, current smoking was independently linked to more pronounced chronic inflammatory infiltration in the inner adventitia.
"The opportunities for detecting aortic inflammation are limited," acknowledges the study's spokesperson, Ivana Hollan, M.D. "Our method of tissue examination allows the condition to be diagnosed in patients undergoing CABG surgery without increasing the preoperative risk".

Despite the limitations of its small sample size, this groundbreaking study of aortic inflammation in patients with inflammatory rheumatic disease indicates the need for further investigation into an inflammatory process that may increase vulnerability to dying from a heart attack or aneurysm.

Friday, May 25, 2007

Impaired Glycemic Control Reversible When Switching Off Diuretic-Based Therapy

American Society of Hypertension 22nd Annual Meeting and Exposition (ASH)

May 19 - 22, 2007, Chicago, Illinois

Impaired Glycemic Control Reversible When Switching Off Diuretic-Based Therapy

from Heartwire

May 25, 2007 Chicago, IL – Results from a six-month extension study have shown that impairment in glycemic control after one year of diuretic-based combination treatment is reversible by switching to treatment not involving a diuretic, in this case, an ACE inhibitor and calcium-channel blocker [1].

"When we looked at who developed new-onset diabetes, the plan was to then switch these patients over to the ACE-inhibitor/calcium-channel-blocker combination to see whether we could regress or bring back to baseline these metabolic changes," lead investigator Dr George Bakris (University of Chicago, IL) told heartwire. "This effect of new-onset diabetes, at least if you intervene within a short time of starting the therapy, does not appear to be permanent."

The hypothesis-generating study, an extension of the Study of Trandolapril/Verapamil SR And Insulin Resistance (STAR), was presented earlier this week at the American Society of Hypertension 2007 Scientific Sessions. In the original STAR study, published in 2006, investigators showed that in patients with impaired glucose tolerance, normal kidney function, and hypertension, the fixed-dose combination of trandolapril and verapamil reduces the risk of new-onset diabetes compared with a losartan/hydrochlorothiazide-based therapy.

Undoing the damage of the diuretic

Speaking with heartwire, Bakris said clinicians previously believed marrying diuretic therapy to an ACE inhibitor or angiotensin receptor blocker (ARB) might provide protection from new-onset diabetes, although this turned out not to be true. The risk of new-onset diabetes is also dose dependent, he said, such that at 25-mg hydrochlorothiazide (HCTZ) there is substantial risk of impairing the glucose response.

Testing the hypothesis that impaired glycemic control might be reversible early in the diuretic/losartan-combination treatment by switching to an ACE-inhibitor/calcium-channel-blocker combination, investigators assessed glycemic changes after six months of additional treatment with trandolapril and verapamil in both treatment groups in the STAR study. Bakris noted that only 53% of the original cohort stayed in the extension trial, although there were no statistically significant demographic differences between those who stayed and those who did not continue in the trial.

Those patients switching from losartan/HCTZ to trandolapril/verapamil experienced greater improvements in glucose and insulin response. The primary outcome measure, change in two-hour glucose using the oral glucose tolerance test (OGTT), decreased from 154 mg/dL at baseline to 131 mg/dL at six months in those who switched from the diuretic to the ACE-inhibitor/calcium-channel-blocker combination. At baseline, 10 patients in the losartan/HCTZ-treatment arm had diabetes, but six months after they switched to trandolapril/verapamil, this number was cut in half.

Blood pressure was sacrificed to some degree, noted Bakris, increasing from 128 mm Hg systolic at baseline to 137 mm Hg at six months. He said that while diuretics are cheap and have decades of outcomes data to support their use, clinicians might decide the cost of using the drug with respect to new-onset diabetes is too high.

"Looking at this overall, from a cost perspective, from a morbidity perspective, and from a patient perspective, why would you use a therapy to treat one condition only to express another condition that now requires additional medicine and has a potentially greater cardiovascular risk?" he said.

1. Bakris G, Molitch M, Sowers J et al. Reversal of new onset diabetes by nondiuretic based fixed dose antihypertensive drug combinations? Results of the STAR 6-month extension (STAR-LET). American Society of Hypertension 2007 Scientific Sessions; May 20, 2007; Chicago, IL.

Related Links:
American Society of Hypertension 22nd Annual Meeting and Exposition

Bariatric Surgery for Morbid Obesity

The New England Journal of Medicine

Volume 356 — May 24, 2007 — Number 21

Bariatric Surgery for Morbid Obesity

Eric J. DeMaria, M.D.

This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the author's clinical recommendations.


Wednesday, May 23, 2007

Rosiglitazone (Avandia) - FDA x Glaco Smith Kleine

FDA Issues Safety Alert on Avandia

ROCKVILLE, MD -- May 21, 2007 -- The U.S. Food and Drug Administration (FDA) is aware of a potential safety issue related to Avandia (rosiglitazone), a drug approved to treat type 2 diabetes. Safety data from controlled clinical trials have shown that there is a potentially significant increase in the risk of heart attack and heart-related deaths in patients taking Avandia. However, other published and unpublished data from long-term clinical trials of Avandia, including an interim analysis of data from the RECORD trial (a large, ongoing, randomized open label trial) and unpublished reanalyses of data from DREAM (a previously conducted placebo-controlled, randomized trial) provide contradictory evidence about the risks in patients treated with Avandia. Patients who are taking Avandia, especially those who are known to have underlying heart disease or who are at high risk of heart attack should talk to their doctor about this new information as they evaluate the available treatment options for their type 2 diabetes. FDA's analyses of all available data are ongoing.

FDA has not confirmed the clinical significance of the reported increased risk in the context of other studies. Pending questions include whether the other approved treatment from the same class of drugs, pioglitazone, has less, the same or greater risks. Furthermore, there is inherent risk associated with switching patients with diabetes from one treatment to another even in the absence of specific risks associated with particular treatments. For these reasons, FDA is not asking GlaxoSmithKline, the drug's sponsor, to take any specific action at this time. FDA is providing this emerging information to prescribers so that they, and their patients, can make individualized treatment decisions. "FDA remains committed to assuring that doctors and patients have the latest information available to make treatment and medication use decisions. In this case, FDA is carefully weighing several complex sources of data, some of which show conflicting results, related to the risk of heart attack and heart-related deaths in patients treated with Avandia," said Steven Galson, M.D., M.P.H., director of FDA's Center for Drug Evaluation and Research. "We will complete our analyses and make the results available as soon as possible. FDA will take the issue of cardiovascular risk associated with Avandia and other drugs in this class to an Advisory Committee as soon as one can be convened." Avandia was approved in 1999 for treatment of type 2 diabetes, a serious and life threatening disease that affects about 18 to 20 million Americans. Diabetes is a leading cause of coronary heart disease, blindness, kidney failure and limb amputation.

Since the drug was approved, FDA has been monitoring several heart-related adverse events (e.g., fluid retention, edema and congestive heart failure) based on signals seen in previous controlled clinical trials of Avandia alone and in combination with other drugs, and from postmarketing reports. FDA has updated the product's labeling on several occasions to reflect these new data, most recently in 2006. The most recent labeling change for Avandia also included a new warning about a potential increase in heart attacks and heart-related chest pain in some individuals using Avandia. This new warning was based on the result of a controlled clinical trial in patients with existing congestive heart failure. Recently, the manufacturer of Avandia provided FDA with a pooled analysis (meta analysis) of 42 randomized, controlled clinical trials in which Avandia was compared to either placebo or other anti-diabetic therapies in patients with type 2 diabetes. The pooled analysis suggested that patients receiving short-term (most studies were 6-months duration) treatment with

Avandia may have a 30-40 percent greater risk of heart attack and other heart-related adverse events than patients treated with placebo or other anti-diabetic therapy. These data, if confirmed, would be of significant concern since patients with diabetes are already at an increased risk of heart disease. Avandia is manufactured by GlaxoSmithKline, which is based in Research Triangle Park, N.C. SOURCE: FDA

Title: GlaxoSmithKline Responds to NEJM Article on Avandia
GlaxoSmithKline Responds to NEJM Article on Avandia

PHILADELPHIA, PA -- May 21, 2007 -- GlaxoSmithKline today issued the following response to an article in the New England Journal of Medicine (NEJM) on Avandia® (rosiglitazone maleate), a widely used and highly effective treatment for type 2 diabetes: GSK strongly disagrees with the conclusions reached in the NEJM article, which are based on incomplete evidence and a methodology that the author admits has significant limitations. The NEJM paper is based on an analysis of summary information that combines a number of studies -- a meta-analysis -- which is not the most rigorous way to reach definite conclusions about adverse events. Each study is designed differently and looks at unique questions: for example, individual studies vary in size and length, in the type of patients who participated, and in the outcomes they investigate. The data compiled from these varied studies is complex and can be conflicting. Importantly, the editorial in the NEJM states: "A few events either way might have changed the findings for myocardial infarction or for death from cardiovascular causes. In this setting, the possibility that the findings were due to chance cannot be excluded. In their discussion, the authors properly emphasize the fragility of their findings." In contrast to a meta-analysis, the most scientifically rigorous way to examine the safety and benefits of a medicine is to conduct large scale, long-term clinical trials in patients with the disease. Several trials of this type have been ongoing for many years. To date concerns regarding patient safety have not been identified by the independent Safety Monitoring Boards for these trials. Several trials have completed and the results published. For example, GSK's long-term, landmark study 'ADOPT' (A Diabetes Outcome Progression Trial) - one of the longest clinical trials in people with type 2 diabetes to date - directly compared both the safety and effectiveness of Avandia with other oral anti-diabetic medicines in over 4,300 patients studied for up to 6 years. Data from ADOPT showed that the overall risk of serious, cardiovascular events (CV death, myocardial infarction, and stroke, or MACE endpoint) for patients on Avandia was comparable to metformin and sulfonylurea (glyburide) -- two of the most commonly used medicines to treat type 2 diabetes. ADOPT showed comparable rates of cardiovascular deaths: Avandia -- 5 reports out of 1,456 patients, or 0.34%; metformin -- 4 out of 1,454, or 0.28%; and glyburide -- 8 out of 1,441 or 0.56%. The ADOPT clinical trial did show a small increase in reports of myocardial infarction among the Avandia -treated group ( Avandia : 24 out of 1,456 or 1.65%) vs metformin (20 out of 1,454 or 1.38%) vs glyburide (14 out of 1,441 or 0.97%); however, the number of events is too small to reach a reliable conclusion about the role any of the medicines may have played in this finding. Importantly, ADOPT also demonstrated that Avandia was superior to metformin and sulfonylurea regarding long-term control of blood sugar over five years, which is a key goal in managing diabetes to avoid the long-term complications of the disease. In another long-term study, DREAM -- which followed over 5,200 patients at high risk of developing of type 2 diabetes for a period of three to five years -- Avandia monotherapy showed no increase in cardiovascular risk when compared to placebo. Furthermore, in 2000, GSK initiated RECORD -- a large, long-term clinical trial in people with diabetes -- which has been prospectively designed to look at cardiovascular outcomes. The independent Safety Monitoring Boards responsible for overseeing the safety of this trial monitors patients closely, and in its regular operations has not found any safety risk that would interrupt continuation of the study. In addition, in a comprehensive analysis of patients in a US managed care database of more than 33,000 people with diabetes -- performed by independent investigators - there was no difference in ischemic cardiovascular events (including myocardial infarction) among patients taking Avandia -containing regimens versus other oral anti-diabetic medicines. The totality of the data show that Avandia has a comparable cardiovascular profile to other oral anti-diabetic medicines. GSK stands firmly behind the safety of Avandia when used appropriately, and we believe its significant benefits continue to outweigh any treatment risks. Because Avandia has been shown to control blood sugar for longer than other standard oral anti-diabetic medicines, it is an important treatment option for physicians who often need to prescribe two or three medicines to help their patients maintain their blood sugar levels. Type 2 diabetes is chronic, relentlessly progressive and life threatening; yet, two-thirds of diabetic patients suffer with uncontrolled disease. If left uncontrolled, diabetes can lead to heart disease, and is the leading cause of blindness, kidney disease and non-traumatic amputations in the US. GSK has consistently shared its data on Avandia from meta-analyses and controlled studies with the FDA and other regulatory agencies. Data is also posted publicly on the company's Clinical Trial Register. We continue to work closely with regulatory authorities and physicians to keep them fully informed so they can make the best decisions for patients based on both the safety and benefit of the medicine. SOURCE: GlaxoSmithKline

Tuesday, May 22, 2007

Well-being, health-related quality of life and cardiovascular disease risk profile in women with subclinical thyroid disease - a community-based study

Clinical Endocrinology

Volume 66 Issue 4 Page 548 - April 2007

To cite this article: Robin J. Bell, Livia Rivera-Woll, Sonia L. Davison, Duncan J. Topliss, Susan Donath, Susan R. Davis (2007) Well-being, health-related quality of life and cardiovascular disease risk profile in women with subclinical thyroid disease - a community-based study Clinical Endocrinology 66 (4), 548–556. doi:10.1111/j.1365-2265.2007.02771.x


Objectives The aim of this study was to evaluate whether subclinical thyroid disease is associated with impaired health-related quality of life and a more adverse cardiovascular disease risk profile.

Design A community-based cross-sectional study.

Setting and participants A total of 1423 non-healthcare-seeking women, aged 18–75 years were randomly recruited from the community via the electoral roll from April 2002 to August 2003.

Main outcome measures These were the scores for the Short-Form 36 (SF-36), the Psychological General Well-being Index (PGWI), thyroid hormone levels, serum lipids and high sensitivity C-reactive protein (hsCRP). Subclinical hypothyroidism (SCH) and subclinical hyperthyroidism (SCHyper) were defined as serum TSH > 4·0 mIU/l and < 0·5 mIU/l, respectively, with a normal free thyroxine (free T4) level.

Results Evaluable data were available for all participants. 10·7% of all women had an abnormal TSH value. The prevalence of a low TSH level by age group ranged from 1·2% to 6·4%, whereas the prevalence of an elevated TSH level ranged from 2·8% to 9·2% and increased with age (P = 0·002). There were no significant differences between women with SCH or SCHyper and age-matched controls for the total PGWI score or the Mental and Physical Component Scores of the SF-36. Women with SCH were no different from controls for serum lipids or hsCRP. Using linear regression, SCH vs. euthyroidism did not make an independent contribution to variation in either total cholesterol or triglycerides, with or without adjustment for age ± age2 ± BMI.

Conclusions Our data indicate that subclinical thyroid disease in women in the community is not associated with lower well-being or impaired health-related quality of life and SCH is not associated with increased serum markers of CVD risk.

Subclinical hyperthyroidism linked with AF

Subclinical hyperthyroidism linked with AF

21 May 2007

Arch Intern Med 2007; 167: 928-934

MedWire News: Subclinical hyperthyroidism is associated with atrial fibrillation (AF) on resting electrocardiogram (ECG), report UK researchers.

Their study showed that serum free thyroxine (T4) levels were linked to AF even in euthyroid patients with normal thyrotropin (TSH) levels.

It is well recognized that overt hyperthyroidism is associated with AF, note M Gammage and colleagues from the University of Birmingham in the Archives of Internal Medicine.

But some studies based on biochemical findings have suggested that even minor changes in thyroid function, which become more likely with increasing age, are associated with AF risk. To investigate further, the researchers set out to determine the relationship between thyroid function and AF in a community-based cohort of elderly people.

The team studied 5860 individuals aged 65 years and older, having excluded anyone being treated for thyroid dysfunction or with previous hyperthyroidism. The participants underwent thyroid function tests and a resting 12-lead ECG.

Fourteen (0.2%) participants were found to have previously undiagnosed overt hyperthyroidism, defined as raised free T4 and free tri-iodothyronine (T3) levels, or raised T3 alone, with serum TSH <0.4 p="0.01)." color="#000099">After adjusting for gender, this translated into an odds ratio for AF associated with subclinical hyperthyroidism of 2.27. There was no difference in AF prevalence between euthyroid individuals and those in other thyroid function categories, however. Further analysis revealed that, for the whole cohort, the median serum free T4 concentration was higher in those with AF than in those without, at 1.14 ng/dl versus 1.10 ng/dl (p<0.001). color="#000099">In contrast, TSH levels were not associated with AF. "The finding of increased likelihood of AF in those with subclinical hyperthyroidism lends support to the small number of studies linking this biochemistry with AF risk," the researchers conclude. The findings add to the debate over screening at-risk populations, such as elderly individuals who are known to have a higher prevalence of undetected (and usually mild) thyroid dysfunction, the team adds.

Free abstract

Rosiglitazone (Avandia) in perspective

Monday, May 21, 2007

Rosiglitazone (Avandia) in perspective

Today the New England Journal of Medicine released, on line ahead of print, a meta-analysis of 42 trials looking at the effect of rosiglitazone on cardiovascular outcomes. The use of rosiglitazone, compared against placebo or other regimens for type 2 diabetes, was associated with a statistically significant increase in myocardial infarction and a non-statistically significant trend toward increased cardiovascular mortality.

This finding begs the question of whether the apparent adverse effect is a class effect of thiazolidinediones (TZDs) or is unique to rosiglitazone. The meta-analysis findings are in contrast to the PROactive study of the other TZD approved in the U.S., pioglitazone, which showed improved cardiovascular outcomes.

A new analysis of PROactive published in the Journal of the American College of Cardiology (JACC), looking at recurrent MI in the cohort of patients with previous MI (2,445, just under half of the PROactive population) showed a statistically significant reduction in the pioglitazone group. The official PROactive web page contains updates.

Is there an explanation for these apparently disparate effects? It may lie in the fact that while rosiglitazone is a pure PPAR gamma agonist pioglitazone is a mixed PPAR gamma and PPAR alpha agonist. PPAR alpha agonism may confer more favorable lipid effects on pioglitazone. Specifically, while both drugs raise HDLC, pioglitazone has little or no effect on LDLC while rosiglitazone raises LDLC. Pioglitazone seems to lower triglycerides more effectively than does rosiglitazone.

Pasty and Furberg commented on the meta-analysis findings in this editorial. They point out that although ongoing trials may shed favorable light on rosiglitazone, a lack of positive outcome data in the long period since approval in 1999 is concerning, and reach this sobering conclusion: “On the basis of this meta-analysis, however, the possibility of cardiovascular benefit associated with the use of rosiglitazone seems remote.”

Other commentaries:

Monday, May 21, 2007

Avandia and heart attack

Could Avandia be the next Vioxx?

The NEJM with some smoke. Will fire be far behind?

Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes.

Update 1 –

The author of the study, Dr. Steven Nissen backs away from suggesting what to do:
Is there a case for prescribing Avandia? Are there some patients for whom the benefits outweigh the risks?Again, I don’t think I want to go there. It’s important for me as a physician-scientist to put the data out there in a very neutral fashion, and not cast judgment about what people ought to do. We’re going to let everybody read our paper and make up their own minds.
I'll be expecting a lot of patient calls tomorrow.

Update 2 –

MedPage Today with the best perspective thus far, comparing the findings to PremPro and Vioxx:

A meta-analysis of data from 42 clinical trials found a 43% increase in relative risk of myocardial infarction among type 2 diabetics treated with rosiglitazone (Avandia).
The odds ratio for MI was 1.43 (95% confidence interval 1.03-1.98, P=0.03), said Steven E. Nissen, M.D., of the Cleveland Clinic, lead author of the meta-analysis, which was released online today by the New England Journal of Medicine . . .

To put those data in perspective, the Women's Health Initiative (WHI), which used patient-level data, found that use of Prempro was associated with a 29% increase in relative risk in the combined endpoint of non-fatal MI and death from coronary heart disease.

A 2001 study co-authored by Dr. Nissen (JAMA 2001; 286:954-959) reported that rofecoxib (Vioxx) was associated with a 2.38 OR for thromboembolic events (95% CI, 1.49-4.00 P=0.002).

Full article and abstract (free):

Other links:

WHO Releases Global Health Statistics

Physician's First Watch for May 21, 2007

David G. Fairchild, MD, MPH, Editor-in-Chief

WHO Releases Global Health Statistics

The World Health Organization has released its 2007 compendium of health statistics.

Among the highlights:

• Life expectancy at birth in 2005 ranged from 37 in Sierra Leone to 80 in San Marino for men and from 37 in Swaziland to 86 in Japan for women. U.S. life expectancy was 75 for men and 80 for women.

• The leading causes of death in 2030 are projected to be cancers, ischemic heart disease, stroke, HIV/AIDS, and chronic obstructive pulmonary disease. Tobacco-related deaths are projected to rise from 5.4 million in 2005 to 6.4 million in 2015 and 8.3 million in 2030.

• Ten percent of the world's children under age 5 years suffer wasting as a result of malnutrition, according to 2005 data.

• In 2004, the world spent $4.1 trillion on health.

• In 2002, depression accounted for 4.5% of the total burden of disease worldwide.

WHO report (Free PDFs)

Aspirin of Small Benefit in Preventing Preeclampsia

Journal Watch - Medicine that Matters

Aspirin of Small Benefit in Preventing Preeclampsia

Although the etiology of preeclampsia is unknown, it is clear that the disorder is associated with decreased intravascular production of the vasodilator prostacyclin and increased production of the vasoconstrictor thromboxane. This association led to the hypothesis that antiplatelet drugs, particularly aspirin, might prevent preeclampsia or might reduce the associated morbidity. Because the results of randomized trials have been mixed, these researchers conducted a systematic review to assess the efficacy of aspirin in preventing preeclampsia and its complications.

This analysis included 39 trials that involved 30,563 women. Use of aspirin (generally, <75 mg) was associated with a 15 percent reduction in the risk for preeclampsia. In addition, there was an 8 percent reduction in the risk for preterm birth and a 14 percent reduction in the risk for fetal or neonatal death. All of these risk reductions were statistically significant.

Comment: The reviewers were careful to note that the true benefit of beginning antiplatelet drugs early in gestation -- particularly among women at risk for preeclampsia -- cannot be determined from the studies conducted to date. Although the benefits identified are modest at best, they may be greater in women at increased risk for preeclampsia.

RW Rebar
Published in Journal Watch General Medicine March 13, 2001 Citation(s): Duley L et al. Antiplatelet drugs for prevention of pre-eclampsia and its consequences: Systematic review. BMJ 2001 Feb 10 322 329-333.

Original article (Subscription may be required)

Medline abstract (Free)

Antiplatelet drugs for prevention of pre-eclampsia and its consequences: systematic review.
Duley L, Henderson-Smart D, Knight M, King J.

Resource Centre for Randomised Trials, Institute of Health Sciences, Oxford OX3 7LF.

OBJECTIVE: To assess the effectiveness and safety of antiplatelet drugs for prevention of pre-eclampsia and its consequences.

DESIGN: Systematic review.

DATA SOURCES: Register of trials maintained by Cochrane Pregnancy and Childbirth Group, Cochrane Controlled Trials Register, and Embase.

INCLUDED STUDIES: Randomised trials involving women at risk of pre-eclampsia, and its complications, allocated to antiplatelet drug(s) versus placebo or no antiplatelet drug. MAIN

OUTCOME MEASURES: Pre-eclampsia, preterm birth, fetal or neonatal death, and small for gestational age baby. Studies were assessed for quality of concealment of allocation and losses to follow up.

RESULTS: 39 trials (30 563 women) were included, and 45 trials (>3000 women) excluded. Use of antiplatelet drugs was associated with a 15% reduction in the risk of pre-eclampsia (32 trials, 29 331 women; relative risk 0.85, 95% confidence interval 0.78 to 0.92; number needed to treat 100, 59 to 167). There was also an 8% reduction in the risk of preterm birth (23 trials, 28 268 women; 0.92, 0.88 to 0.97; 72, 44 to 200), and a 14% reduction in the risk of fetal or neonatal death (30 trials, 30 093 women; 0.86, 0.75 to 0.98; 250, 125 to >10 000) for women allocated antiplatelet drugs. Small for gestational age babies were reported in 25 trials (20 349 women), with no overall difference between the groups (relative risk 0.92, 0.84 to 1.01). There were no significant differences in other measures of outcome.

CONCLUSIONS: Antiplatelet drugs, largely low dose aspirin, have small to moderate benefits when used for prevention of pre-eclampsia.

Sunday, May 20, 2007

Should women be offered cholesterol lowering drugs to prevent cardiovascular disease

Docs debate cholesterol lowering for women in BMJ

May 15, 2007

Head to head

Should women be offered cholesterol lowering drugs to prevent cardiovascular disease?

Scott M Grundy, professor : Yes

Malcolm Kendrick, general practitioner: No

Dallas, TX and Macclesfield, UK - British general practitioner Dr Malcolm Kendrick takes on the eminent Dr Scott Grundy (University of Texas Southwestern Medical Center, Dallas) in a head-to-head debate in the May 12, 2007 issue of BMJ about whether women should be offered cholesterol-lowering treatment for the primary prevention of cardiovascular disease [1,2].

Kendrick—the author of a book recently published in the UK entitled The Great Cholesterol Con—says this discussion "is effectively about the use of statins," since no other cholesterol-lowering drug has been shown to improve survival. He maintains that statins fail to provide any overall health benefit in women and represent a massive financial drain on health resources. In addition, they cause substantial adverse effects, a problem that is underrecognized, he says.

Grundy, who supports the use of cholesterol-lowering drugs in women at moderate risk, told heartwire that his article was deliberately not statin-specific: "Statins are but one drug among others. Just because Dr Kendrick tried to frame the question in terms of statins, I made it very clear to BMJ that I would only discuss cholesterol-lowering therapy. What about the other drugs for lowering LDL—where do they fit in? And where does diet fit in? "
Lack of data should not mean lack of treatment

Grundy—a consultant to most of the major statin manufacturers—says: "The essential issue here is whether women as well as men should be considered for cholesterol-lowering drugs when their 10-year risk is 10% to 20%—that is, moderately high."

He accepts that there is insufficient evidence of the benefit of cholesterol-lowering drugs in primary-prevention trials in women and that some people use this as a reason not to give such therapy to women at risk of cardiovascular disease.

But he argues—and says most investigators believe—that primary and secondary prevention "is an artificial distinction that should give way to a strategy based on absolute risk for future cardiovascular events, regardless of whether previous events have occurred."

Clinical trials that have included both men and women at moderately high risk have shown overall risk reduction from cholesterol-lowering therapy. But post hoc analyses limited to women failed to show significant risk reduction because of a lack of statistical power. "Not enough women were included to provide a definitive result. . . . Some investigators take this result to mean lack of efficacy. But without adequate power, the results are simply not informative," Grundy maintains.

Until a large-scale trial of cholesterol lowering is performed in women at moderately high risk of CVD, there are two options, he says. One is to exclude such women from therapy; the alternative is to consider treatment based on a combination of clinical-trial evidence and epidemiological data.

He notes that dietary therapy is also important, but that there is even less clinical-trial evidence for the benefits of this intervention than for drug treatment in this specific group of women.

"Since a substantial proportion of women ultimately develop cardiovascular disease and die from it, withholding treatment in moderately high-risk women that has proved protective in men and in women at high risk seems to be stretching the restrictions of evidence-based medicine beyond reason," he concludes.

Should women receive statins at all?

GP Kendrick reduces the discussion to one on statins alone. He not only disagrees with Grundy regarding the treatment of women at moderate risk, he also questions whether women should be receiving statins at all.

"None of the large trials of secondary prevention with statins has shown a reduction in overall mortality in women. Perhaps more critically, the primary-prevention trials have shown neither an overall mortality benefit nor even a reduction in cardiovascular end points in women," he maintains.

Kendrick told heartwire that Grundy's main point "appears to be that, although there is no evidence of benefit in giving women statins (no overall mortality benefit at all, in any study, ever) that we shouldn't be too bothered about this."

Kendrick also questions Grundy's notion that the difference between primary and secondary prevention is an artificial distinction: "He states that the concept of primary prevention is arbitrary and should not really be used. Well, the major clinical trials on statins—the ones that everyone uses to quote benefit—did exactly this. Should we now go back and strike all primary-prevention trials/data from the record? In which case, you wouldn't have much data to go on and we would end up not prescribing statins at all."

Kendrick says he does prescribe statins in his practice, on the basis that in secondary prevention, in men, they have been shown to have cardiovascular and overall benefit. However, he does not prescribe statins to women, "but if other doctors in the practice do so, I do not take them off, as that is not my clinical decision to make. I try to convince as many people as I can that statins are not of value in women and only of value in secondary prevention in men."

And don't forget adverse events and costs

Kendrick also says that studies show doctors often dismiss adverse events associated with statins and that the side effects are not as benign as they have been made out to be. For example, the US FDA adverse-event reporting system shows that between November 1997 and May 2004, simvastatin was reported as a direct cause of 49 350 adverse events and 416 deaths, he notes.

"If a patient complains of side effects that I believe are related to their statin, I will not hesitate to lower the dose or take them off to see if the side effects go," he added to heartwire.
And statins represent the single greatest drug expenditure in the UK National Health Service, Kendrick notes. In 2006, the cost in England was £625 million ($1.2 billion), and this is expected to reach £1 billion in 2007. This money could be diverted to treatments of proven value, he argues.

"Spending millions on a treatment that has no proven benefit and may cause serious harm goes against the rationale of evidence-based prescribing," Kendrick concludes.
Costs trivial, decision should be made in terms of safety, efficacy.

Grundy told heartwire that the cost of statins is now "trivial" since generic versions became available. "At Wal-Mart in the US, you can get statins for 13 cents per tablet (per day). I am sure that the UK health system can get them for less. Therefore, Dr Kendrick cannot use the cost argument any longer but must argue on the basis of lack of efficacy and/or lack of safety."

Grundy continues: "The FDA's postmarketing reports are not a good way to assess safety, and the vast majority of people who take statins and other approved cholesterol-lowering drugs do not have side effects. But of course, drugs should not be taken without any expectation of benefit (efficacy).

"I personally do not believe that there is a distinction between primary and secondary prevention, but it is the absolute risk of patients that determines whether they are candidates for cholesterol-lowering drugs," he concludes.


Kendrick M. Should women be offered cholesterol-lowering drugs to prevent cardiovascular disease? No. BMJ 2007; 334: 983.

Grundy SM. Should women be offered cholesterol-lowering drugs to prevent cardiovascular disease? Yes. BMJ 2007; 334: 982.

Related links

Lancet Comment questions benefit of statins in primary prevention [HeartWire > Cardiometabolic risk; Jan 25, 2007]

ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation

This article has been copublished in the August 15, 2006, issues of Circulation and the Journal of the American College of Cardiology and the August 16, 2006, issue of the European Heart Journal.

ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation—Executive Summary

A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation)



American Family Physician
May 15, 2007 Vol. 75 No. 10

Practice Guidelines
Joint Guideline Released for Atrial Fibrillation


Saturday, May 19, 2007

SAEM: Clinical Protocol Can Rule Out Pulmonary Embolism

SAEM: Clinical Protocol Can Rule Out Pulmonary Embolism

CHICAGO, May 17 -- Simple clinical criteria to rule out a pulmonary embolism can substitute for blood tests and CT scanning, according to researchers here.

The criteria, making up the so-called the PERC rule, consider eight clinical factors. If all eight are absent (PERC-negative) the probability of pulmonary embolism is quite low, said Jeff Kline, M.D., of the Carolinas Medical Center in Charlotte, N.C., and colleagues, at a Society for Academic Emergency Medicine meeting here.

The PERC rule includes clinical criteria such as age less than 50, pulse rate less than 100, 95% oxygen saturation level, no prior pulmonary embolism or deep vein thrombosis, and no recent surgery.

Ninety percent of the blood tests and ultrafast CT scans to detect pulmonary embolism turn out to be negative, the investigators said.

Over-testing for pulmonary embolism has emerged as a contentious issue, the researchers said. The CT scan may cost $2,500, has the potential for kidney damage in one of 12 patients, and has a heavy radiation dose. Yet physicians are ordering these tests for 2% to 3% of all emergency department patients, or 3.5 million patients a year, Dr. Kline said. Furthermore, the fear of medical malpractice has led to doing tests rather than using the data available through clinical evaluation.

To evaluate PERC, the authors from 2004 to 2006 enrolled 8,138 consecutive or random patients from 13 U.S. academic and community emergency departments staffed by emergency physicians. The patients' chief complaints were chest pain (52%), dyspnea (30%), cough (3%), syncope (2%), or other (12%).

The physicians' evaluations preceded the test results. Tests for pulmonary embolism were D-dimer (72%), CT (54%) and VQ scans (8%).

In the best case, PERC could reduce testing for pulmonary embolism by about 20% to 25%, the researchers said. Fully two-thirds of the testing was done for patients where the physician believed the probability of pulmonary embolism was less than 15%.

The authors found that the emergency physicians thought another diagnosis was more likely than pulmonary embolism in 83% of the cases, and that 67% were at low risk.

Of the patients, 524 (6.9%) were positive for image proven venous thromboembolism (pulmonary embolism or deep vein thrombosis). The median prevalence of positive venous thromboembolism across the 13 emergency departments was 6.7%.

From the entire cohort, 25% were PERC-negative, and only 1.2% of these patients were positive for venous thromboembolism. This equaled a diagnostic sensitivity of 95.6% (93.5 to 97.2%) and a specificity of 25.6% (24.6 to 26.6%).

Among low-risk patients, 1,519 (20% of the cohort) were PERC-negative, 14 (0.9%, 0.5 to 1.5%) were positive for venous thromboembolism, but none died.

Thus, low risk and PERC-negative had a sensitivity of 97.3% and specificity of 21.5%.

The combination of an emergency physician's impression that a patient is at low risk for pulmonary embolism, together with a negative PERC, provides compelling rationale to not order a test for pulmonary embolism, the researchers concluded.

This multicenter collaborative project shows that a careful history and physical examination can achieve the same degree of certainty without the cost and side effects of diagnostic testing.

The ability to document "PERC Rule negative" on the chart will provide physicians with the scientific and medicolegal backstop they need to justify not ordering a test on every patient with even a hint of pulmonary embolism, the investigators said.

Primary source:

Society for Academic Emergency Medicine 2007 MeetingSource reference: Kline J et al "Prospective, Multicenter Validation of the Pulmonary Embolism Rule-Out Criteria," presented May 16.

Abstracts are published in Vol. 14, Issue 5S, the May 2007 supplement of the official journal of the SAEM, Academic Emergency Medicine

Anxiety and Coronart Artery Disease

Anxiety Worsens Prognosis in Patients With Coronary Artery Disease

J Am Coll Cardiol, 2007; 49:2021-2027

Objectives: This study examined the effect of anxiety on mortality and nonfatal myocardial infarction (MI) in patients with coronary artery disease (CAD).

Background: Inconsistent data exist regarding the impact of anxiety on the prognosis of patients with CAD.

Methods: The authors conducted a prospective cohort study at an outpatient cardiology clinic of 516 patients with CAD (mean age 68 years at entry, 82% male) by administering the Kellner Symptom Questionnaire annually. The primary outcome was the composite of nonfatal MI or all-cause mortality.

Results: During an average follow-up of 3.4 years, we documented 44 nonfatal MIs and 19 deaths. A high cumulative anxiety score was associated with an increased risk of nonfatal MI or death. Comparing the highest to lowest tertile of anxiety score, the age-adjusted hazard ratio was 1.97 (95% confidence interval 1.03 to 3.78, p = 0.04). In a multivariate Cox model after adjusting for age, gender, education, marital status, smoking, hypertension, diabetes mellitus, previous MI, body mass index, and total cholesterol, each unit increase in the cumulative mean anxiety score was associated with increased risk of nonfatal MI or total mortality; the hazard ratio was 1.06 (95% confidence interval 1.01 to 1.12, p = 0.02).

Conclusions: A high level of anxiety maintained after CAD diagnosis constitutes a strong risk of MI or death among patients with CAD.


Statin Therapy Acute Coronary Syndrome: A Systematic Review

Long-Term Benefit of Statin Therapy Initiated during Hospitalization for an Acute Coronary Syndrome: A Systematic Review of Randomized Trials.

American Journal of Cardiovascular Drugs. 7(2):135-141, 2007.

Bavry, Anthony A 1; Mood, Girish R 1; Kumbhani, Dharam J 2; Borek, Peter P 1; Askari, Arman T 1; Bhatt, Deepak L 1


Objective: This study sought to determine if the initiation of statin (HMG-CoA reductase inhibitor) therapy during acute coronary syndromes reduces long-term mortality and other adverse cardiac outcomes.

Background: Initiation of statin therapy during acute coronary syndromes has not been shown to reduce mortality, myocardial infarction or stroke within 4 months of follow-up.

Methods: Clinical trials that randomized patients with acute coronary syndromes to early statin therapy compared with less intensive lipid reduction (placebo/lower-dose statin/usual care), and reported long-term outcomes were included for analysis.

Results: In all, there were seven studies (L-CAD, PTT, FLORIDA, Colivicchi et al., PROVE-IT, ESTABLISH, and A-to-Z) with 9553 patients who started statin therapy within 12 days of hospital presentation. The incidence of all-cause mortality was 3.4% in the statin group versus 4.6% in the less intensive lipid reduction group over a weighted mean follow-up of 22.9 months (relative risk [RR] 0.74; 95% CI 0.61, 0.90; p = 0.003). The number of patients needed to treat to prevent one death was 84 patients. Similarly, the incidence of cardiovascular mortality in the statin versus the less intensive lipid reduction group was 2.4% versus 3.3% (RR 0.74; 95% CI 0.58, 0.93; p = 0.010), unstable angina 4.1% versus 5.0% (RR 0.81; 95% CI 0.68, 0.98; p = 0.027), revascularization 11.2% versus 12.9% (RR 0.86; 95% CI 0.78, 0.96; p = 0.006), stroke 1.1% versus 1.2% (RR 0.90; 95% CI 0.62, 1.30; p = 0.56), and myocardial infarction 6.6% versus 7.0% (RR 0.94; 95% CI 0.81, 1.09; p = 0.41).

Conclusions: The benefit of early initiation of statin therapy during acute coronary syndromes slowly accrues over time so that a survival advantage is seen around 24 months. Relatively few patients need to be treated to prevent one death over this time period. Furthermore, this approach significantly reduces unstable angina and the need for revascularization.

Rimonabant: A novel selective cannabinoid-1 receptor antagonist

Rimonabant: A novel selective cannabinoid-1 receptor antagonist for treatment of obesity

American Journal of Health-System Pharmacy, Vol. 64, Issue 5, 481-489

PRITI N. PATEL, PHARM.D., BCPS, is Assistant Clinical Professor, College of Pharmacy and Allied Health Professions, and Director, Drug Information Center, St. John’s University, Queens, NY. ROLEE PATHAK, PHARM.D., BCPS, is Clinical Assistant Professor, Ernest Mario College of Pharmacy, Rutgers University, Piscataway, NJ, and Clinical Coordinator, Englewood Hospital and Medical Center, Englewood, NJ.

Purpose. The pharmacology, pharmacokinetics, clinical efficacy, safety, drug interactions, and dosage and administration of rimonabant in the treatment of obesity and related metabolic factors are reviewed.

Summary. Discovery of the cannabinoid receptors has led to the development of rimonabant, a cannabinoid-1 (CB1) antagonist. Selective blockade of this receptor has been shown to lead to decreased appetite and food intake in animal models. Clinical studies have shown that rimonabant 20 mg once daily produces significant decreases in weight and waist circumference in obese human subjects and improves the lipid profile and glucose control. The frequency of metabolic syndrome also decreased significantly with rimonabant 20 mg daily. Limited data are available regarding the pharmacokinetics and pharmacodynamics of rimonabant. Preclinical data have demonstrated a long duration of action. As of yet, no drug–drug, drug–food, or drug– disease interactions have been identified with rimonabant. Adverse reactions occurred rarely, with nausea, dizziness, diarrhea, arthralgia, and back pain being the most common. Psychiatric disorders, including depression and anxiety, were the most common reasons for subjects to withdraw from rimonabant studies. Rimonabant has been shown to be safe for up to two years of treatment. Further research will clarify currently unknown areas, including pharmacokinetics, drug interactions, and the drug’s role in standard therapy.

Conclusion. Rimonabant, a selective CB1 antagonist, is a novel treatment option for obese and overweight individuals. Significant weight loss, decrease in waist circumference, and improvements in lipid profile and glucose control have been shown in clinical trials of rimonabant.

Thursday, May 17, 2007

Stent implants in U.S. declined in April - Wall Street Journal

Stent implants in U.S. declined in April-WSJ

Thu May 17, 2007 4:41am ET

NEW YORK, May 17 (Reuters) - The number of coronary stents implanted in the United States dropped in April, the Wall Street Journal reported on its Web site on Thursday, citing a market research firm.

Stents are tiny wire mesh tubes used to prop open diseased heart arteries. Stent makers include Boston Scientific Corp. (BSX.N: Quote, Profile , Research), Abbott Laboratories (ABT.N: Quote, Profile , Research) and Johnson & Johnson (JNJ.N: Quote, Profile , Research).

Doctors performed about 71,200 stentings in April, the Journal reported, citing estimates from Millennium Research Group, a Toronto firm that surveys about 140 U.S. hospitals. The number was down more than 10 percent from March and more than 15 percent from a year earlier, it said.

The Journal cited doctors as saying that the drop was an unusually quick response to a study showing the devices provided little advantage over drug therapy in some patients.

Wall Street Journal - FREE PREVIEW

Stent Implants Declined in April

By Keith J. Winstein

Companies Featured in This Article: Boston Scientific, Abbott Laboratories, Johnson & Johnson
The number of coronary stents implanted in the U.S. dropped sharply in April, according to a leading market researcher, in what doctors said was an unusually quick response to a study showing the devices provided little advantage over drug therapy in some patients.

The new figures are the latest evidence that the tiny scaffolds used to prop open arteries are no longer a powerful growth engine for the medical industry. Americans spent at least $14 billion on coronary-stent procedures last year, including surgical and hospital fees. World-wide sales of the devices totaled about $6 billion.

Doctors performed about 71,200 stentings ...



Higher serum phosphorus levels are associated with an increased CVD risk

Relations of Serum Phosphorus and Calcium Levels to the Incidence of Cardiovascular Disease in the Community

Ravi Dhingra, MD; Lisa M. Sullivan, PhD; Caroline S. Fox, MD; Thomas J. Wang, MD; Ralph B. D’Agostino, Sr, PhD; J. Michael Gaziano, MD, MPH; Ramachandran S. Vasan, MD

Arch Intern Med. 2007;167:879-885.

Background Higher levels of serum phosphorus and the calcium-phosphorus product are associated with increased mortality from cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) or prior CVD. However, it is unknown if serum phosphorus levels influence vascular risk in individuals without CKD or CVD.

Methods We prospectively evaluated 3368 Framingham Offspring study participants (mean age, 44 years; 51% were women) free of CVD and CKD. We used multivariable Cox models to relate serum phosphorus and calcium levels to CVD incidence.

Results On follow-up (mean duration, 16.1 years), there were 524 incident CVD events (159 in women). In multivariable analyses and adjusting for established risk factors and additionally for glomerular filtration rate and for hemoglobin, serum albumin, proteinuria, and C-reactive protein levels, a higher level of serum phosphorus was associated with an increased CVD risk in a continuous fashion (adjusted hazard ratio per increment of milligrams per deciliter, 1.31; 95% confidence interval, 1.05-1.63; P = .02; P value for trend across quartiles = .004). Individuals in the highest serum phosphorus quartile experienced a multivariable-adjusted 1.55-fold CVD risk (95% confidence interval, 1.16%-2.07%; P = .004) compared with those in the lowest quartile. These findings remained robust in time-dependent models that updated CVD risk factors every 4 years and in analyses restricted to individuals without proteinuria and an estimated glomerular filtration rate greater than 90 mL/min per 1.73 m2. Serum calcium was not related to CVD risk.

Conclusion Higher serum phosphorus levels are associated with an increased CVD risk in individuals free of CKD and CVD in the community. These observations emphasize the need for additional research to elucidate the potential link between phosphorus homeostasis and vascular risk.

The Ottawa Aggressive Protocol for ED Management of Acute Atrial Fibrillation

Acad Emerg Med Volume 14, 5 Supplement 1 9,

The Ottawa Aggressive Protocol for ED Management of Acute Atrial Fibrillation

Ian Stiell, Catherine Clement, Garth Dickinson, Cheryl Symington, Jeffrey Perry and Christian Vaillancourt

University of Ottawa

There is no consensus as to the optimal emergency department (ED) management of acute atrial fibrillation (AAF) or atrial flutter (AAFL). Our objective was to examine the efficacy and safety of the Ottawa Aggressive Protocol to convert and discharge ED patients with AAF/AAFL.

This 5-year cohort study included consecutive visits to a university hospital ED for adults presenting with acute-onset AAF/AAFL and who were managed with the Ottawa Aggressive Protocol. Patients were identified from the National Ambulatory Care Reporting System (NACRS) database. The Aggressive Protocol was overseen by the attending emergency physicians and included: (1) IV procainamide as infusion of 1 gram over 1 hour; (2) electrical cardioversion if necessary, by ED staff; (3) discharge from the ED with outpatient cardiology follow-up. Outcomes included conversion, adverse events, and relapse. The authors conducted descriptive data analyses with 95% CIs.

Characteristics of the 660 eligible patient visits were mean age 64.5 years, mean heart rate 113.4, and mean duration symptoms 8.9 hours, AAF 95.2%, AAFL 4.9%. Overall, 96.8% of patients were discharged home from the ED and 90.3% were discharged in normal sinus rhythm. The respective discharge rates were 97.0% and 93.5% for those in AAF and 93.8% and 87.5% for those in AAFL. All patients received procainamide with a conversion rate of 58.3% (AAF 59.9%, AAFL 28.1%). Electrical cardioversion was attempted in 36.8% of visits with a success rate of 91.7% (AAF 91.0%, AAFL 100%). Adverse events occurred in 7.6% of cases: hypotension 6.7%, bradycardia 0.3%, AAF relapse within 7 days 8.6%, Torsades de Pointes 0%, cerebrovascular accident 0%, mortality 0%.


Acute atrial fibrillation managed in emergency department

17 May 2007
MedWire News: Over 90% of patients with acute atrial fibrillation (AAF) or atrial flutter (AAFL) can be discharged from the emergency department (ED) with a normal heart rhythm using the Ottawa Aggressive Protocol, a study from Canada shows.

The protocol involves an IV procainamide infusion of 1 g over 1 hour, electrical cardioversion if necessary, by ED staff, and discharge from the ED with outpatient cardiology follow-up. This contrasts with current practice in the USA, for example, where patients with AAF and AAFL are admitted to hospital and treated by cardiologists. Ian Stiell and colleagues from the University of Ottawa in Ontario studied the efficacy and safety of the Ottawa protocol in 660 consecutive patients, whose mean age was 64.5 years, mean heart rate 113.4 beats per minute, and mean duration of symptoms 8.9 hours. AAF was present in 95.2% and AAFL in 4.9%.

Overall, 96.8% of patients were discharged home from the ED and 90.3% were discharged with normal sinus rhythm. The corresponding discharge rates for patients in AAF and AAFL were 97.0% and 93.5%, and 93.8% and 87.5%.

All patients received procainamide with a conversion rate of 58.3% (AAF 59.9%, AAFL 28.1%) and electrical cardioversion was attempted in 36.8% patients, which was successful in 91.7% (AAF 91.0%, AAFL 100%).

Adverse events occurred in 7.6% of cases: hypotension in 6.7%, bradycardia in 0.3%, and AAF relapse within 7 days in 0.6%.

“This is the largest reported study of AAF/AAFL in the ED and demonstrates that the Ottawa Aggressive Protocol is extremely effective for the rapid cardioversion and discharge of patients by ED physicians,” said Stiell.

“This protocol is safe and could lead to a significant decrease in hospital admissions.”
The researchers presented their results at the annual meeting of the Society for Academic Emergency Medicine, held in Chicago, Illinois, USA.

Society for Academic Emergency Medicine Annual Meeting; Chicago, Illinois, USA: 16-19 May, 2007

Even low-level physical activity improves the cardiorespiratory fitness

Effects of Different Doses of Physical Activity on Cardiorespiratory Fitness Among Sedentary, Overweight or Obese Postmenopausal Women With Elevated Blood Pressure

A Randomized Controlled Trial

Timothy S. Church, MD, MPH, PhD; Conrad P. Earnest, PhD; James S. Skinner, PhD; Steven N. Blair, PED

JAMA. 2007;297:2081-2091.

Context Low levels of cardiorespiratory fitness are associated with high risk of mortality, and improvements in fitness are associated with reduced mortality risk. However, a poor understanding of the physical activity–fitness dose response relation remains.

Objective To examine the effect of 50%, 100%, and 150% of the NIH Consensus Development Panel recommended physical activity dose on fitness in women.

Design, Setting, and Participants Randomized controlled trial of 464 sedentary, postmenopausal overweight or obese women whose body mass index ranged from 25.0 to 43.0 and whose systolic blood pressure ranged from 120.0 to 159.9 mm Hg. Enrollment took place between April 2001 and June 2005 in the Dallas, Tex, area.

Intervention Participants were randomly assigned to 1 of 4 groups: 102 to the nonexercise control group and 155 to the 4-kcal/kg, 104 to the 8-kcal/kg, and 103 to the 12-kcal/kg per week energy-expenditure groups for the 6-month intervention period. Target training intensity was the heart rate associated with 50% of each woman's peak O2.

Main Outcome Measure The primary outcome was aerobic fitness assessed on a cycle ergometer and quantified as peak absolute oxygen consumption ( O2abs, L/min).

Results The mean (SD) baseline O2abs values were 1.30 (0.25) L/min. The mean (SD) minutes of exercising per week were 72.2 (12.3) for the 4-kcal/kg, 135.8 (19.5) for the 8-kcal/kg, and 191.7 (33.7) for the 12-kcal/kg per week exercise groups. After adjustment for age, race/ethnicity, weight, and peak heart rate, the exercise groups increased their O2abs compared with the control group by 4.2% in the 4-kcal/kg, 6.0% in the 8-kcal/kg, and 8.2% in the 12-kcal/kg per week groups (P<.001 for each vs control; P for trend <.001). There was no treatment x subgroup interaction for age, body mass index, weight, baseline O2abs, race/ethnicity, or baseline hormone therapy use. There were no significant changes in systolic or diastolic blood pressure values from baseline to 6 months in any of the exercise groups vs the control group. Conclusion In this study, previously sedentary, overweight or obese postmenopausal women experienced a graded dose-response change in fitness across levels of exercise training.

COMMENTARIES Even small doses of activity boost heart fitness 16 May 2007 MedWire News: Even low-level physical activity improves the cardiorespiratory fitness of overweight, sedentary individuals, study findings reveal.
National Institutes of Health (NIH) guidelines recommend at least 30 minutes of moderate-intensity physical activity to promote general health, but it is not clear if sedentary people will benefit from lower levels of activity than this, explain Timothy Church (Louisiana State University System, Baton Rouge, USA) and colleagues.
To investigate, the researchers conducted a study in 464 sedentary, postmenopausal overweight or obese women with elevated blood pressure.
The women’s body mass indices ranged from 25.0 to 43.0 and systolic blood pressure from 120.0 to 159.9 mmHg.
The participants were randomly assigned to three different levels of exercise or to a no-exercise control group. The three exercise levels were cycling or walking sessions designed to expend 4 kcal/kg, 8kcal/kg, or 12 kcal/kg per week.
These levels corresponded to 50%, 100%, and 150% of the NIH consensus recommended activity level for such women.
Women who exercised participated in three or four training sessions each week for 6 months, at a training intensity of the heart rate associated with 50% peak oxygen consumption (VO2). Although maximal effort was obtained during exercise testing, the mean peak absolute (VO2abs) and relative (VO2rel) values were very low, at 1.30 l/min and 15.5 ml/kg/min, respectively, at baseline.
This demonstrated that the group had very low fitness levels at the start of the study, the authors note.
The 4-kcal/kg group exercised for a mean of 72.2 minutes per week over 2.6 sessions, the 8-kcal/kg group for 135.8 minutes per week during 2.8 sessions, and the 12-kcal/kg group for 191.7 minutes per week during 3.1 sessions.
There was a strong dose-response relationship between the amount of exercise and change in fitness, Church and team report in the Journal of the American Medical Association.
Peak absolute oxygen consumption VO2abs were significantly increased at all three exercise levels versus no exercise (1.33, 1.35, and 1.39 vs 1.28 l/min).
These values represented a 4.2% increase in VO2abs in the 4-kcal/kg group, a 6.0% increase in 8-kcal/kg group, and an 8.2% increase in the 12-kcal/kg group, compared with the control no-exercise group (all p<0.001 versus control; p for trend <0.001).
The dose-response relationship was seen across age, race, weight, baseline fitness, and hormone therapy subgroups.
Participants’ systolic and diastolic blood pressure levels, weight, and most other cardiovascular risk factors were not significantly altered with any level of exercise.
However, waist circumference, which was similar in each group at baseline, was significantly reduced at the end of the study in all 3 exercise groups compared with the control group (p<0.05 for each).
This was a significant finding given the importance of increased risk of insulin resistance, diabetes, and metabolic syndrome, and mortality associated with abdominal obesity, Church and team emphasize.
“Perhaps the most striking finding of our study is that even activity at the 4-kcal/kg per week level (approximately 72 min per week) was associated with a significant improvement in fitness compared with women in the nonexercise control group,” the team comments. JAMA 2007; 297: 2081-2091