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Newswise — PHILADELPHIA – After nearly 13 years of study and intense debate, a pair of new papers from the Perelman School of Medicine, at the University of Pennsylvania have confirmed exactly how a once-popular class of anti-inflammatory drugs leads to cardiovascular risk for people taking it.

It has been almost eight years since Vioxx® was withdrawn by Merck from the market, provoking an intense controversy about the role inhibitors of the enzyme COX-2 play in causing heart attacks and strokes. Since then, other drugs in the class from Pfizer, Novartis, and Merck have been withdrawn (Bextra®); have failed to be approved (Arcoxia®, Prexige®); or have been retained on the market in the US with a “black box” warning on the label (Celebrex®).

COX-2 is one of two similar enzymes that churn out short-lived fats called prostaglandins. The other, COX-1, works in platelets — cells in the blood that stick together in the first stages of clotting. COX-2 is active in the cells that line blood vessels. These enzymes have diverse, potent, and often contrasting effects in the body. For example, low-dose aspirin protects against heart attacks and strokes by blocking COX-1 from forming a prostaglandin called thromboxane A2 in platelets. On the other hand, COX-2 is the more important source of prostaglandins, particularly one called prostocyclin, which causes pain and inflammation.

COX-2 inhibitors are a subclass of nonsteroidal anti-inflammatory drugs (NSAIDs), among the most common drugs consumed on the planet. Older NSAIDs include drugs like Naprosyn, which inhibits mostly COX-1; Advil®, which inhibits COX-1 and COX-2; and Voltaren® and Mobic®, which mostly inhibit COX-2. The newer drugs were developed because targeting COX-2 reduced serious gastrointestinal side effects like bleeding ulcers. However, aggressive direct-to-consumer advertising meant that drugs like Vioxx and Celebrex were taken mostly by patients who had never had the GI problems with the older, cheaper NSAIDs.

Just before Celebrex and Vioxx were approved and launched, a group led by Garret FitzGerald, MD, chair of the department of Pharmacology, and director of the Institute for Translational Medicine and Therapeutics at Penn, observed that both drugs suppressed prostacyclin in humans, as reflected by its major metabolite in urine, PGI-M. Based on the potentially cardioprotective properties of prostacyclin, which relaxes blood vessels and unglues platelets in test tube experiments, the team predicted that shutting down this protection with inhibitors would cause heart attacks and strokes.

More than 10 years later, it is now clear what the COX inhibitors do in the body. Eight placebo-controlled, randomized trials, performed to find new uses of these drugs, showed that they posed a cardiovascular hazard, similar in magnitude to that resulting from being a smoker or a diabetic, notes FitzGerald. “Despite this, controversy has continued about how all this came about, until now.”

Arguments against the proposed mechanism were threefold. First, it was proposed that COX-2 didn’t exist under normal circumstances in the blood-vessel lining and PGI-M came from some other source. The kidneys were suggested as the source by some researchers. Second, even if blood-vessel prostacyclin was blocked, other protective mechanisms, especially formation of nitric oxide (NO) would take over. And third, although NSAIDs elevate blood pressure, it was proposed that this observation was unrelated to COX-2 and treating high blood pressure would deal with the problem.

FitzGerald’s group has now “closed the loop” with its earlier clinical studies and answered these questions in a paper just published in Science Translational Medicine. In it, they confirm that COX-2 is expressed in cells lining blood vessels and that selectively removing it predisposes mice to blood clotting and high blood pressure. These mice, just like humans taking COX-2 inhibitors, also see a fall in PGI-M. What’s more, the Penn group discovered that COX-2 in lining cells controls the expression of eNOS, the enzyme that makes NO in the body. “So, rather than replacing the missing prostacyclin, as others have proposed, NO is lost and amplifies the effects of COX-2 inhibition on the cardiovascular system,” says FitzGerald.

Indeed, the lost NO may not be the only step that magnifies the effects of losing prostacyclin. In a second paper, published in April 2012, in the Proceedings of the National Academy of Sciences, FitzGerald’s group shows that arachidonic acid, the fat broken down by COX-2 to make prostacyclin, can be shunted down another pathway to make a new series of dangerous fats called leukotrienes when COX-2 is disrupted.

Clinical studies have shown that those most at risk from COX-2 inhibitors are patients who already have heart disease. However, the Penn group now suggests broader implications. Here, the group resolves one aspect of the controversy, showing that COX-2 disruption causes hardening of the arteries in mice. This result is provocative because randomized trials of Vioxx and Celebrex in patients at low risk of heart disease detected an increase in heart attacks after patients had been taking the drugs for more than a year. These current Penn studies raise the disturbing prospect that heart-healthy patients taking NSAIDs for prolonged periods might be gradually increasing their risk of heart attacks and strokes by progressively hardening their arteries.

“However, it’s not all bad news,” says FitzGerald. This risk of hardening of the arteries was diminished in mice by reducing leukotriene formation, via blocking a critical protein called the 5-lipoxygenase activating protein, or FLAP. Inhibitors of FLAP are already in trials in humans to see if they work in asthma. Perhaps, FitzGerald concludes, they can now find an additional use — protecting the heart from NSAIDs.

SAN FRANCISCO, CA – NOVEMBER 9, 2011 – The relationship of platelet responsiveness to antiplatelet medications; and, the correlation of poor response, and overall platelet aggregation while on dual antiplatelet therapy to the risk of drug-eluting stent thrombosis after 30 days was examined in ADAPT-DES, the largest registry to date to fully examine these relationships.

Results of ADAPT-DES (Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents) were presented today at the 23rd annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium, sponsored by the Cardiovascular Research Foundation.

While prior studies have emphasized the absolute level of platelet activation/aggregation to antiplatelet medications, the role of the baseline level of platelet activation and the percentage of platelet inhibition in response to these therapies have largely been unstudied prior to ADAPT-DES.

In addition, the impact of poor platelet response to aspirin, and overall platelet aggregation while on dual antiplatelet therapy (DAPT) on the risk of stent thrombosis has not been fully examined.

In the registry, 8,575 patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents were enrolled at 11 sites between January 2008 and September 2010. The researchers assessed platelet reactivity to aspirin and clopidogrel as well as overall platelet responsiveness with the VerifyNow Aspirin, P2Y12, and IIb//IIIa tests after successful implantation of drug-eluting stents. Definite or probable stent thrombosis occurred in 39 patients (0.46%) after 30 days.

The researchers found that absolute and relative levels of platelet inhibition in response to ADP antagonists as assessed by the VerifyNow P2Y12 test are powerful independent predictors of stent thrombosis within 30 days, with a significant proportion of events independently attributable to clopidogrel hyoporesponsivenes.

In contrast, the baseline level of platelet P2Y12 response, as well as aspirin and overall platelet responsiveness after DAPT loading as assessed by VerifyNow were not shown to be related to the 30-day rate of stent thrombosis.

“These results suggest that agents which more effectively inhibit ADP-induced platelet activation should reduce 30-day stent thrombosis when applied to large patient populations,” said lead investigator, Gregg W. Stone, MD. Dr. Stone is Director of Cardiovascular Research and Education at NewYork-Presbyterian Hospital/Columbia University Medical Center and Professor of Medicine, Division of Cardiology at Columbia University College of Physicians and Surgeons. Dr. Stone also serves as Co-Director, Medical Research & Education Division at the Cardiovascular Research Foundation.

“However, the modest sensitivity and specificity of platelet function testing, coupled with the low prevalence of events, implies that testing of platelet ADP antagonist responsiveness is unlikely to provide useful information to guide clinical decision-making in most individual patients for the prevention of stent thrombosis at 30 days,” said Dr. Stone.

“The degree of platelet responsiveness to antiplatelet loading is useful to predict 30-day stent thrombosis in diabetic and non-diabetic patients, as well as those with ACS, but may have less clinical utility in patients with stable coronary artery disease (CAD),” Dr. Stone said.

“There was a low stent thrombosis rate in patients with stable CAD, which coupled with the poor prognostic utility of platelet function testing in this setting, suggests that assessing DAPT response in patients without ACS undergoing PCI is unlikely to provide incremental clinical utility. The relationship between platelet responsiveness testing and the occurrence of late and very late stent thrombosis, in patients who have maintained and discontinued DAPT, will be assessed during the two-year clinical follow-up phase of the ADAPT-DES study.”

The ADAPT-DES trial is sponsored by the Cardiovascular Research Foundation with research support from Boston Scientific, Abbott Vascular, Medtronic, Cordis, Biosensors, The Medicines Company, Daiichi Sankyo, Eli Lilly, Volcano, and Accumetrics.
Dr. Stone reported consulting fees and honoraria from Abbott Vascular, Boston Scientific, Medtronic, Volcano, The Medicines Company, Daiichi Sankyo and Eli Lilly.

SAN FRANCISCO, CA – NOVEMBER 9, 2011 – The risk of late stent thrombosis (ST) in the first generation of drug-eluting stents continues for up to seven years after implantation, and certain types of patients, including smokers and those who are younger, are at higher risk, according to results of the DESERT registry. Results of the trial were presented today at the 23rd annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium, sponsored by the Cardiovascular Research Foundation.

Stent thrombosis, a condition in which blood clots form following the implantation of a stent, frequently presents as an acute event triggering myocardial infarction (MI, heart attack) or death. As single center studies are limited in their evaluation of ST, there is an existing need to understand the factors predicting ST and define those patients are that are at highest risk.

DESERT (Drug Eluting Stent Event Registry of Thrombosis), in which 922 patients from 20 sites from the United States, Canada and Switzerland have been enrolled in this multi-center, observational, case-control study of definite, late or very late ST in patients with drug-eluting stents (DES). DESERT is the largest case-control registry of late and very late definite stent thrombosis.

In the registry, the majority of late ST occurred after one year (~75%) and continued for up to 7.3 years. The clinical presentation of late ST was mainly myocardial infarction (66.9% STEMI; 22% NSTEMI). Nearly 30% of the patients with late stent thrombosis were on dual antiplatelet therapy (DAPT) at the time of the event.

“Patients who had first generation drug-eluting stents continue to be at risk for late stent thrombosis up to seven years,” said lead investigator, Ron Waksman, MD. Dr. Waksman is Associate Director, Division of Cardiology at Washington Hospital Center (WHC) and Director of Experimental Angioplasty and Emerging Technologies at the Cardiovascular Research Institute (CRI) at WHC.

“Younger patients, smokers, African Americans, patients with multi-vessel disease, STEMI or saphenous vein grafts (SVG) should be reevaluated for drug-eluting stents or for a strong and longer term regimen of dual antiplatelet therapy,” Dr. Waksman said.

The DESERT trial was investigation driven study is funded in part by Medtronic Vascular and by the investigators of the study. Dr. Waksman serves on the advisory board of several of the DES manufacturers tested in the study.

Research by the University of Liverpool has found that intervention policies that promote healthy eating could cut the death rate for cardiovascular disease (CVD) by up to 50%.

Professor Simon Capewell from the Institute of Psychology, Health and Well-being found that intervention policies which reduce unhealthy eating habits can have a significant effect on levels of CVD at both an individual and population level.

Poor diet is one of the major causes of CVD and small improvements can make a positive and rapid impact on both the individual and the wider population. However, the information about healthy eating, whilst plentiful, has been unclear and often caused confusion.

The study identifies six foods which make could a significant improvement to cardiovascular disease rate. Researchers estimate that eating more fruit, vegetables, whole grains, nuts (in place of starch), vegetable oils (in place of animal fats) and fish and seafood in the diet it would result in 9.2million fewer deaths globally. Likewise, limiting our intake of salt and industrial trans fats would have a positive effect on CVD rates and could save 2.6 million lives globally.

Research found that population-wide prevention programmes are cost-effective and even cost-saving. Effective intervention policies work best as part of a wide ranging programme which include both legislative and educational policies, for example pricing policies to subsidise healthier food and tax less healthy ones; long-term agricultural government strategies promoting infrastructure for production; improved transportation and marketing of healthier food; strict guidelines on marketing of food and beverages to children; mandatory product and menu labelling; increased support for local markets providing healthier foods; school-based interventions incorporating dietary curricula as well as trained teachers and the availability of healthy food menus.

Cardiovascular disease kills around 20 million people, including 10 million prematurely before the age of 65. CVD is the UK’s biggest killer, with 191,000 deaths from the disease in 2008. There are some 124,000 heart attacks in the UK every year.

Whilst drug and hospital based prevention are successful for high-risk individuals with CVD, this is relatively costly and not sustainable in many countries.

The study was published in the British Medical Journal.

Of 180 patients in this study in whom a reference committee later identified coronary heart disease (CHD), 31.7% had originally been misdiagnosed by their family doctors as not having CHD (“false negative”). Stefan Bösner and his colleagues present the results of their cross-sectional study in the current edition of Deutsches Ärzteblatt International (Dtsch Arztebl Int 2011; 108[26]: 445-51).

When a patient presents with chest pain as the main symptom, the family doctor has to decide whether immediate action is called for or whether watchful waiting is an option. In this diagnostic cross-sectional study the authors evaluated the data of a total of 1249 patients over the age of 35 years who presented to 74 participating family doctors with chest pain.

From this data pool, Bösner and colleagues extracted the doctors’ initial suspected diagnosis in respect of coronary heart disease (CHD). In a total of 57 patients the doctor wrongly suspected another cause than CHD for the chest pain.

Nevertheless, the family doctors still referred one in three of the patients given such a false negative diagnosis to a cardiologist. In view of the number of missed cases of CHD, there is an argument for considering a diagnosis of CHD in patients with less pronounced symptoms.

However, the researchers believe that if the “diagnostic threshold” were to be lowered, the result would be a dramatic rise in false positive diagnoses.

DETROIT – The incidence of internal bleeding was higher in the most commonly implanted heart device than in an earlier model, according to two studies at Henry Ford Hospital in Detroit.

The HeartMate II, a left ventricular assist device (LVAD) is a continuous-flow mechanical pump connected to the patient’s heart that takes over the pumping of the weakened heart’s left ventricle.

“Although there were more instances of bleeding in the skull and gastrointestinal track with the HeartMate II, as opposed to the earlier model, there was no increase in mortality,” says lead author Jeffrey A. Morgan, M.D., associate director of Mechanical Circulatory Support in the Edith and Benson Ford Heart &Vascular Institute at Henry Ford.

Dr. Morgan will present the studies on June 11 at the annual conference of the American Society of Artificial Internal Organs in Washington, D.C.

From March 2006 through May 2010, 64 patients with chronic heart failure underwent implantation of a HeartMate II LVAD as a bridge to transplant or a permanent therapy for those ineligible for transplants.

The incidence of gastrointestinal bleeding or adverse neurological events (ANE) was evaluated to determine their impact on survival and identify predictors of occurrence.

The overall incidence of gastrointestinal bleeding was nearly 22 percent, and the incidence of major ANEs was eight percent. Patients with an ANE were significantly older, with a higher incidence of chronic renal insufficiency. They also had higher International Normalized Ratios (INRs), a lab test that measures the time it takes for blood to clot, and compares it to an average, at the time of the event. The higher the INR, the longer it takes blood to clot.

No complications due to blood clots occurred in those with gastrointestinal bleeding, but for patients with an ANE, there were four intracranial hemorrhages and one thromboembolic stroke.

There was no significant difference in gender, race, cause of heart failure, diabetes, or body mass index (BMI) between patients who had post-operative bleeding and those who did not.

Study co-author Robert J. Brewer, M.D., surgical director of the Mechanical Circulatory Support Program at Henry Ford, believes that as data accumulates on the relatively low incidence of thromboembolic events with the HeartMate II for patients on low-dose or no anticoagulation, it may be prudent to lower the goal INR, with the intent of lowering bleeding complications.

The HeartMate II is smaller, with fewer moving parts, than the previous model, the HeartMate I XVE, and requires less invasive surgery. Its size makes it available to a larger number of advanced-stage heart failure patients, and it has been predicted to greatly increase patients’ quality of life. The device can cover the full output of a healthy heart. Studies have shown that continuous-flow pumps last much longer than pulsing pumps before they must be replaced.

Usage of LVADs has increased in the United States, where heart failure affects five million people, but there are less than 3,000 donor organs available annually worldwide. Last year, nearly 2500 patients were implanted with the device in the United States, which is used chiefly for those waiting for a heart transplant due to the chronic donor shortage. In other cases, it is used for long-term support in patients who are not candidates for a heart transplant.

The study was funded by Henry Ford Hospital.

A new study published in the journal Clinical Cardiology reveals that in men with chronic heart failure, cardiac resynchronization therapy (CRT) improves patients’ libido, erectile dysfunction, and sexual performance.

Chronic heart failure (HF) is a common, complex clinical syndrome characterized by fatigue and exercise intolerance. HF patients experience decreased libido and erectile dysfunction (ED). CRT, which is a type of pacemaker that paces the right and left ventricle, is used to treat patients with HF.

Led by Ahmet Vural of Kocaeli University, researchers investigated the effects of CRT on libido and ED. 31 male patients with advanced HF, scheduled for implantation of a CRT device, were included in the study. They were assessed before and six months after CRT.

At the six-month follow-up after CRT, 23 patients reported no ED, and only two patients had moderate ED. Severe ED was not found in any patient. A significant increase in patients with normal libido was found, with 25 men reporting improvement compared to only three reporting normal libido prior to CRT.

The findings show that CRT results in significant improvement in libido, ED, and sexual performance as a consequence of the improvement in functional capacity and ejection fraction.

“Not only does CRT decrease mortality in heart failure patients, it also brings improvement in sexual health to the patient’s life,” Vural concludes.

ATS 2011, DENVER – Continuous positive airway pressure (CPAP) effectively decreases the risk of cardiovascular death in elderly patients who suffer from obstructive sleep apnea (OSA), according to a study conducted by researchers in Spain. The study is the first large-scale study to assess the impact of OSA and the effectiveness of CPAP treatment in cardiovascular mortality in the elderly.

The findings will be presented at the ATS 2011 International Conference in Denver.

“Our study offers two key conclusions,” said Miguel Angel Martinez-Garcia, MD, study lead author pneumonologist at the Hospital General de Requena in Valencia, Spain.”First, with younger patients, elderly patients with severe, untreated sleep apnea have a higher cardiovascular mortality than those with mild to moderate disease or those without sleep apnea; and second, treatment with CPAP can reduce cardiovascular mortality in elderly OSA patients to levels similar to those found in patients without disease or with mild to moderate sleep apnea.”

Millions of people worldwide suffer from sleep apnea, which has been associated with cardiovascular health risks and poorer quality of life. Most studies, however, have been conducted in younger populations, Dr. Martínez-García noted.

“CPAP has been shown to be a very effective treatment for severe and symptomatic forms of sleep apnea,” he said. “However, virtually all studies on the effectiveness of CPAP to date have been conducted in middle-aged individuals, despite the fact that a growing percentage of the patients we see in our sleep units are elderly and are treated with CPAP.

“This is a very important issue considering the gradual increase in longevity worldwide,” he added.

Patients with severe OSA typically experience regular interruptions in their sleep when breathing temporarily stops. In these patients, normal airflow is blocked as the soft tissue of the airway collapse and sag into the throat, preventing normal respiration. In CPAP, pressurized air is delivered continuously through a mask worn over the nose or nose and mouth to help keep the soft tissues of the airway from collapsing.

For their study, Dr. Martínez-García and colleagues enrolled 939 elderly patients referred with suspected sleep apnea between 1999 and 2007, and followed these patients through 2009. Patients were divided into four groups: a control group without OSA; mild to moderate OSA patients without CPAP treatment; patients with severe OSA without CPAP treatment; and patients with any degree of OSA who received CPAP treatment. Complete health histories, including cardiovascular and respiratory data, were obtained from all patients at enrolment and mortality causes were obtained from death certificates. Fatal cardiovascular events included sudden death, stroke, heart failure (HF), cardiac arrhythmias and ischemic heart disease (IHD). Median follow-up time was 69 months.

The researchers found that untreated severe OSA (but not untreated mild-moderate OSA) was independently associated with all-cause and cardiovascular mortality, as well as stroke and HF mortality, but not with IHD mortality. In addition, they found that CPAP treatment reduced these increased risks of mortality in OSA patients.

Dr. Martínez-García said the results were not entirely unexpected, since anecdotal evidence and several smaller studies have indicated CPAP offers improved outcomes in certain patients, notably patients at risk for stroke.

“Our study provides an excellent scientific basisfor further studies in this area given a lack of scientific evidence on the impact of sleep apnea and the role of CPAP treatment in elderly patients,” Dr. Martínez-García said. “These findings clearly support the fact that treatment with CPAP is effective in elderly people and therefore, within logical limits, it must be a treatment that is offered to patients with severe or symptomatic OSA regardless of their age.

“The next step is to assess the effect of CPAP treatment in elderly OSA patients in large, randomized clinical trials,” he added. “These studies should explore not only cardiovascular outcomes, but other outcomes such as neurocognitive dysfunction.”

“All-Cause And Cardiovascular Mortality In Elderly Patients With Sleep Apnea. Role Of CPAP Treatment. A 6-Year Follow-Up Study” (Session A19, Sunday, May 15, 8:15-10:45 a.m., Room 201-203 (Street Level), Colorado Convention Center; Abstract 20052)

Scientists are reporting development of a process for producing large quantities of a much-needed new imaging agent for computed tomography (CT) scans in heart disease, breast cancer and other diseases, and the first evidence that the material is safe for clinical use. The imaging agent is a tantalum oxide nanoparticle, which is inexpensive, and stays in the body long enough to image many different organs. The report appears in the Journal of the American Chemical Society.

Taeghwan Hyeon, Seung Hong Choi, and colleagues explain that CT is one of the most widely used medical imaging tests and highly effective in diagnosing disease. However, CT requires use of large amounts of imaging agents, which make body structures more visible. Today’s imaging agents have many disadvantages. They don’t stay in the body for very long, for instance, limiting the types of images that physicians can obtain. Nanoparticles have been developed as imaging agents, but they have been made of either gold (very expensive) or bismuth (toxic). So, the researchers wanted to develop a new nanoparticle imaging agent that would overcome those disadvantages.

The researchers describe development and successful initial tests of large batches of tantalum oxide nanoparticles that exhibited “remarkable performances” in imaging tests of the heart, lymph nodes, kidneys, and other structures in laboratory rats, which are stand-ins for humans in such research. Regarding safety, they say, “The nanoparticles did not affect normal functioning of organs.” The particles could have especially important uses in checking blood vessels in the heart for blockages, and lymph nodes for the spread of breast cancer, the report states.

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The authors acknowledge funding from the Korean Ministry of Education, Science, and Technology, as well as the National Research Foundation of Korea.