Wednesday, October 31, 2007

Are Beta Blockers Effective First-line Treatments for Hypertension?

Are Beta Blockers Effective First-line Treatments for Hypertension?

Cochrane for Clinicians

Putting Evidence into Practice

WILLIAM E. CAYLEY, JR., md, University of Wisconsin Eau Claire Family Medicine Residency, Eau Claire, Wisconsin

Cochrane Abstract

Two recent systematic reviews found first-line beta blockers to be less effective in reducing the incidence of stroke and the combined end point of stroke, myocardial infarction, and death compared with all other antihypertensive drugs taken together. However, beta blockers might be better or worse than a specific class of drugs for a particular outcome measure; therefore, comparing beta blockers with all other classes taken together could be misleading. In addition, these systematic reviews did not assess the tolerability of beta blockers relative to other antihypertensive medications. Thus, we undertook this review to reassess the place of beta blockers as first-line therapy for hypertension compared with other major classes of antihypertensive drugs.

Objectives: To quantify the effectiveness and safety of beta blockers on morbidity and mortality end points in adults with hypertension.

Search Strategy: We searched eligible studies up to June 2006 in the Cochrane Controlled Trials Register, Medline, Embase, and reference lists of previous reviews, and by contacting hypertension experts.

Selection Criteria: We selected randomized controlled trials (RCTs) that assessed the effects of beta blockers compared with placebo, no therapy, or other drug classes (as monotherapy or first-line therapy for hypertension) on mortality and morbidity end points in men and nonpregnant women 18 years or older.

Data Collection and Analysis: At least two authors independently applied study selection criteria, assessed study quality, and extracted data; differences were resolved by consensus. We expressed study results as relative risks (RRs) with 95% confidence intervals (CIs), and conducted quantitative analyses with trial participants in groups to which they were randomly allocated, regardless of which or how much treatment they actually received. In the absence of significant heterogeneity among studies (P > .1), we performed a meta-analysis using a fixed-effects method. Otherwise, we used the random-effects method and investigated the cause of heterogeneity by stratified analysis. In addition, we used the Higgins statistic (I2) to quantify the amount of between-study variability in effect attributable to true heterogeneity rather than chance.

Main Results: Thirteen RCTs (n = 91,561) that met our inclusion criteria compared beta blockers with placebo or no treatment (four trials with 23,613 participants), diuretics (five trials with 18,241 participants), calcium channel blockers (four trials with 44,825 participants), and renin-angiotensin system (RAS) inhibitors (three trials with 10,828 participants). The risk of all-cause mortality was not different between first-line beta blockers and placebo (RR = 0.99; 95% CI, 0.88 to 1.11; I2 = 0 percent); diuretics; or RAS inhibitors, but the risk was higher for beta blockers compared with calcium channel blockers (RR = 1.07; 95% CI, 1.00 to 1.14; I2 = 2.2%; absolute risk increase [ARI] = 0.5 percent; number needed to harm [NNH] = 200).

The risk of total cardiovascular disease was lower for first-line beta blockers compared with placebo (RR = 0.88; 95% CI, 0.79 to 0.97;I2 = 21.4 percent; absolute risk reduction [ARR] = 0.7 percent; number needed to treat [NNT] = 140). This is primarily a reflection of the significant decrease in stroke (RR = 0.80; 95% CI, 0.66 to 0.96; I2 = 0 percent; ARR = 0.5 percent; NNT = 200). Coronary heart disease risk was not significantly different between beta blockers and placebo. The effect of beta blockers on cardiovascular disease was significantly worse than that of calcium channel blockers (RR = 1.18; 95% CI, 1.08 to 1.29; I2 = 0 percent; ARI = 1.3 percent; NNH = 80) but was not significantly different from that of diuretics or RAS inhibitors. Increased total cardiovascular disease was caused by an increase in stroke compared with calcium channel blockers (RR = 1.24; 95% CI, 1.11 to 1.40; I2 = 0 percent; ARI = 0.6 percent; NNH = 180). There was also an increase in stroke with beta blockers compared with RAS inhibitors (RR = 1.30; 95% CI, 1.11 to 1.53; I2 = 29.1 percent; ARI = 1.5 percent; NNH = 65).

Coronary heart disease risk was not significantly different between beta blockers and diuretics or calcium channel blockers or RAS inhibitors. In addition, patients taking beta blockers were more likely to discontinue treatment because of adverse effects than those taking diuretics (RR = 1.86; 95% CI, 1.39 to 2.50; I2 = 78.2 percent; ARI = 6.4 percent; NNH = 16) or RAS inhibitors (RR = 1.41; 95% CI, 1.29 to 1.54; I2 = 12.1 percent; ARI = 5.5 percent; NNH=18); there was no significant difference between beta blockers and calcium channel blockers.

Authors' conclusions: The available evidence does not support the use of beta blockers as first-line drugs in the treatment of hypertension. This conclusion is based on the relatively weak effect of beta blockers to reduce stroke and the absence of an effect on coronary heart disease when compared with placebo or no treatment. More importantly, it is based on the trend towards worse outcomes compared with calcium channel blockers, RAS inhibitors, and thiazide diuretics. Most of the evidence for these conclusions comes from trials in which atenolol (Tenormin) was the beta blocker used (75 percent of participants taking beta blockers in this review). However, it is not known whether beta blockers have differential effects on younger and older patients or whether there are differences among the subtypes of beta blockers.

Monday, October 29, 2007

Acute Noncardiac Conditions and In-Hospital Mortality in Patients With Acute Myocardial Infarction

Acute Noncardiac Conditions and In-Hospital Mortality in Patients With Acute Myocardial Infarction

Judith H. Lichtman, John A. Spertus, Kimberly J. Reid, Martha J. Radford, John S. Rumsfeld, Norrina B. Allen, Frederick A. Masoudi, William S. Weintraub, and Harlan M. Krumholz

Circulation. 2007;116:1925-1930; published online before print October 8 2007, doi:10.1161/CIRCULATIONAHA.107.722090

Background— Acute myocardial infarction may be accompanied by acute, severe, concomitant, noncardiac conditions, but their prevalence and prognostic importance is not well defined. We sought to evaluate the prevalence of acute, severe, noncardiac conditions present at the time of hospital admission with acute myocardial infarction and to assess the association of these conditions with in-hospital mortality.

Methods and Results— A total of 3907 patients admitted with an acute myocardial infarction were prospectively enrolled in 19 US centers between January 2003 and June 2004. Acute noncardiac conditions present at admission with imminent threat to life were identified from medical record review within 24 hours of admission. Using multivariable analyses, we evaluated the relationship between these conditions and in-hospital mortality. We documented a concomitant acute, severe, noncardiac condition in 6.8% (n=267) of the study sample. The most common concomitant conditions were severe pneumonia (potentially requiring intubation; 18.4%), severe gastrointestinal bleeding/anemia (15.7%), stroke (9.7%), and sepsis (9.4%). These patients were less likely to be ideal for or to receive evidence-based therapies at the time of admission. The in-hospital mortality was 21.3% (57 of 267) for patients with concomitant conditions versus 2.7% (100 of 3640) for those without these conditions. The presence of an acute noncardiac condition was associated with an increased risk of in-hospital mortality after adjustment for demographic and clinical characteristics and disease severity (odds ratio, 5.0; 95% confidence interval, 3.3 to 7.7).

ConclusionsConcomitant, acute, noncardiac conditions are common and associated with a marked increase in the risk of in-hospital mortality.

Ethnic Differences In Sleep Quality And Blood Pressure

Ethnic Differences In Sleep Quality And Blood Pressure

ScienceDaily (Oct. 29, 2007) — In the United States, African Americans have higher blood pressure and are at greater risk of hypertension than whites. In addition, African Americans report poorer sleep quality and exhibit a smaller nighttime decrease in blood pressure than whites, a phenomenon called blood pressure “dipping.”

“This ethnic difference in blood pressure dipping may help explain why African Americans are at greater risk of hypertension,” says Dr. Joel Hughes, Kent State assistant professor of psychology, “as a smaller dip in nighttime blood pressure has been associated with increased left ventricular mass and wall thickness in the heart.”

In the American Journal of Hypertension, Hughes and his colleagues examine the possibility that sleep quality may help account for ethnic differences in blood pressure dipping.
They found that African-American college students, compared to whites, spent less time in bed, slept for a shorter period of time and took longer to fall asleep. Thus, ethnic differences in sleep quality seemed to accompany ethnic differences in blood pressure dipping; however, it was not shown that these differences in sleep quality caused ethnic differences in nighttime blood pressure.

“Obviously, more research is needed,” says Hughes. “There are too few studies of ethnic differences in sleep, and the importance of sleep for health is becoming increasingly recognized.”

Adapted from materials provided by Kent State University.

Blood Pressure Drug Might Work Against Alzheimer's

Blood Pressure Drug Might Work Against Alzheimer's

By Ed Edelson
HealthDay ReporterThu Oct 25, 6:59 PM ET

THURSDAY, Oct. 25 (HealthDay News) -- The blood pressure drug valsartan shows the ability to reduce Alzheimer's disease-like symptoms in mice, researchers report.

The potential value of valsartan, marketed as Diovan, emerged from a screening program that started with 55 high blood pressure drugs, said study author Dr. Giulio Maria Pasinetti, a professor of psychiatry and neurosciences at Mount Sinai School of Medicine in New York City.

"With screening in vivo [animal studies], we came up with seven candidates," Pasinetti said, adding that valsartan was the most promising of the lot.

Specifically, valsartan interfered with the formation of clumps of the protein beta-amyloid in the brains of mice genetically engineered to be susceptible to an Alzheimer's-like disease, Pasinetti said. Beta-amyloid deposits are a leading feature of Alzheimer's disease in humans.

"We also found that in this animal model, there was some kind of effect of valsartan even at doses that were threefold lower than the common equivalent doses given to patients with hypertension [high blood pressure]," he said.

The findings are published in the Oct. 26 issue of the Journal of Clinical Investigation.

Valsartan is a member of the family of angiotensin II blockers that are widely used to control high blood pressure. Other studies already have linked a related class of blood pressure drugs, called ACE inhibitors, to a reduced risk of Alzheimer's disease. Pasinetti said his group's research with mice has identified three other blood pressure drugs that have the same effect as valsartan. He did not identify the drugs, saying, "That will be the subject of another paper."

The next step with valsartan, Pasinetti said, will be "to develop a series of clinical studies to see if the same effect seen in mice can be replicated in humans."

Dr. Sam Gandy, chairman of the Alzheimer's Association's medical and scientific advisory council, said recent experiences with other medications have shown that such tests are essential, because the experimental therapies often don't pan out.

"This is another example of laboratory work on Alzheimer's disease testing existing drugs to see if they have activity," said Gandy, who's also director of Emory University's Center for Neurodegenerative Diseases. "We have been down this road with Epogen, with non-steroidal anti-inflammatory drugs; now we're going down the road with statins."

What's needed, he said, is "a real controlled clinical trial to see if it [valsartan] works. Just because it makes sense, and the evidence looks good, doesn't mean that it is going to work. The acid test is a clinical trial."

Gandy said he has become wary of reports such as the one from Pasinetti "because of our experience with estrogen." Early reports said the female sex hormone was highly promising as an Alzheimer's preventive treatment, but it failed in a controlled trial.

Panisetti said his group now is trying to determine the potential mechanism by which valsartan and the other drugs might work against Alzheimer's disease. "We are working primarily on the brain rather than on blood pressure," he said.

More information:
To learn more about Alzheimer's, visit the Alzheimer's Association.

How to diagnose diastolic heart failure

How to diagnose diastolic heart failure

How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology

European Heart Journal

Volume 28, Number 20 : October 2007

Diastolic heart failure (DHF) currently accounts for more than 50% of all heart failure patients. DHF is also referred to as heart failure with normal left ventricular (LV) ejection fraction (HFNEF) to indicate that HFNEF could be a precursor of heart failure with reduced LVEF. Because of improved cardiac imaging and because of widespread clinical use of plasma levels of natriuretic peptides, diagnostic criteria for HFNEF needed to be updated. The diagnosis of HFNEF requires the following conditions to be satisfied: (i) signs or symptoms of heart failure; (ii) normal or mildly abnormal systolic LV function; (iii) evidence of diastolic LV dysfunction. Normal or mildly abnormal systolic LV function implies both an LVEF > 50% and an LV end-diastolic volume index (LVEDVI) <97>16 mmHg or mean pulmonary capillary wedge pressure >12 mmHg) or non-invasively by tissue Doppler (TD) (E/E' > 15). If TD yields an E/E' ratio suggestive of diastolic LV dysfunction (15 > E/E' > 8), additional non-invasive investigations are required for diagnostic evidence of diastolic LV dysfunction. These can consist of blood flow Doppler of mitral valve or pulmonary veins, echo measures of LV mass index or left atrial volume index, electrocardiographic evidence of atrial fibrillation, or plasma levels of natriuretic peptides. If plasma levels of natriuretic peptides are elevated, diagnostic evidence of diastolic LV dysfunction also requires additional non-invasive investigations such as TD, blood flow Doppler of mitral valve or pulmonary veins, echo measures of LV mass index or left atrial volume index, or electrocardiographic evidence of atrial fibrillation. A similar strategy with focus on a high negative predictive value of successive investigations is proposed for the exclusion of HFNEF in patients with breathlessness and no signs of congestion.
The updated strategies for the diagnosis and exclusion of HFNEF are useful not only for individual patient management but also for patient recruitment in future clinical trials exploring therapies for HFNEF.

Saturday, October 27, 2007

ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction—Executive Summary

ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction—Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction): Developed in Collaboration With the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons.

Anderson JL, Adams CD, Antman EM, et al.

J Am Coll Cardiol. 2007;50:652-726.

Twenty points to remember about these guidelines are:

Initial Evaluation:

1. Patients with chest discomfort whose symptoms are not improved 5 minutes after taking nitroglycerin (NTG) are advised to call emergency medical service (EMS) before taking more NTG. Patients with chronic stable angina may take up to a maximum of three doses, 5 minutes apart, if symptoms are significantly improved by the first dose of NTG. They should still call EMS if symptoms are not resolved completely.

2. An electrocardiogram (ECG) should be performed on the patient with chest pain within 10 minutes of arrival to the emergency department (ED). Patients with chest pain should be rapidly stratified into one of four categories: noncardiac diagnosis, definite acute coronary syndrome (ACS), possible ACS, and chronic stable angina.

3. A cardiac-specific troponin is the preferred biomarker in patients presenting with symptoms consistent with ACS.

4. Patients with possible ACS, but with normal ECG and biomarkers over 12 to 16 hours should generally have a stress test performed prior to ED discharge or within 72 hours of discharge. These patients should be treated with appropriate pharmacotherapy while awaiting the stress test.

5. Patients with low probability of coronary artery disease (CAD) and possible ACS can also be evaluated by computed tomography angiography in lieu of a stress test.

Early Management:

6. Patients with hemodynamic instability or those with ongoing symptoms should be admitted to a coronary care unit, whereas others should be admitted to a step-down unit.

7. Oral beta-blockers should be instituted within the first 24 hours in absence of contraindications. Intravenous beta-blockers should only be used for specific indications and not as a routine therapy.

8. Nonsteroidal anti-inflammatory drugs (COX-1 or COX-2 inhibitors) other than aspirin (ASA) should be discontinued on admission to the hospital in a patient with ACS.

9. Use of morphine as an analgesic has been associated with a worse outcome in observational studies. The guidelines have downgraded it from a Class I to a Class IIa recommendation.

10. Antiplatelet therapy:

a. ASA should be administered to patients with ACS as soon as possible (unless contraindicated) and continued lifelong. Patients with ASA allergy or intolerance should be treated with clopidogrel.

b. Clopidogrel, in addition to ASA, should be initiated in patients in whom either a conservative or an early invasive therapy is considered, but the likelihood of surgical disease requiring early coronary artery bypass grafting (CABG) is low.

c. Upstream use of eptifibatide or tirofiban should be considered in high-risk patients and those with troponin elevation, especially if an invasive therapy is contemplated. Abciximab should not be used unless there is no appreciable delay to percutaneous coronary intervention (PCI). Abciximab can be used safely for PCI in patients who have not received upstream glycoprotein (GP) IIb/IIIa inhibitors and may be better than tirofiban in this population. GP IIb/IIIa inhibitors provide incremental benefit in patients with elevated troponin undergoing PCI even among those pretreated with clopidogrel.

11. Anticoagulant therapy:

a. In patients treated with conservative therapy, the preferred anticoagulant may be fondaparinux, enoxaparin (for 8 days or duration of hospitalization), or unfractionated heparin (UFH) (for 48 hours) (in that order).

b. In patients treated with invasive therapy, enoxaparin or UFH-based regimens have the most supporting evidence.

c. For patients undergoing CABG, ASA should be continued while clopidogrel should be stopped 5-7 days before, and low-molecule GP IIb/IIIa inhibitors stopped 4 hours before the surgery. Enoxaparin should be stopped 12-24 hours prior and fondaparinux stopped 24 hours prior to CABG, and UFH started.

d. All patients receiving intravenous GP IIb/IIIa inhibitors must also receive concomitant UFH or another antithrombotic agent.

12. Early invasive therapy is preferable in the high-risk patients with ongoing symptoms or hemodynamic instability, whereas either early invasive or conservative therapy can be used in other patients based on physician and patient preference. In patients who are stable for 12-24 hours on conservative therapy, noninvasive stress testing should be performed prior to discharge.

13. Choice of surgical versus percutaneous revascularization (similar to that in a patient with stable disease) should be determined by a patient’s anatomy, left ventricular function, and presence or absence of diabetes and other comorbidities.

14. Patients with non–ST-elevation myocardial infarction (NSTEMI) who had totally occluded vessels on angiography did not benefit from PCI in the OAT trial (similar to those with STEMI) and should not be intervened upon.

15. The risk of death or recurrent MI in patients with NSTEMI ACS is highest in the first 2 months and returns to a baseline risk of those with stable CAD by 3 months. Low-risk patients (and fully revascularized patients) should be followed up at 2-6 weeks, whereas high-risk patients should be re-evaluated within 2 weeks.

16. All patients with ACS should receive ASA, statins, beta-blockers, and clopidogrel (for at least 1 year). Angiotensin-converting enzyme inhibitors (or angiotensin-receptor blockers) should be initiated in patients with abnormal left ventricular ejection fraction, hypertension, diabetes, or heart failure. These medications are best initiated in the hospital since the likelihood that they will be continued long-term is highest. The blood pressure goal should be less than 140/90 mm Hg for all patients and less than 130/80 mm Hg for patients with diabetes mellitus or chronic kidney disease.

17. Hormone replacement therapy (HRT) should not be started in patients with ACS. Patients on HRT at the time of ACS should be advised to discontinue it.

18. Patients with diabetes should be treated with aggressive glucose control while hospitalized. Other diagnostic and therapeutic interventions should be in a manner similar to those of nondiabetics.

19. Special attention to drug dosing and altered pharmacodynamics is warranted while treating the elderly and patients with renal impairment.

20. Return to activity should be guided by an exercise tolerance test. Exercise training can begin within 1-2 weeks after coronary revascularization. Patients should be encouraged to walk (or engage in other physical activity) for 30-60 minutes daily. Patients with uncomplicated NSTEMI ACS can return to driving within 1 week of discharge unless prohibited by State law. Patients with complicated MI should delay driving for 2-3 weeks. Hitinder S. Gurm, M.B.B.S., F.A.C.C.

Friday, October 26, 2007

Resolution of Asymptomatic Myocardial Ischemia in Patients With Type 2 Diabetes in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) Study

Resolution of Asymptomatic Myocardial Ischemia in Patients With Type 2 Diabetes in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) Study

Diabetes Care 2007 30: 2892-2898

Frans J. Th. Wackers, MD, Deborah A. Chyun, PHD, Lawrence H. Young, MD, Gary V. Heller, MD, Ami E. Iskandrian, MD, Janice A. Davey, MSN, Eugene J. Barrett, MD, Raymond Taillefer, MD, Steven D. Wittlin, MD, Neil Filipchuk, MD, Robert E. Ratner, MD, Silvio E. Inzucchi, MD for the Detection of Ischemia in Asymptomatic Diabetics (DIAD) Investigators


The porrpose of this study was to assess whether the prevalence of inducible myocardial ischemia increases over time in patients with type 2 diabetes.

Participants enrolled in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study underwent repeat adenosine-stress myocardial perfusion imaging 3 years after initial evaluation. Patients with intervening cardiac events or revascularization and those who were unable or unwilling to repeat stress imaging were excluded.

Of the initial 522 DIAD patients, 358 had repeat stress imaging (DIAD-2), of whom 71 (20%) had ischemia at enrollment (DIAD-1). Of 287 patients with normal DIAD-1 studies, 259 (90%) remained normal in DIAD-2, whereas 28 (10%) developed new ischemia in DIAD-2. Of the 71 patients with abnormal DIAD-1 studies, 56 (79%) demonstrated resolution of ischemia, whereas 15 (21%) remained abnormal. During this 3-year interval, medical treatment was intensified, with more patients using statins, aspirin, and ACE inhibitors than at baseline. Patients with resolution of ischemia had significantly greater increases in these medications than patients who developed new ischemia (P = 0.04).

Thus, the majority of asymptomatic patients with type 2 diabetes demonstrated resolution of ischemia upon repeat stress imaging after 3 years. This resolution was associated with more intensive treatment of cardiovascular risk factors.

Monday, October 22, 2007

Universal Definition of Myocardial Infarction

Title: Universal Definition of Myocardial Infarction

Author(s): Thygesen K, Alpert JS, White HD, et al., on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction.Citation: Eur Heart J. 2007;28:2525-2538.

Date Posted: 10/22/2007

Perspective: The following are 12 points to remember about this expert consensus document:

1. Clinically, one can classify myocardial infarction (MI) into different types.

2. Type 1 is spontaneous MI related to ischemia due to a primary coronary event such as plaque erosion and/or rupture, fissuring, or dissection.

3. Type 2 is MI secondary to ischemia due to either increased oxygen demand or decreased supply (e.g., coronary artery spasm, coronary embolism, anemia, arrhythmias, hypertension, or hypotension).

4. Type 3 is sudden unexpected cardiac death, including cardiac arrest, often with symptoms suggestive of myocardial ischemia, accompanied by presumably new ST elevation, or new left bundle branch block, or evidence of fresh thrombus in a coronary artery by angiography and/or at autopsy, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood.

5. Type 4a is MI associated with percutaneous coronary intervention.

6. Type 4b is MI associated with stent thrombosis, as documented by angiography or at autopsy.

7. Type 5 is MI associated with coronary artery bypass grafting.
8. Myocardial cell death can be recognized by the appearance in the blood of different proteins released into the circulation from the damaged myocytes: myoglobin, cardiac troponin T and I, creatine kinase, lactate dehydrogenase, as well as many others.

9. The preferred biomarker for myocardial necrosis is cardiac troponin (I or T), which has nearly absolute myocardial tissue specificity as well as high clinical sensitivity, thereby reflecting even microscopic zones of myocardial necrosis.

10. An increased value for cardiac troponin is defined as a measurement exceeding the 99th percentile of a normal reference population (one-quarter upper reference limit). Detection of a rise and/or fall of the measurements is essential to the diagnosis of acute MI.

11. New ST elevation at the J-point in two contiguous leads with the cut-off points: ≥0.2 mV in men or ≥0.15 mV in women in leads V2–V3 and/or ≥0.1 mV in other leads suggests acute myocardial ischemia.

12. The change in the definition of MI based on elevated biomarker measurement exceeding the 99th percentile of a normal reference population will have a substantial impact on the identification, prevention, and treatment of cardiovascular disease throughout the world.

Debabrata Mukherjee, M.D., F.A.C.C.

Friday, October 19, 2007

MI redefined; troponin remains gold standard

MI redefined; troponin remains gold standard

by Judith Rusk

Cardiology Today

October 2007

VIENNA, Austria – Just as not every patient with an elevated liver function test has hepatitis B, not every patient with elevated troponin levels has had myocardial infarction.

Using this analogy, a group of experts unveiled the new definition of MI at the European Society of Cardiology Congress 2007 last month. Joseph S. Alpert, MD, special assistant to the dean and a professor of medicine in the department of medicine at University Medical Center, Tucson, Ariz., and co-chair of the universal MI definition committee, said that despite the confusion and consternation troponin measurement can cause, it is still the gold standard to define MI.

“However, the advance of science has created a number of nuances that are reflected in the new document,” said Alpert, also a member of the Coronary Heart Disease section of the Cardiology Today Editorial Board.

First update since 2000

The new definition, which will be simultaneously published this month in the European Heart Journal, Circulation and the Journal of the American College of Cardiology is divided into five types (see chart).

According to the ESC’s pocket guideline on the universal definition, “The term myocardial infarction should be used when there is evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia.”

Alpert said type 4 is the most controversial addition to the redefinition. It was added in light of data from meta-analysis trials presented at last year’s Congress. Those trials, presented in hotline sessions, demonstrated more late stent thrombosis with drug-eluting stents.

Imaging will help demonstrate whether a patient has prior MI, Alpert said. If the patient has new Q waves or pathological healings, imaging evidence of a region of loss of viable myocardium that is thinned or fails to contract in the absence of a nonischemic cause will help.


Despite the changes, Alpert said the committee does not expect the reported numbers of MI to change much.

“There were 10% and 30% increases (in MI) following first definition,” he said.

Allan Jaffe, MD, professor of medicine at the Mayo Clinic, said defining reinfarction remains a challenge. “We used CK-MB for so long,” said Jaffe, also a member of the Coronary Heart Disease section of the Cardiology Today Editorial Board. Despite one paper published in 2005 that had a small population, trials validating the criteria for recurrent MI have not been done since 1988.

Another challenge is universal definition of MI in clinical trials. Maarten Simoons, MD, Rotterdam, said researchers should complete a small chart – that will be included in the guidelines – that asks pointed questions in defining MI.

When it comes down to it, Jaffe said, clinicians have to rely on their gut when identifying MI.

“There is still a need for good bedside clinical judgment,” he said.

For more information:

Alpert JS, Jaffe A, Underwood SR, Wallentin LC, Simoons ML. Universal definition of myocardial infarction. Symposium #2466-2470. Presented at: European Society of Cardiology Congress 2007; Sept. 1-5, 2007; Vienna, Austria.

Thursday, October 18, 2007

Obese children show early signs of heart disease

Obese children show early signs of heart disease

Oct. 16, 2007 -- Children who are obese or who are at risk for obesity show early signs of heart disease similar to obese adults with heart disease, a study by researchers at Washington University School of Medicine in St. Louis has found.

"Based on this study, these subtle markers can help us predict who could be at risk for heart disease and heart attacks," said Angela Sharkey, M.D., associate professor of pediatrics at Washington University School of Medicine and a pediatric cardiologist at St. Louis Children's Hospital.

The study was published in the Winter 2007 issue of the Journal of Cardiometabolic Syndrome

Childhood obesity in the United States is an epidemic — nationwide, 19 percent of children ages 6 to 11 and 17 percent of those 12 to 19 are overweight, according to the Centers for Disease Control and Prevention (CDC). Those who are overweight during childhood also have an increased risk of obesity in adulthood and are at greater risk for complications such as diabetes, high blood pressure and heart disease, because obesity increases total blood volume, which leads to extra stress on the heart.

Sharkey and Steven M. Lorch, M.D., a former fellow at the School of Medicine now at University of Texas Health Science Center at Houston, analyzed data from 168 children ages 10 to 18 who had been referred to them for cardiac ultrasound with symptoms including heart murmur, chest pain, acid reflux or high blood cholesterol. Based on CDC guidelines for body mass index for age (BMIA), 33 patients were found to have a BMIA as obese, or the 95th percentile or above for their age; 20 had a BMIA that classified them as at risk for obesity, or between the 85th and 94th percentile; and 115 were considered normal, or below the 85th percentile.

To analyze the hearts of the obese children and those at risk, Sharkey and Lorch used a new tissue Doppler imaging technique called vector velocity imaging which tracks the movement of the heart's muscular wall. Any changes in the rate of motion of heart muscle were averaged within each group and compared to the normal rate of motion.

"In the patients who are obese, the rate of motion of heart muscle changed," Sharkey said. "As a child's BMIA increases, we see alterations in both the relaxation and contraction phase of the heartbeat. Many of these changes that have been seen in adults were assumed to be from long-standing obesity, but it may be that these changes start much earlier in life than we thought."

As vector velocity imaging becomes more broadly available, Sharkey said, it could potentially help pediatric cardiologists follow these children more closely over time to see if changes in the heart progress.

"We may be able to determine whether we could intervene in the process, such as focusing the families on understanding the importance of regular exercise and dietary modifications for weight loss and prescribing statin drugs for high-blood cholesterol," she said.

Sharkey said the results of the study give more ammunition to physicians to use in counseling pediatric patients and their parents about the risks of obesity and the need to attain a healthy weight.

"Even in teenagers, obesity leads to decreased myocardial performance and abnormal diastolic function," she said.

Further study is needed to determine how soon the changes in the heart set in after a child becomes obese and whether those changes are reversible with weight loss.

Lorch SM, Sharkey A. Myocardial Velocity, Strain, and Strain Rate Abnormalities in Healthy Obese Children. Journal of Cardiometabolic Syndrome. 2007 Winter; 2(1):30-4.

The influence of gender on the effects of aspirin in preventing myocardial infarction

The influence of gender on the effects of aspirin in preventing myocardial infarction

Todd Yerman, Wen Q Gan and Don D Sin

BMC Medicine 2007, 5:29doi:10.1186/1741-7015-5-29


There is considerable variation in the effect of aspirin therapy reducing the risk of myocardial infarction (MI). Gender could be a potential explanatory factor for the variability. We conducted a systematic review and meta-analysis to determine whether gender mix might play a role in explaining the large variation of aspirin efficacy across primary and secondary MI prevention trials.

Randomized placebo-controlled clinical trials that examined the efficacy of aspirin therapy on MI were identified by using the PUBMED database (1966 to October 2006). Weighted linear regression technique was used to determine the relationship between log-transformed relative risk (RR) of MI and the percentage of male participants in each trial. The reciprocal of the standard error of the RR in each trial (1/SE) was used as the weight.

A total of 23 trials (n = 113 494 participants) were identified. Overall, compared with placebo, aspirin reduced the risk of non-fatal MI (RR = 0.72, 95% confidence interval (CI) 0.64-0.81, p < 0.001) but not of fatal MI (RR = 0.88, 95% CI 0.75-1.03, p = 0.120). A total of 27% of the variation in the non-fatal MI results could be accounted for by considering the gender mix of the trials (p = 0.017). Trials that recruited predominantly men demonstrated the largest risk reduction in non-fatal MI (RR = 0.62, 95% CI 0.54-0.71), while trials that contained predominately women failed to demonstrate a significant risk reduction in non-fatal MI (RR = 0.87, 95% CI 0.71-1.06).

Gender accounts for a substantial proportion of the variability in the efficacy of aspirin in reducing MI rates across these trials, and supports the notion that women might be less responsive to aspirin than men.

Wednesday, October 17, 2007

Combined resynchronisation and implantable defibrillator therapy in left ventricular dysfunction

Combined resynchronisation and implantable defibrillator therapy in left ventricular dysfunction: Bayesian network meta-analysis of randomised controlled trials

BMJ, doi:10.1136/bmj.39343.511389.BE (published 11 October 2007)

Simon K H Lam, MSc student1, Andrew Owen, consultant2

1 National Heart and Lung Institute, London SW3 6LY, 2 Department of Cardiology, Kent and Canterbury Hospital, Canterbury


Objective To review the evidence base from randomised controlled trials of combined cardiac resynchronisation therapy and implantable cardioverter defibrillator therapy in left ventricular impairment and symptomatic heart failure.

Review methods Two reviewers independently assessed trial eligibility and quality. Included trials compared cardiac resynchronisation therapy, implantable cardioverter defibrillator therapy, combined resynchronisation and implantable defibrillator therapy, and medical therapy alone, in patients with impaired left ventricular systolic function. Bayesian random effects network models were used to examine overall number of deaths.

Results 12 studies including 1636 events in 8307 patients were identified. Combined cardiac resynchronisation and implantable cardioverter defibrillator therapy reduced the number of deaths by one third compared with medical therapy alone (odds ratio 0.57, 95% credible interval 0.40 to 0.80) but did not further improve survival when compared with implantable defibrillator therapy (0.82, 0.57 to 1.18) or resynchronisation (0.85, 0.60 to 1.22) therapy alone.

Conclusion Evidence from randomised controlled trials is insufficient to show the superiority of combined cardiac resynchronisation and implantable cardioverter defibrillator therapy over cardiac resynchronisation therapy alone in patients with left ventricular impairment.

Amiodarone raises hypothyroidism in older atrial fibrillation patients

Amiodarone raises hypothyroidism in older atrial fibrillation patients

By Liam Davenport

16 October 2007

Am J Med 2007; 120: 880-885

MedWire News: Older males treated with amiodarone for persistent atrial fibrillation are substantially more likely to develop hypothyroidism than patients with atrial fibrillation who not given the treatment, US study findings indicate.

The majority of patients who are given amiodarone, which has recently been found to have unparalled effectiveness in maintaining sinus rhythm, are male, say Elizabeth Batcher, from West Los Angeles Veterans Affairs Medical Center in California, and colleagues. However, the long-term risk of amiodarone-induced thyroid dysfunction has not been thoroughly investigated.

The team therefore performed a substudy of 612 patients from the Sotalol Amiodarone Atrial Fibrillation Efficacy Trial, of whom 247 were treated with amiodarone and 365 were given sotalol or placebo. Sotalol and placebo patients were combined to form a control group, as neither would be expected to alter thyroid function, the authors note. The average age of the groups was 67.1 years for amiodarone-treated patients and 66.9 years among controls.

Thyroid function was measured at baseline, 3 month, 6 months, and every 6 months for up to 4.5 years by measuring serum thyroid-stimulating hormone (TSH) concentrations. There were no statistical differences in TSH levels at baseline between the groups.

The results indicate that subclinical hypothyroidism, defined as a TSH level of 4.5-10 mU/l, occurred in 25.8% of patients treated with amiodarone, compared with 6.6% of those from the control group, the team reports in the American Journal of Medicine.

In addition, 5.0% of amiodarone patients were found to have overt hypothyroidism, defined as a TSH level of over 10 mU/l, compared with just 0.3% of controls. In both cases, the difference between the amiodarone and control groups was significant.

Of the patients who developed TSH levels of more than 10 mU/l, 93.8% were detected by 6 months. It was also observed that amiodarone patients had a trend towards a greater prevalence of hyperthyroidism, defined as a TSH level of less than 0.35 mU/l, than controls, at 5.3% versus 2.4%.

The researchers write: "In summary, amiodarone-induced hypothyroidism developed in 30.8% of older men treated with amiodarone for chronic atrial fibrillation compared with the control group and presented early during therapy."

They add: "Given the high rate of hypothyroidism among patients taking amiodarone, monitoring of thyroid function is recommended at baseline, 3 months, and every 6 months thereafter during the therapy."

Free abstract

Monday, October 15, 2007

Systematic Review: The Comparative Effectiveness of Percutaneous Coronary Interventions and Coronary Artery Bypass Graft Surgery

Systematic Review: The Comparative Effectiveness of Percutaneous Coronary Interventions and Coronary Artery Bypass Graft Surgery

Annals of Internal Medicine

20 November 2007 Volume 147 Issue 10

Dena M. Bravata, MD, MS; Allison L. Gienger, BA; Kathryn M. McDonald, MM; Vandana Sundaram, MPH; Marco V. Perez, MD; Robin Varghese, MD, MS; John R. Kapoor, MD, PhD; Reza Ardehali, MD, PhD; Douglas K. Owens, MD, MS; and Mark A. Hlatky, MD

Background: The comparative effectiveness of coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) for patients in whom both procedures are feasible remains poorly understood.

Purpose: To compare the effectiveness of PCI and CABG in patients for whom coronary revascularization is clinically indicated.

Data Sources: MEDLINE, EMBASE, and Cochrane databases (1966–2006); conference proceedings; and bibliographies of retrieved articles.

Study Selection: Randomized, controlled trials (RCTs) reported in any language that compared clinical outcomes of PCI with those of CABG, and selected observational studies.

Data Extraction: Information was extracted on study design, sample characteristics, interventions, and clinical outcomes.

Data Synthesis: We identified 23 RCTs in which 5019 patients were randomly assigned to PCI and 4944 patients were randomly assigned to CABG. The difference in survival after PCI or CABG was less than 1% over 10 years of follow-up. Survival did not differ between PCI and CABG for patients with diabetes in the 6 trials that reported on this subgroup. Procedural strokes were more common after CABG than after PCI (1.2% vs. 0.6%; risk difference, 0.6%; P = 0.002). Angina relief was greater after CABG than after PCI, with risk differences ranging from 5% to 8% at 1 to 5 years (P < 0.001). The absolute rates of angina relief at 5 years were 79% after PCI and 84% after CABG. Repeated revascularization was more common after PCI than after CABG (risk difference, 24% at 1 year and 33% at 5 years; P < 0.001); the absolute rates at 5 years were 46.1% after balloon angioplasty, 40.1% after PCI with stents, and 9.8% after CABG. In the observational studies, the CABG–PCI hazard ratio for death favored PCI among patients with the least severe disease and CABG among those with the most severe disease.

Limitations: The RCTs were conducted in leading centers in selected patients. The authors could not assess whether comparative outcomes vary according to clinical factors, such as extent of coronary disease, ejection fraction, or previous procedures. Only 1 small trial used drug-eluting stents.

Conclusion: Compared with PCI, CABG was more effective in relieving angina and led to fewer repeated revascularizations but had a higher risk for procedural stroke. Survival to 10 years was similar for both procedures

A Meta-Analysis of 94,492 Patients With Hypertension Treated With Beta Blockers to Determine the Risk of New-Onset Diabetes Mellitus

A Meta-Analysis of 94,492 Patients With Hypertension Treated With Beta Blockers to Determine the Risk of New-Onset Diabetes Mellitus

The American Journal of Medicine

Volume 100, Issue 8, Pages 1254-1262 (15 October 2007)

Sripal Bangalore, MD, MHAa, Sanobar Parkar, MD, MPHa, Ehud Grossman, MDb, Franz H. Messerli, MDa

Beta blockers used for the treatment of hypertension may be associated with increased risk for new-onset diabetes mellitus (DM).

A search of Medline, PubMed, and EMBASE was conducted for randomized controlled trials of patients taking β blockers as first-line therapy for hypertension with data on new-onset DM and follow-up for ≥1 year. Twelve studies evaluating 94,492 patients fulfilled the inclusion criteria. Beta-blocker therapy resulted in a 22% increased risk for new-onset DM (relative risk 1.22, 95% confidence interval [CI] 1.12 to 1.33) compared with nondiuretic antihypertensive agents. A higher baseline fasting glucose level (odds ratio [OR] 1.01, 95% CI 1.00 to 1.02, p = 0.004) and greater systolic (OR 1.05, 95% CI 1.05 to 1.08, p = 0.001) and diastolic (OR 1.06, 95% CI 1.01 to 1.10, p = 0.011) blood pressure differences between the 2 treatment modalities were significant univariate predictors of new-onset DM.

Multivariate meta-regression analysis showed that a higher baseline body mass index (OR 1.17, 95% CI 1.01 to 1.33, p = 0.034) was a significant predictor of new-onset DM. The risk for DM was greater with atenolol, in the elderly, and in studies in which β blockers were less efficacious antihypertensive agents and increased exponentially with increased duration on β blockers. For the secondary end points, β blockers resulted in a 15% increased risk for stroke, with no benefit for the end point of death or myocardial infarction.

In conclusion, β blockers are associated with an increased risk for new-onset DM, with no benefit for the end point of death or myocardial infarction and with a 15% increased risk for stroke compared with other agents. This risk was greater in patients with higher baseline body mass indexes and higher baseline fasting glucose levels and in studies in which β blockers were less efficacious antihypertensive agents compared with other treatments.

Sunday, October 14, 2007

Use caution with drug-eluting stents in patients with STEMI

Use caution with drug-eluting stents in patients with STEMI

VIENNA, Austria — Results from the GRACE registry suggest caution when considering drug-eluting stents in patients with ST-elevated myocardial infarction.

The Global Registry of Acute Coronary Events (GRACE) trial results, presented at the European Society of Cardiology Congress 2007, demonstrated that patients with STEMI were at an increased risk for mortality. More patients with STEMI had reinfarction than patients with bare metal stents.

“Personally, I never implant drug-eluting stents in patients with STEMI undergoing primary PCI nowadays,” said Philippe Gabriel Steg, MD, professor of cardiology at Hopital Bichat-Claude Bernard, Paris.

In other registry trial results presented at the congress, Stefan James, MD, said updated data from the SCAAR (Swedish Coronary Angiography and Angioplasty Registry) no longer indicated increased mortality in patients treated with drug-eluting stents vs. bare metal stents.

For more on GRACE, click here. For more on SCAAR, click here.

Preliminary Results Indicate Carotid Intima-Media Thickness Is Biomarker of Atherosclerosis

Title: Preliminary Results Indicate Carotid Intima-Media Thickness Is Biomarker of Atherosclerosis: Presented at DALM

"Preliminary Results Indicate Carotid Intima-Media Thickness Is Biomarker of Atherosclerosis: Presented at DALM"By Crina Frincu-Mallos, PhD NEW YORK, NY -- October 12, 2007 -- Overall data from the IMPROVE trial support the concept that carotid intima-media thickness (IMT) and IMT progression constitute novel biomarkers of atherosclerotic disease, according to a study presented here on at the XVI International Symposium on Drugs Affecting Lipid Metabolism (DALM).

Elena Tremoli, MD, Professor and Director, Department of Pharmacological Sciences, University of Milan, and Research Coordinator, Centro Cardiologico Monzino, IRCCS, Milan, Italy, presented the data on October 6.

The Carotid IMT and IMT-PROgression as Predictors of Vascular Events in a High Risk European Population (IMPROVE) study is an ongoing prospective, multicentre, longitudinal study with 3,711 patients from six European countries. All patients were classified as being at high risk for cardiovascular disease with at least three vascular risk factors, said Dr. Tremoli.

Patient enrollment ended in April 2005; patients were recruited from Finland (n=1,050), Sweden (n=533), The Netherlands (n=532), France (n=501), and Italy (n=1,095).

This patient population consists of men and women in approximately a 1:1 ratio (aged 64 +- 5 years). The largest percentage of patients have familial hypercholesterolaemia (78.6%); 23.9% of patients have diabetes.

The study is designed to determine whether it is feasible to predict new vascular events based on the progression of carotid IMT, "alone or after integration with conventional and nonconventional risk factors," explained Dr. Tremoli. IMT, a novel surrogate marker of atherosclerosis, is measured by high-resolution B-mode ultrasound.

Preliminary results indicate a significant connection between high sensitivity C-reactive protein (hs-CRP) and gender in the overall population. "Hs-CRP is a determinant of carotid IMT in men only," said Dr. Tremoli. However, cigarette smoking unmasks the association between hs-CRP and carotid IMT in women, she added.

The study monitored the occurrence of cardiovascular events over a period of 36 months.

A total of 135 first events occurred in the 3,393 patients enrolled in the trial, the most common event being angina pectoris (n=45), angioplasty/stent (n=39), stroke (n=21), and coronary bypass (n=16).

In addition, the researchers observed a geographic (North-South) gradient in carotid IMT when they analysed the baseline data.

The preliminary data support the concept that carotid IMT is a biomarker of atherosclerotic disease, concluded Dr. Tremoli. Data on the predictive capacity of carotid IMT-progression should be available by the end of next year.

Funding for this study was provided by the Italian Ministry of Health, European Commission, and the IMPROVE project.

Presentation title: Carotid Intima Media Thickness as Marker of Atherosclerosis: Results of the IMPROVE Study. Abstract 159.

Saturday, October 13, 2007

Deaths Prompt New Warnings for Micro-Bubble Contrast Agents

Deaths Prompt New Warnings for Micro-Bubble Contrast Agents

By Crystal Phend, Staff Writer, MedPage TodayOctober 12, 2007

ROCKVILLE, Md., Oct. 12 -- Eleven deaths and nearly 200 reports of serious cardiopulmonary events have been linked to microbubble contrast agents (Definity and Optison) used in echocardiography, the FDA reported today.

DuPont Pharmaceuticals, maker of Definity, and GE Healthcare, maker of Optison, agreed to labeling changes emphasizing the risk for serious cardiopulmonary reactions and contraindication for use in patients with unstable cardiopulmonary status, said the agency.

Most of the deaths occurred within 12 hours of administration among patients with severe underlying conditions. In four cases, patients died after cardiac arrest within 30 minutes of receiving Definity.

Many of the 190 serious non-fatal reactions reported with Definity and nine reports with Optison also occurred within minutes of administration and were suggestive of anaphylactic or cardiopulmonary reactions, the FDA said.

The labeling changes included:

A boxed warning for cardiopulmonary reactions.

Warnings for cardiopulmonary and hypersensitivity reactions with recommendations to monitor vital signs, cardiac rhythm, oxygen saturation and to have equipment and trained personnel readily available for resuscitation.

Contraindications for high-risk patients, specifically those with known cardiac shunts, clinically unstable or recent worsening of congestive heart failure, symptomatic arrhythmias or at elevated risk for arrhythmias.

A cautionary statement that the safety and efficacy of Definity in exercise or pharmacological stress testing have not been established.

The manufacturers will conduct a postmarketing safety study to monitor risk of serious cardiovascular reactions, the FDA said.

Meanwhile, the FDA suggested that physicians should monitor all patients receiving these contrast agents for serious cardiopulmonary reactions during infusion and for 30 minutes after administration.

The FDA also recommended that all patients should be assessed for the following conditions before use:

Right-to-left, bi-directional, or transient right-to-left cardiac shunts

Clinically unstable or recent worsening congestive heart failure.

Acute myocardial infarction.

Serious ventricular arrhythmias or at high risk for arrhythmias due to QT prolongation.

Respiratory failure.

Severe emphysema, pulmonary emboli or other conditions that compromise pulmonary arterial vasculature.

Bristol-Myers Strengthens Warning on Ultrasound Drug

Bristol-Myers Strengthens Warning on Ultrasound Drug (Update2)

By Beth Jinks

Oct. 11 (Bloomberg) -- Bristol-Myers Squibb Co. strengthened the warning on its drug Definity, used to enhance heart images from ultrasound scans, after a U.S. inquiry into the medicine's safety.

The new prescribing information, highlighted in a black box on the package insert and warning of the risk of "serious cardiopulmonary reactions,'' was posted today on the Food and Drug Administration's Web site. The black box represents the agency's most serious safety caution.

The FDA said Oct. 8 that regulators would soon alert health-care professionals of serious risks and new safety guidelines in using the agents Definity and Optison before echocardiography, a form of ultrasound used to diagnose heart ailments.

Bristol-Myers, which makes Definity, and General Electric Co., which sells Optison, confirmed this week they were discussing package insert revisions with regulators. The safety information for Optison was unchanged on the FDA Web site today.

“The changes are designed to help ensure the safe and appropriate use of Definity,'' Bristol-Myers spokesman Tony Plohoros said. ``We believe that Definity still has significant medical value when used properly and in accordance with the label.''

Bristol-Myers will send doctors FDA-approved letters when "the changes are final,'' Plohoros said. Sales of Definity were $65 million in the U.S. last year and less than $1 million abroad, company spokesman Jeffrey Macdonald said Oct. 8.

New Alert

Definity's new boxed alert warns that "serious cardiopulmonary reactions, including fatalities, have occurred during or within 30 minutes following Definity administration,'' advising that patients be closely monitored and resuscitation equipment be on hand for half an hour after injecting the drug.

Bristol-Myers fell 13 cents to $29.50 at the 4 p.m. close in New York Stock Exchange composite trading. General Electric fell 21 cents to $41.60.

Definity, approved by the FDA in 2001, and Optison, allowed since 1997, enhance ultrasound images to help doctors see the heart more clearly. The drugs are a gas enclosed in small capsules of protein or fatty material that make heart borders clearer, letting doctors rule out small clots and identify abnormalities on the heart wall.

“FDA has been investigating reports of deaths and serious cardiopulmonary reactions after people were given'' the drugs, Karen Riley, an FDA spokeswoman, said Oct. 8. “FDA has also asked manufacturers to update their product labeling and they have agreed to do so.''

“We are currently working with the FDA on how this should be implemented for Optison,'' Graeme Holland, a GE spokesman, said Oct. 8. "To date more than 1 million doses of Optison have been given, and very few adverse reactions have been reported.''

To contact the reporter on this story: Beth Jinks in New York at

Last Updated: October 11, 2007 16:51 EDT

Friday, October 12, 2007

Long-Term Follow-up of the West of Scotland Coronary Prevention Study

Long-Term Follow-up of the West of Scotland Coronary Prevention Study

Ford I et al. for the West of Scotland Coronary Prevention Study Group. Long-term follow-up of the West of Scotland Coronary Prevention Study.

N Engl J Med 2007 Oct 11; 357:1477.


Background The West of Scotland Coronary Prevention Study was a randomized clinical trial comparing pravastatin with placebo in men with hypercholesterolemia who did not have a history of myocardial infarction, with an average follow-up of approximately 5 years. The combined outcome of death from definite coronary heart disease or definite nonfatal myocardial infarction was reduced from 7.9 to 5.5% (P<0.001) in the treatment group. Extended follow-up data were obtained for approximately 10 years after completion of the trial.

Methods For the survivors of the trial, all deaths, hospitalizations and deaths due to coronary events and stroke, and incident cancers and deaths from cancer were tracked with the use of a national computerized record-linkage system. The results were analyzed with time-to-event analyses and use of Cox proportional-hazards models.

Results Five years after the trial ended, 38.7% of the original statin group and 35.2% of the original placebo group were being treated with a statin. In the period approximately 10 years after completion of the trial, the risk of death from coronary heart disease or nonfatal myocardial infarction was 10.3% in the placebo group and 8.6% in the pravastatin group (P=0.02); over the entire follow-up period, the rate was 15.5% in the placebo group and 11.8% in the pravastatin group (P<0.001). Similar percentage reductions were seen in the combined rate of death from coronary heart disease and hospitalization for coronary events for both periods. The rate of death from cardiovascular causes was reduced (P=0.01), as was the rate of death from any cause (P=0.03), over the entire follow-up period. There were no excess deaths from noncardiovascular causes or excess fatal or incident cancers.

Conclusions In this analysis, 5 years of treatment with pravastatin was associated with a significant reduction in coronary events for a subsequent 10 years in men with hypercholesterolemia who did not have a history of myocardial infarction.

The West of Scotland Coronary Prevention Study: Long-Term Results

Published in Journal Watch Cardiology October 10, 2007

The benefits of statins for primary prevention of coronary heart disease stand the test of time.

Results published in 1995 from the West of Scotland Coronary Prevention Study (WOSCOPS), a randomized, double-blind, placebo-controlled clinical trial of pravastatin in middle-aged men without a history of MI, demonstrated a significant benefit after approximately 5 years of treatment (Journal Watch Cardiology Dec 1 1995). Now, the WOSCOPS investigators report outcomes over the subsequent 10 years.

About one third of the study subjects took statins during the post-trial period; the percentages were slightly higher in those who were originally randomized to pravastatin. During follow-up (mean, 13.2 years for cancer and 14.7 years for other outcomes), 18.8% of the participants originally assigned to pravastatin died, compared with 20.5% of those originally assigned to placebo. During the entire 15-year study period, the original pravastatin group had significant reductions in death from all causes (hazard ratio, 0.88), death from cardiovascular causes (HR, 0.81), and the composite of death from coronary heart disease and nonfatal MI (HR, 0.73), compared with the original placebo group. The greatest benefits with pravastatin occurred during the trial period — e.g., the reduction in death from cardiovascular causes was 34% during the trial and 14% in the post-trial period. Pravastatin treatment was not associated with an increase in cancer rates.

Comment: This study extends the findings of a classic statin trial: The benefits manifested during the trial were maintained — and perhaps expanded — through 10 years of follow-up. These results add to an already large literature supporting the value of statins for secondary prevention of coronary heart disease.

Thursday, October 11, 2007

Ultrasound Imaging Drug Gets Black-Box Warning

Ultrasound Imaging Drug Gets Black-Box Warning

October 11, 2007

Posted by Jacob Goldstein

The FDA posted a black-box warning added to Definity, a Bristol-Myers Squibb drug used in conjunction with ultrasound imaging to diagnose heart problems, Dow Jones Newswires reports.

The Health Blog reported on Sunday that the agency has been investigating reports of deaths and serious side effects associated with the drug, and that the warning was imminent.

The warning says: “Serious cardiopulmonary reactions, including fatalities, have occurred during or within 30 minutes following DEFINITY administration.” It also says patients should be assessed for risk factors that make the drug unsafe, and patients who do receive the drug should be monitored for 30 minutes. The warning ends with an imperative: “Always have resuscitation equipment and trained personnel readily available.”

The drug is also contraindicated for patients with worsening or clinically unstable congestive heart failure and acute myocardial infarction or acute coronary syndromes.

Most echocardiograms are performed without the drug, but doctors sometimes use it when a first ultrasound is inconclusive or in difficult cases.

The stiffer warnings are expected to reduce the use of Definity, several cardiologists told the Health Blog.

High BP greatly increases women's diabetes risk

High BP greatly increases women's diabetes risk

MedWire News

10 October 2007

Eur Heart J 2007; Advance online publication

MedWire News: Women with high blood pressure (BP) levels are three times more likely to develop Type 2 diabetes than those with optimal BP levels, irrespective of their body mass index (BMI) and presence of other cardiovascular and diabetes risk factors, US study findings reveal.

The authors report in the European Heart Journal that both baseline BP and BP progression strongly predict incident Type 2 diabetes in initially healthy women, and say their findings highlight the need to consider cardiovascular risk factors in combination.

David Conen (Harvard Medical School, Boston, Massachusetts, USA) and colleagues followed-up over 38,000 female health professionals enrolled in the Women's Health Study for 10 years. The women were all free of diabetes and cardiovascular disease at study entry.

"Despite several studies finding a close relationship between hypertension and Type 2 diabetes, little information exists on the relationship between BP levels and the subsequent development of Type 2 diabetes," explained Conen. "Data for women are particularly limited."

The team divided the women into four groups: those with optimal BP (<120/75 mmHg); those with normal BP (120-129/75-84 mmHg); those with high normal BP (130-139/85-89 mmHg); and those with established hypertension (≥140/90 mmHg), and/or self-reported history of hypertension or antihypertensive treatment.

At follow-up, the incidence of Type 2 diabetes was 1.4% in the optimal BP group, 2.9% in those with normal BP, 5.7% in high-normal BP participants, and 9.4% in the established hypertension group.

Multivariable adjusted hazard ratios (HRs) for diabetes across the BP categories were 0.66, 1.00 (referent group), 1.45, and 2.03 (p for trend <0.0001).

Stratification by BMI gave similar results. "Analyses showed that the relationship... was similar among women who were normal weight, overweight, or obese," Conen reported. "There was a three-fold increase in risk from the lowest to the highest BP category within all three weight categories."

Women whose BP increased over time during the study also had an increased risk for developing diabetes. Adjusted HRs for incident diabetes at 2 years among women who had no BP progression, those in whom BP increased but remained normotensive, and women who developed hypertension were 1.0, 1.26, and 1.64, respectively, compared with 2.39 in women with baseline hypertension (p for trend <0.0001).

The authors conclude: "Our findings provide strong evidence that BP and progression of BP are associated with an increased risk of diabetes. They highlight the fact that cardiovascular risk factors are interrelated and occur in clusters.

"Thus, an important message for physicians and future guidelines is that none of the cardiovascular risk factors should be looked at individually. The combination of all risk factors should be used to make treatment decisions."


Banked Blood Loses Ability to Deliver Oxygen to Tissues

Banked Blood Loses Ability to Deliver Oxygen to Tissues

Duke University Medical Center - DukeMed News -

DURHAM, N.C. –Almost immediately after it is donated, human blood begins to lose a key gas that opens up blood vessels to facilitate the transfer of oxygen from red blood cells to oxygen-starved tissues.

Thus, millions of patients are apparently receiving transfusions with blood that is impaired in its ability to deliver oxygen, according to Duke University Medical Center researchers, who reported the results of their studies in two separate papers appearing early on-line in the Proceedings of the National Academy of Sciences.

They also found that adding this gas back to stored blood before transfusion appears to restore red blood cells' ability to transfer oxygen to tissues. These studies go a long way toward answering a major problem which many physicians are beginning to appreciate – blood transfusions with banked human blood may do more harm than good for a majority of patients, according to the researchers.

Over the past five years, many studies, including some performed at Duke, have demonstrated that patients who receive blood transfusions have higher incidences of heart attack, heart failure, stroke and even death. While it is known that the banked blood is not the same as blood in the body, the reasons behind blood's association with worse outcomes have not been well-understood.

The key to the current findings is that nitric oxide in red blood cells is crucial to the delivery of oxygen to tissues. Nitric oxide keeps the blood vessels open. The new studies demonstrated that nitric oxide in red blood cells begins breaking down almost immediately after red blood cells leave the body.

"It doesn't matter how much oxygen is being carried by red blood cells, it cannot get to the tissues that need it without nitric oxide," said Duke's Jonathan Stamler, M.D., senior author of one of the PNAS papers, whose group originally discovered the role of red blood cell nitric oxide in oxygen delivery. "Nitric oxide opens up the tiny blood vessels, allowing red blood cells to pass and deliver oxygen. If the blood vessels cannot open, the red blood cells back up in the vessel and tissues go without oxygen. The result can be a heart attack or even death.

"The issue of transfused blood being potentially harmful to patients is one of the biggest problems facing American medicine," continued Stamler, who is a professor of cardiovascular and pulmonary medicine. "Most people do not appreciate that blood has the intrinsic capacity to open blood vessels, thereby enabling oxygen to get to tissues. Banked blood cannot do this properly."

However, transfusions are still critically important, Stamler said.

"Banked blood is truly a national treasure that needs to be protected," Stamler said. "Blood can be life saving, only it is not helping the way we had hoped and in many cases it may be making things worse. In principle, we now have a solution to the nitric oxide problem--we can put it back--but it needs to be proven in a clinical trial."

It is estimated that close to 14 million units of red blood cells are administered to about 4.8 million Americans each year. National blood banks require that blood be stored for no more than 42 days after donation. After that time, unused blood must be discarded.

One team of Duke researchers, led by Timothy McMahon, M.D., Ph.D., wanted to document exactly what happens to banked blood over those 42 days. Using human blood stored according to national standards, the researchers sampled the blood at regular intervals.

"We were surprised at how quickly the blood changes – we saw clear indications of nitric oxide depletion within the first three hours," said McMahon, an associate professor of pulmonary medicine. "Of concern to us is that nitric oxide levels become depressed soon after collection, suggesting that even 'fresh' blood may have adverse biological characteristics."

Nitric oxide is not only needed for red blood cells to off-load oxygen, it may also influence the flexibility of the saucer-shaped cells. As nitric oxide levels decrease, the red blood cells become stiffer, making it more difficult for them to deform their shape in order to squeeze through tiny blood vessels.

Stamler's team confirmed that nitric oxide levels started dropping quickly in stored human blood, and that this resulted loss of its ability to dilate blood vessels. So they wanted to see if adding the gas back to stored blood might restore the ability to open vessels, using dogs as a model.

Since blood is often given to patients to prevent heart attacks, and yet paradoxically may cause heart attacks, the investigators measured blood flow to the hearts of oxygen-deprived animals.

"When we gave stored blood it couldn't increase blood flow properly," Stamler said. "However, after replacing the nitric oxide, blood flow to the heart was increased, reflecting increased blood vessel dilation. This suggests that adding nitric oxide to human banked blood could theoretically improve its ability dilate blood vessels and thus prevent heart attacks and even death in patients."

Both McMahon and Stamler believe that a large-scale randomized clinical trial in humans is needed, arguing that blood has both benefits and risks, and therefore should be evaluated in the same manner as medications.

"There is little doubt that transfused blood can be harmful," said Stamler. "We are only uncertain about how serious the problem is. The availability of a potential solution will hopefully focus the attention of the medical community on the potential magnitude of this problem."

Stamler's research was supported by the National Institutes of Health and Duke Anesthesiology Fund. McMahon's study was supported by the American Heart Association and N30 Pharma, a company that has a license agreement with Duke to develop nitric oxide-based therapies.

A video clip of Jonathan Stamler is available.

Tuesday, October 9, 2007

Job Strain and Risk of Acute Recurrent Coronary Heart Disease Events

Job Strain and Risk of Acute Recurrent Coronary Heart Disease Events

Corine Aboa-Éboulé, MD, PhD; Chantal Brisson, PhD; Elizabeth Maunsell, PhD; Benoît Mâsse, PhD; Renée Bourbonnais, PhD; Michel Vézina, MD, MPH; Alain Milot, MD, MSc; Pierre Théroux, MD; Gilles R. Dagenais, MD

JAMA. 2007;298:1652-1660. (October10, 2007)

Context There is evidence that job strain increases the risk of a first coronary heart disease (CHD) event. However, little is known about its association with the risk of recurrent CHD events after a first myocardial infarction (MI).

Objective To determine whether job strain increases the risk of recurrent CHD events.

Design, Setting, and Patients Prospective cohort study of 972 men and women aged 35 to 59 years who returned to work after a first MI and were then followed up between February 10, 1996, and June 22, 2005. Patients were interviewed at baseline (on average, 6 weeks after their return to work), then after 2 and 6 years subsequently. Job strain, a combination of high psychological demands and low decision latitude, was evaluated in 4 quadrants: high strain (high demands and low latitude), active (high demands and high latitude), passive (low demands and low latitude), and low strain. A chronic job strain variable was constructed based on the first 2 interviews, and patients were divided into those exposed to high strain at both interviews and those unexposed to high strain at 1 or both interviews. The survival analyses were presented separately for 2 periods: before 2.2 years and at 2.2 years and beyond.

Main Outcome Measure The outcome was a composite of fatal CHD, nonfatal MI, and unstable angina.

Results The outcome was documented in 206 patients. In the unadjusted analysis, chronic job strain was associated with recurrent CHD in the second period after 2.2 years of follow-up (hazard ratio [HR], 2.20; 95% CI, 1.32-3.66; respective event rates for patients exposed and unexposed to chronic job strain, 6.18 and 2.81 per 100 person-years). Chronic job strain remained an independent predictor of recurrent CHD in a multivariate model adjusted for 26 potentially confounding factors (HR, 2.00; 95% CI, 1.08-3.72).

Conclusion Chronic job strain after a first MI was associated with an increased risk of recurrent CHD.

Adverse Effects of Combination Angiotensin II Receptor Blockers Plus Angiotensin-Converting Enzyme Inhibitors for Left Ventricular Dysfunction

Adverse Effects of Combination Angiotensin II Receptor Blockers Plus Angiotensin-Converting Enzyme Inhibitors for Left Ventricular Dysfunction

A Quantitative Review of Data From Randomized Clinical Trials

Christopher O. Phillips, MD, MPH; Amir Kashani, MS, MD; Dennis K. Ko, MD; Gary Francis, MD; Harlan M. Krumholz, MD, SM

Arch Intern Med. 2007;167:1930-1936. (October 8, 2007)

Background We performed a meta-analysis of randomized controlled trials to assess ongoing concerns about the safety profile of combination angiotensin II receptor blockers (ARBs) plus angiotensin-converting enzyme (ACE) inhibitors in symptomatic left ventricular dysfunction.

Methods MEDLINE (January 1966–December 2006) and Web sites for the National Institute of Health Clinical Trials and the Food and Drug Administration were searched for eligible RCTs that included 500 or more subjects, had a follow-up of 3 months or longer, and reported adverse effects. We used a random effects model to calculate the relative risk (RR) and 95% confidence interval (CI) for the following outcome measures: medication discontinuations because of adverse effects, worsening renal function (an increase in serum creatinine level of > 0.5 mg/dL [to convert to micromoles per liter, multiply by 88.4]), hyperkalemia (serum potassium level > 5.5 mEq/L [to convert to millimoles per liter, multiply by 1]), and symptomatic hypotension.

Results Four studies (N = 17 337; mean follow-up, 25 months [range, 11-41 months]) were selected. Combination ARB plus ACE inhibitor vs control treatment that included ACE inhibitors was associated with significant increases in medication discontinuations because of adverse effects in patients with chronic heart failure (RR, 1.38 [95% CI, 1.22-1.55]) or in patients with acute myocardial infarction with symptomatic left ventricular dysfunction (RR, 1.17 [95% CI, 1.03-1.34]), and for both conditions there were significant increases in worsening renal function (RR, 2.17 [95% CI, 1.59-2.97] and RR, 1.61 [95% CI, 1.31-1.98], respectively), hyperkalemia (RR, 4.87 [95% CI, 2.39-9.94] and RR, 1.33 [95% CI, 0.90-1.98], respectively; the latter was not significant), and symptomatic hypotension (RR, 1.50 [95% CI, 1.09-2.07], and RR, 1.48 [95% CI, 1.33-3.18], respectively).

Conclusion Combination ARB plus ACE inhibitor therapy in subjects with symptomatic left ventricular dysfunction was accompanied by marked increases in adverse effects.

The Case for Early Statin Therapy After AMI

The Case for Early Statin Therapy After AMI

A Japanese study suggests that initiating standard statin therapy immediately after patients suffer an acute myocardial infarction (AMI) appears to decrease long-term mortality and subsequent cardiac events. Among AMI patients, the researchers found that male patients older than 60 and patients with high LDL cholesterol levels (155 mg/dL or greater) appeared to benefit most from early statin therapy. Early statin therapy strongly correlated with a lower risk of cardiovascular death, less recurrence of AMI, and less heart failure. “The hazard ratio for statin therapy was 0.64 throughout the study.” The study was published in the June 1, 2007 American Journal of Cardiology.

An abstract of the study is available at

New Prediction Model To Guide Prevention Of Heart Disease

New Prediction Model To Guide Prevention Of Heart Disease

09 Oct 2007

A University of Rochester Medical Center researcher has been awarded a National Institutes of Health grant to study whether accounting for social risk factors, in addition to traditional predictors, can be useful in assessing patients' risk and ultimately preventing coronary heart disease.

Kevin A. Fiscella, M.D., M.P.H., associate professor in the Department of Family Medicine, was awarded $823,199 by the National Heart, Lung and Blood Institute, part of the NIH, to demonstrate that inclusion of social risk factors -- socioeconomic status, race, ethnicity and marital status -- into overall risk assessment and preventive treatment guidelines offers the potential for reducing disparities in coronary heart disease (CHD).

Traditional tools to make predictions -- indicators such as age and gender, whether a patient is a smoker, diabetic or has high blood pressure -- have been used for decades by health care professionals to calculate a patient's risk of heart disease, Fiscella said. Such predictions ultimately drive treatment.

A large body of research shows that a socioeconomic component also predicts risk in determining heart disease. Disparities in coronary heart disease mortality by socioeconomic status, race and ethnicity, have been extensively documented, but translating them into clinical practice to reduce CHD disparities has proven challenging and the data is not yet incorporated into formal health assessments, Fiscella said.

"We're proposing to modify the risk tools to include socioeconomic factors and calculate the impact on prediction. If you're less educated or make less money, you have a much higher risk of heart disease. An inaccurate estimate impacts what tests and therapies a patient receives, and when." As a result, more intensive behavioral interventions focusing on diet, exercise, smoking cessation and medical adherence may be implemented.

Fiscella's three-year study will use a database containing more than 30,000 adult patient cases representative of the nation's population. It will compare the performance of predicting risk using only existing tools, to a formula that incorporates socioeconomic factors with conventional tools. His team will determine whether persons of lower economic position could be more appropriately treated using an updated, supplemented risk model.

Risk scoring using traditional criteria is currently available electronically. When a physician sees a patient, their risk factor is determined with just a few clicks.

"If we're successful in validating our prediction model, in the future physicians may see it available through a paper version or through a handheld device," Fiscella said.

A handful of studies have been done in Europe regarding the issue of social risk factors. Findings show that adding social class into the equation of risk prediction models does help to identify those in a lower social class who are at higher risk of CHD, even in the UK, where there is universal health care access.

"We know intuitively that social risk factors have a significant impact on the care of a patient but no one has said how can we apply this to decision-making at the bedside."

Article adapted by Medical News Today from original press release.

Source: Karin Christensen University of Rochester Medical Center

IDSA: No Evidence of Infectious Link to Coronary Disease Revealed

IDSA: No Evidence of Infectious Link to Coronary Disease Revealed


SAN DIEGO, Oct. 8 -- The infectious link to coronary artery disease, if there is one, remained as elusive as ever after scrutiny of peripheral blood mononuclear cells (PMBCs), investigators said here.

The examination of PMBCs from patients with coronary disease failed to turn up any evidence of Chlamydia pneumoniae, Sarah West, M.D., of Oregon Health & Science University in Portland reported at the Infectious Diseases Society of America meeting.

However, Dr. West and colleagues are not ready to close the door on investigation of an infectious etiology for coronary disease.

"All we can say on the basis of this work is that we were unable to detect the pathogen with the methods we used," said Dr. West. "We're confident in our results, but the data on human atheromas and from animal models are just too compelling to say there is nothing to this."

Previous studies of C. pneumoniae and coronary disease have yielded mixed results. Nucleic acid from the pathogen has been reported in 0% to 90% of atherosclerotic plaques. Similar variation has emerged from studies of C. pneumoniae nucleic acid in PBMCs of patients with coronary disease.

"I think our study differs from some of the others in that we used a very sensitive PCR assay, and we performed the assay three times with each specimen to ensure reliability," said Dr. West. "We also sent samples to an outside laboratory for confirmation."

Investigators tested the theory that C. pneumoniae spread to atherosclerotic plaque by PBMCs or vice versa would be detectable and serve as a marker for coronary disease. The study involved 86 patients with angiographically proven coronary disease and 90 age- and sex-matched controls without coronary disease or modifiable risk factors for coronary disease.

PBMCs in blood samples from patients and controls were probed for C. pneumoniae DNA and RNA by means of two different real-time PCR assays. Additionally, microimmunofluorescence assays were used to screen specimens for IgG for C. pneumoniae.

Three fourths of the patients and controls had serologic evidence of prior exposure to C. pneumoniae, as determined by microimmunofluorescence. Even so, none of the patients or controls had evidence of C. pneumoniae nucleic acid in PBMCs.

Samples sent to an outside laboratory yielded the same results.

"Our results were uniformly negative, using highly sensitive PCR techniques," said Dr. West. "The results indicate that PBMCs can't be used as a means of determining whether C. pneumoniae is in atheromatous lesions and that the presence or absence of C. pneumoniae nucleic acid in PBMCs is not a useful risk factor for coronary artery disease."

Primary source: Infectious Diseases Society of America

Source reference:

West SK et al. "No evidence of circulating C. pneumoniae nucleic acid in patients with coronary artery disease (CAD) or healthy controls." Infectious Diseases Society of American 45th Annual Meeting. Oct. 4-7, 2007. San Diego. Final Program and Abstracts. Abstract 464.