FDA panel rejects rivaroxaban again for acute coronary syndrome

SILVER SPRING, MD. – Collection of missing data and additional analyses from a large study on rivaroxaban failed to convince a Food and Drug Administration advisory panel to recommend approval of the anticoagulant drug for acute coronary syndrome.

At a meeting Jan. 16, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 10 to 0, with 1 abstention, that the factor Xa inhibitor rivaroxaban (Xarelto) should not be approved as a treatment for acute coronary syndromes (ACS). Rivaroxaban maker Janssen Pharmaceuticals had proposed an indication to reduce the risk of thrombotic cardiovascular events in patients with ACS, based on the results of the ATLAS ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With/Without Thienopyridine Therapy in Subjects With Acute Coronary Syndrome) trial.

That study compared two doses of rivaroxaban (2.5 mg twice a day, the proposed dose, and 5 mg twice a day) plus standard antiplatelet therapy (aspirin and a thienopyridine) to placebo plus standard therapy in more than 15,000 people with recent ACS. The primary endpoint – the risk of a composite of cardiovascular death, MI, or stroke – was significantly reduced (P = .039) by 15% among patients on the 2.5-mg twice-daily dose, compared with patients on placebo. The difference was primarily driven by a reduction in cardiovascular deaths among rivaroxaban patients.

But in May 2012, the FDA panel voted 4 to 6 against approval of rivaroxaban for the ACS indication, citing safety concerns and the large amount of missing data from the study. In June 2012, the FDA declined to approve the indication, and the agency refused again in March 2013, after Janssen provided more information. The company disputed the decision and continued to pursue approval. Janssen submitted new analyses and proposed that treatment be limited to 90 days.

At the Jan. 16 advisory committee meeting, panel members commended the study investigators and Janssen for that new work. But they still voted against approval, noting that the missing data remained a problem, the P value for the primary endpoint was not low enough to support approval based on a single trial, and concerns continued about bleeding risk.

The additional work “didn’t really add in a substantial way to the primary endpoint analysis,” explained advisory panel member Dr. Philip Sager. Overall, the study “wasn’t robust enough in terms of statistical significance to be considered as a positive study,” added Dr. Sager, chair of the scientific programs committee at the Cardiac Safety Research Consortium, San Francisco.

The FDA has approved rivaroxaban for several indications, including reduction of the risk of stroke and systemic embolism in nonvalvular atrial fibrillation, treatment of deep vein thrombosis, and prevention of deep vein thrombosis after hip or knee replacement surgery.

Janssen will work with the FDA to address the questions raised at the meeting, according to a statement issued by the Johnson & Johnson subsidiary.

In May 2013, European Union drug regulators approved an ACS indication for rivaroxaban, to prevent atherothrombotic events (cardiovascular death, myocardial infarction, or stroke) after an ACS in adults with elevated cardiac biomarkers, at a dose of 2.5 mg twice a day, co-administered with acetylsalicylic acid alone or with acetylsalicylic acid plus clopidogrel or ticlopidine.

The FDA usually follows the recommendations of its advisory panels. Advisory panel members have been cleared of potential conflicts related to the meeting topic. Occasionally, a panelist is given a waiver, but no waivers were given at this meeting.

 

http://www.ecardiologynews.com/specialty-focus/acute-coronary-syndromes/single-article-page/fda-panel-rejects-rivaroxaban-again-for-acute-coronary-syndrome/1e39b163a23e41d43cb9d885dd68c68f.html

 

 

Mild coronary artery disease is gender blind

CHICAGO – Men and women may not really be all that different when it comes to mild coronary artery disease.

A prospective, multinational registry analysis found that 1.2% of women and 1.1% of men with mild, nonobstructive coronary artery disease on coronary CT angiography experience a major adverse cardiovascular event, either heart attack or death, each year.

For those free of coronary artery disease (CAD), the event rate was 0.3% for both sexes, Dr. Jonathon A. Leipsic reported at the annual meeting of the Radiological Society of North America.

Women’s heart disease is typically viewed as different from men’s heart disease, in part because of women’s unique presenting symptomatology. Studies such as the Women’sHealth Initiative have also reported that women with nonspecific or atypical chest pain have a twofold greater risk for nonfatal MI.

Importantly, all prior data has been reliant on invasive coronary angiography for anatomical coronary assessment, observed Dr. Leipsic, codirector of advanced cardiac imaging, Providence Health Care Heart Center at St. Paul’s Hospital, Vancouver, B.C.

The current analysis, however, used data from the prospective CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) registry, which tracks roughly 28,000 individuals in North America, Europe, and Asia who have undergone coronary CT angiography.

The results represent a major shift in thinking, Dr. Leipsic said in an interview.

“What we realize is that CT identifies mild disease in the wall in a way that the invasive angiogram does not,” he said. “So suddenly, when you say you have a normal invasive angiogram, there may still be mild disease in the arteries, whereas when you have a normal CT in a woman, our data would suggest that those women do very well, even if they have symptoms.”

Dr. Leipsic and his associates identified 18,158 patients in the CONFIRM registry with no disease or mild CAD with less than 50% stenosis. Propensity matching for risk factors, chest pain, and extent of disease left 11,462 patients.

Their average age was 55 years, 34% were asymptomatic, 45% had hypertension, 12% were diabetic, and 18% were current smokers.

Of these, 37 had an MI; 120 died; and 7 had an MI and died (1.4%).

The annual major adverse cardiovascular event (MACE) rate was 0.6% overall, and was significantly different between patients with a normal CT and those with nonobstructive disease (0.3% vs. 1.1%), Dr. Leipsic said.

“This mild disease we see on CT is not just incidental,” he said during a press briefing at the meeting. “It actually identifies patients who are at increased risk of having a heart attack and dying, with an increased risk of 1.84 for the overall cohort (P = .001).”

Notably, 3-year MACE-free survival was similar among men and women without coronary plaque on CT as well as those with non-obstructive disease.

Dr. Leipsic commented that detractors of the data have argued that the analysis failed to focus on women at the greatest risk – those with atypical symptoms. A further sub-analysis, however, based on the presence or absence of symptoms and the type of symptoms (nonanginal chest pain, atypical angina, and typical angina), once again “found that men and women behave similarly,” he said.

Event rates were lower in men and women with normal CT scans and elevated in both sexes in the setting of nonobstructive disease, “regardless of the nature of chest pain and even in the absence of chest pain,” he noted.

Press briefing moderator Dr. Candice Johnstone of the Medical College of Wisconsin, Milwaukee, said in an interview, “Observational studies have limits, but at the same time, I think it may be a paradigm shift, in that it may be a new tool in our toolbox for people at lower risk of heart disease to avoid an invasive procedure.”

Dr. Leipsic reported financial relationships with several entities including GE Healthcare, HeartFlow, Edwards LifeSciences, and TC3.

 

http://www.ecardiologynews.com/specialty-focus/acute-coronary-syndromes/single-article-page/mild-coronary-artery-disease-is-gender-blind/af896023058856d37e5da374caaee515.html?tx_ttnews%5BsViewPointer%5D=1

 

Picture courtesy of www.cdc.gov

 

 

 

Blood pressure control tied to decline in stroke mortality over past 50 years

Antihypertensive therapy is probably the main reason why stroke fatalities have dropped dramatically in the United States over the past 50 years, according to an American Heart Association study published Dec. 5 in Stroke.

Despite an aging and heavier population, “the accelerated decline in stroke mortality that began in the 1970s is consistent with the aggressive hypertension treatment and control strategies implemented in that period. … The decrease in blood pressure with drug therapy … appears to be the major determinant of reduction in the risk of stroke and stroke deaths,” wrote lead author Dr. Daniel Lackland, professor of epidemiology at the Medical University of South Carolina, Charleston, and his colleagues (Stroke 2013 Dec. 5 [doi:10.1161/01.str.0000437068.30550.cf]).

Statins, diabetes drugs, public health efforts, increased research, improved imaging, and quicker and better stroke treatment, among other things, have helped, too. People have also begun to lose weight, cut salt from their diets, and eat and smoke less.

But when it comes to accounting for the stroke mortality rate reduction from 88/100,000 in 1950 to 23/100,000 in 2010 – a reduction that holds across racial, age, and gender lines – the evidence is strongest for hypertension control, the authors said.

“Although the decline in stroke mortality in the United States started at the beginning of the 20th century, decades before hypertension treatment, the slope of the decline in mortality accelerated significantly after the introduction of tolerable antihypertensive drug therapy in the 1960s,” they wrote. Stroke is now the fourth leading cause of death in the United States, instead of the third, and both recurrent and first-time strokes are down. Europe has had a similar decline.

Although great racial disparities still exist in stroke mortality, particularly for blacks, “the decline in stroke mortality for all racial/ethnic groups has reduced the magnitude of the racial/ethnic gap in stroke mortality risks and likewise the variation in stroke mortality by geographic area, with particular emphasis in the Stroke Belt,” Dr. Lackland and his colleagues wrote.

“The decline is real, not a statistical fluke or the result of more people dying of lung disease, the third leading cause of death,” Dr. Lackland said in a statement. It’s also not due to changes in billing codes, diagnostic improvements, death certificate causes of death, or other factors the team considered. Instead, it is “one of the major public health successes of the past 50 years,” the authors wrote.

The findings are based on literature reviews, morbidity and mortality reports, clinical and public health guidelines, expert opinion, and other sources.

The authors noted that “increased application of advanced neuroimaging … might improve the diagnosis of milder, less-fatal strokes over time. This would result in an apparent decline in the stroke case-fatality rate, solely as a result of improved detection. However, this should not result in a change in stroke mortality over time unless technological advances improve the diagnosis of more severe, fatal strokes also, which seems unlikely.”

Dr. Lackland said he had no relevant financial disclosures. One of the 13 authors on the paper is a speaker and consultant for Allergan and a consultant for Reata.

http://www.ecardiologynews.com/single-view/blood-pressure-control-tied-to-decline-in-stroke-mortality-over-past-50-years/fc57a0e668c105d151ba383c265cdace.html

Successful anti-TNF therapy may cancel excess coronary risk in RA

SAN DIEGO – Rheumatoid arthritis patients with a good response to tumor necrosis factor inhibitor therapy when assessed roughly 5 months into treatment had an acute coronary syndrome risk during the next 2 years that was no different than that of the matched general population in a large, Swedish national registry study.

“We could see that the risk of acute coronary syndrome in the TNF inhibitor–exposed population was doubled in the first year compared to the general population. But all this increased risk was carried by patients with a moderate or nonresponse to therapy. We saw no difference in risk between the general population and patients with a good response to treatment. My belief is that this benefit is not due to the TNF inhibitor as such, but rather it’s the control of inflammation that is crucial,” Dr. Lotta Ljung said at the annual meeting of the American College of Rheumatology.

‘Good response’ was defined in this study via the EULAR response criteria: that is, a greater than 1.2-point improvement in the widely used Disease Activity Score 28 (DAS28) over baseline to a score of 3.2 or less at the 5-month evaluation.

Dr. Ljung, a senior consultant in rheumatology at Umea (Sweden) University Hospital, presented two analyses drawn from the Swedish Biologics Register, a national registry that captures 90% of all Swedes on biologic therapy for rheumatoid arthritis (RA). The study population included 7,704 RA patients with no history of ischemic heart disease when they started on their first TNF inhibitor during 2001-2010. They were matched by age, gender, and location to 23,112 RA patients who never took a biologic agent and to a second matched control group comprised of 38,520 individuals in the general population.

The crude incidence rate of acute coronary syndrome (ACS) in patients actively on TNF inhibitor therapy throughout follow-up was 5.7 events per 1,000 person-years, compared with 8.6 per 1,000 in biologic-naive RA patients and 3.3 per 1,000 in the matched general population.

In a fully adjusted Cox multivariate regression analysis factoring in socioeconomic variables, RA duration, joint surgery, and baseline atherosclerotic disease and other comorbid conditions, patients on anti-TNF therapy had a highly significant 27% reduction in ACS risk, compared with biologic-naive RA patients.

Nonetheless, patients on TNF inhibitor therapy remained at an adjusted 1.5-fold increased risk of ACS, compared with general population controls. However, this was significantly lower than the 2.3-fold elevated risk in biologic-naive RA patients.

In a separate analysis, the investigators took a closer look at the Swedish Biologics Register subgroup of the 4,931 RA patients on anti-TNF therapy for whom EULAR response data 5 months into treatment were available. Thirty-eight percent of these patients had a EULAR good response, 37% had a moderate response, and 25% had no response.

During 2 years of follow-up starting at the time of the EULAR response evaluation, the crude incidence rate of ACS among all TNF inhibitor–exposed RA patients, with close to 8,600 person-years of follow-up, was 6.9 cases per 1,000 person-years, compared with 3.4 per 1,000 among the matched general population controls. In an adjusted multivariate regression analysis, the ACS risk was 1.94-fold greater in moderate responders to anti-TNF therapy than in the general population and 2.53-fold greater in the nonresponders, but not significantly different between good responders and controls.

In addition, patients with an erythrocyte sedimentation rate (ESR) below 20 mm/hour at the time of their EULAR response evaluation had a subsequent 66% lower 1-year risk of ACS than did those with a higher ESR. And patients with a DAS28 remission at the 5-month evaluation – that is, a DAS28 below 2.6 – had a 79% lower ACS risk than did those with a DAS28 of 2.6 or above.

“This is dramatic,” Dr. Ljung said in an interview. “I think it’s the first time we see a population in our RA cohorts that doesn’t have any proven cardiovascular risk increase compared with the general population. But it raises additional questions, of course, such as who are these patients who receive the good response: Is it due to factors related to their disease or background that gives them the opportunity to have the good response? We adjusted for a number of factors, but still …”

She added that these studies contain two key take-home messages for rheumatologists: “I think the first thing for us to do is to treat our patients’ inflammation perfectly using traditional and biologic DMARDs. And the second thing is to be more aware of the traditional risk factors and start modifying those more aggressively for our patients.”

The Swedish Biologics Register is funded by the Swedish Rheumatology Association, with support from half a dozen pharmaceutical companies. Dr. Ljung disclosed ties with AbbVie and Bristol-Myers Squibb.

http://www.ecardiologynews.com/single-view/successful-anti-tnf-therapy-may-cancel-excess-coronary-risk-in-ra/b5c011441103b562af236684c1920cf3.html

The heart’s intrinsic pacemaker

A specific cell population is responsible for ensuring that our heartbeat remains regular. LMU researchers have now elucidated the mode of action of one of the crucial components of the heart’s intrinsic pacemaker.

The heart possesses a pacemaker of its very own. Specialized pacemaker cells in the so-called sinoatrial node in the left ventricle of the heart control its rate of contraction and relaxation by orchestrating a recurring sequence of electrical signals. Specific proteins known as HCN channels, which are located in the surface membranes of pacemaker cells, play a central role in the generation and transmission of these signals. These proteins function as pores for the passage of electrically charged atoms (ions) across the cell membrane. Because the pore diameter can be regulated, the channels can control the flow of ions across the membrane, and thus determine the difference in electrical potential between the inner and outer surfaces of the cell. Cyclical changes in this parameter give rise to autonomously generated, rhythmic electrical impulses that dictate heartbeat and cardiac rhythmicity.

HCN channels are found primarily in the heart and in the brain, and come in four subtypes, HCN1-4. HCN4 is responsible for about 80% of the total ion current that passes through HCN channels in the sinoatrial node. The other 20% is carried by HCN1 and HCN2. “But while the functions of HCN2 and HCN4 in the sinoatrial node have been extensively studied, the impact of HCN1 on heart rate has so far remained unknown,” says Professor Christian Wahl-Schott of the Department of Pharmacy at LMU, who has now closed this gap in our knowledge of the heart’s intrinsic pacemaker.

Wahl-Schott and his team and also researchers from Professor Martin Biel’s group, tackled the problem by using a mouse strain in which the HCN1 channels in the cells of the sino-atrial node are defective. With the aid of this new experimental model, they were able to demonstrate, for the first time, that HCN1 is involved not in generating the electrical impulse but also in its propagation within the node. Defects in HCN1 function compromise the normal operation of the pacemaker. This results in bradycardia ­- a pathological reduction in heart rate – and increases the incidence of arrhythmias. As a consequence, overall cardiac output is significantly reduced. “We were also able to confirm these effects in vivo by means of telemetric electrocardiography,” Wahl-Schott adds.

Defects in cells of the sino-atrial node are associated with sudden cardiac arrest, and more than half of all implantations of artificial pacemakers worldwide are carried out on patients who suffer from such conditions. But the new findings regarding the role of HCN1 in the regulation of heart function are actually of clinical interest for two reasons. On the one hand, this channel subtype offers a promising target for drugs designed to normalize heartbeat frequency. However, HCN1 is also found in nerve cells in the brain, where it likewise acts to control rates of neural firing. This explains why HCN1 blockers are under consideration for use in the treatment of epilepsy, chronic pain and depression. “In light of our results, the potential effects of HCN1 blockers on cardiac function should be carefully assessed before such agents are used in other contexts,” Wahl-Schott warns.

http://www.medicalnewstoday.com/releases/268746.php

My Entry into the Leading Physicians of the World

Hey Everyone!  Check out my official entry into the Leading Physicians of the World:

“Steven S. Shayani, MD, FACC, FASNC, Represents New York with Inclusion into Renowned Publication The Leading Physicians of the World…”