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An Extensive UCSF Study Questions Previous Study’s Analytic Methods

A popular smoking cessation medication has been under a cloud of suspicion ever since the Canadian Medical Association Journal (CMAJ) published a study July 2011 reporting “risk of serious adverse cardiovascular events associated with varenicline.” Varenicline, also known as Chantix, blocks the pleasant effects of nicotine on the smoker’s brain and lessens nicotine withdrawal symptoms.

UCSF researchers, however, question the way the previous study was conducted, and their new analysis, scheduled to be published May 4 in BMJ, reaches a very different conclusion.

“We found no clinically or statistically significant increase in serious adverse cardiovascular events associated with using varenicline,” said lead author Judith J. Prochaska, PhD, MPH, an associate professor in UCSF’s Department of Psychiatry and researcher with the Center for Tobacco Control Research and Education. “The findings from 22 trials with more than 9,200 participants indicate a difference in risk of only 0.27 percent between those on varenicline versus placebo, or about a quarter of one percent.”

Prochaska identified the need for the re-analysis after reading the CMAJ publication and finding the conclusion inconsistent with the small differences within trials. Prochaska had received an “investigator-initiated research award” from Pfizer, the maker of Chantix, that spring for a separate study of varenicline in hospitalized smokers, many with heart disease. Prochaska says she was compelled to more closely examine the data to quantify the level of risk before using the medication on UCSF patients.

DIFFERENCES IN META-ANALYTIC METHODS

Prochaska and Joan F. Hilton, ScD, MPH, a professor in UCSF’s Department of Epidemiology & Biostatistics, conducted the new study, which, like the prior one, used meta-analytic statistical techniques to combine results from different trials of varenicline with tobacco users. The UCSF and prior analysis, however, differed in several fundamental ways.

The previous study, led by Sonal Singh, MD, MPH, assistant professor of medicine at Johns Hopkins University, looked at a sample size of 8,216 patients in 14 trials and ¬¬¬reported a 72 percent (relative) increase in risk of heart attack or other serious heart problems.

The UCSF analysis included 22 double-blind, randomized controlled trials with 9,232 participants. More than half of the studies included participants with active or past history of cardiovascular disease. Eight trials had no events. The UCSF study found a 0.27 percent (absolute) risk difference, which it determined was neither clinically nor statistically significant.

“We identified eight separate trials with nearly 1,600 tobacco users randomized to varenicline or placebo that did not have a single serious cardiovascular event,” Prochaska said. “This information is meaningful and the Singh analysis excluded these trials.”

UCSF researchers say varenicline lasts in the body about seven days after a person stops using the medication. The new analysis examined events occurring during the drug treatment window or within 30 days after a patient stopped using the drug, rather than the entire trial period, which in many cases was a year in Singh’s study.

“The longer you follow heavy, long-term tobacco users – and in these studies, the average participant smoked a pack a day for 25 years – the more likely you will see serious cardiovascular events related to their compromised health,” Prochaska said. “In addition, 13 of the 14 studies in the Singh analysis experienced greater attrition in the placebo group than in the test group, which could inflate the treatment effect.”

ABSOLUTE DIFFERENCE VS. RELATIVE DIFFERENCE

Singh’s study found that 1.06 percent of those who took varenicline had serious heart-related complications, compared to 0.82 percent of the placebo group. Although the simple absolute difference was only 0.24 percent – similar to the UCSF study finding based on meta-analytic methods – Singh’s paper reported the weighted, relative difference, which was 72 percent.

“What made the headlines is this claim of a huge increase, but it’s a relative measure; it’s a unit-less measure,” Prochaska said. “And so if you increase something small by a little bit, you can claim that it’s a 72 percent increase, but that obscures the fact that it’s still a very small risk.”

“For someone not accustomed to these measures, it might not be obvious that the 72 percent increase was relative to a very small base – interpretations the Singh study didn’t stress,” Hilton said.

The new meta-analysis provides a more comprehensive examination of varenicline by presenting and comparing the four most relevant summary measures for this type of analysis.

“Among these, we found that the methods used by Singh and colleagues produced the most extreme estimates of treatment effect,” said Hilton. “We identified the specific conditions under which this statistic is inflated. We recommended the summary based on the (absolute) risk difference because it is methodologically appropriate in our setting and gives a clear quantitative sense of the excess risk.”

SMOKING AND CARDIOVASCULAR RISK

Cardiovascular disease is the leading cause of death among smokers. Tobacco use also increases a person’s risk of stroke, cancer and lung disease.

“One of the most important things you can do for your heart is to quit smoking,” Prochaska said. “Clinical practice guidelines recommend the use of FDA medications to quit smoking. All medications carry some risk; however, we hope the FDA and other experts compare the Singh analysis to ours to determine what action, if any, should be taken with regard to varenicline and cardiovascular risk. Tobacco is a deadly addiction, and patients need effective treatments.”

Funding for this meta-analysis was provided by grants to Prochaska from the State of California Tobacco-Related Disease Research Program (TRDRP) and the National Institute on Drug Abuse.

Newswise — DALLAS – Oct. 25, 2011 – A simple blood test could someday quantify a smoker’s lung toxicity and danger of heart disease, researchers at UT Southwestern Medical Center have found.

Nearly one in five adults in the U.S. smoke, and smoking-related medical expenses and loss of productivity exceeds $167 billion annually, according to the Centers for Disease Control and Prevention. Levels of a lung protein found in the blood of smokers could indicate their risk of dangerous plaque buildup in blood vessels, said Dr. Anand Rohatgi, assistant professor of internal medicine at UT Southwestern and co-lead author of the study available in Arteriosclerosis, Thrombosis, and Vascular Biology, a publication of the American Heart Association.

“We now are close to having a blood test to help measure the smoking-related effects that contribute to atherosclerotic heart disease,” Dr. Rohatgi said. “Smoking is one of the biggest contributors to the development of heart disease.”

Smokers are at an increased risk of heart attack, stroke and dying from heart disease, but the risk varies among individuals. Until this study, there had been no simple blood test to measure the varied effects of smoking on heart disease.

Researchers determined the amount of circulating pulmonary surfactant B (SP-B), a protein found in damaged lung cells, in more than 3,200 Dallas Heart Study participants ages 30 to 65. The Dallas Heart Study was a groundbreaking investigation of cardiovascular disease that first involved more than 6,100 Dallas County residents who provided blood samples and underwent blood vessel scans with magnetic resonance imaging and computerized tomography.

The researchers found that smokers who had higher levels of SP-B also had more buildup of dangerous plaque in the aorta – the largest artery in the body, with branches leading to the abdomen, pelvis and legs.

The test is still being evaluated and is not available for commercial use. The next step, said Dr. Rohatgi, is to investigate whether SP-B causes atherosclerosis or is simply a marker of the disease, and to determine whether decreasing levels of SP-B will improve heart disease outcomes.

Other UT Southwestern researchers involved in the study were co-lead author Dr. Ann Nguyen, resident in internal medicine; Dr. Christine Garcia, assistant professor in the Eugene McDermott Center for Human Growth and Development and in internal medicine; Colby Ayers, faculty associate in clinical sciences; Dr. Sandeep Das, assistant professor of internal medicine; Dr. Susan Lakoski, assistant professor of internal medicine; Dr. Jarett Berry, assistant professor of internal medicine; Dr. Amit Khera, associate professor of internal medicine; Dr. Darren McGuire, associate professor of internal medicine; and Dr. James de Lemos, professor of internal medicine.

The study was funded by the Donald W. Reynolds Foundation and the National Institutes of Health. Alere provided assay measurements.

(Reuters) – Pfizer’s stop-smoking drug Chantix can lead to a small increase in cardiovascular problems such as heart attacks for patients who already have cardiovascular disease, U.S. drug regulators said on Thursday.

The Food and Drug Administration is changing the label for Chantix after reviewing the results of a clinical trial.

An independent randomized trial of 700 smokers with cardiovascular disease who were treated with Chantix or a placebo showed that Chantix was effective in helping patients quit smoking for as long as one year.

However, patients who took the pill were also slightly more likely to have a heart attack or other adverse cardiovascular event versus patients on a placebo.

Many smokers who try to quit do so to prevent the risk of heart attacks, which may now be associated with Chantix.

“The known benefits of Chantix should be weighed against its potential risks when deciding to use the drug in smokers with cardiovascular disease,” the FDA said in a statement.

The FDA said it is also requiring Pfizer to evaluate the cardiovascular safety of Chantix by conducting a large, combined analysis of randomized, placebo-controlled trials.

Pfizer’s non-nicotine pill has already come under fire for psychiatric side effects, which have crimped global sales and prompted the FDA to issue a restrictive “black box” warning label for the drug.

Investors had high hopes for the drug — called Champix in Europe — when Pfizer first launched its smoking-cessation aid in 2006, but reports of serious side effects have prevented strong sales growth.

Annual sales are now about $800 million, making the pill a moderate-sized product for the world’s biggest drug maker.

Chantix has been associated with agitation, depression and suicidal thoughts, and, in clinical trials, linked with nightmares. Psychiatric symptoms have occurred in people without a history of mental illness and have worsened in people who already had mental illness.

(Reporting by Anna Yukhananov; editing by Dave Zimmerman)

WASHINGTON, DC (March 18, 2011) – Finding that the availability of menthol cigarettes increases the number of children and African Americans who smoke, the Food and Drug Administration’s Tobacco Products Scientific Advisory Committee today concluded, “Removal of menthol cigarettes from the marketplace would benefit public health in the United States.”

We strongly support the committee’s findings and conclusions, which are based on an exhaustive review of the scientific evidence regarding the public health impact of menthol cigarettes. We urge the FDA to implement the committee’s recommendation in a way that maximizes the public health benefits.

The committee based its recommendation on findings that menthol cigarettes increase the number of children who experiment with cigarettes and the number of children who become regular smokers, increasing overall youth smoking. It also concluded that the availability of menthol cigarettes reduces smoking cessation, especially among African-Americans, and increases the overall prevalence of smoking among African Americans. It found that “menthol cigarettes are marketed disproportionately to younger smokers” and “disproportionately marketed per capita to African Americans.”

The committee’s conclusions leave no doubt that menthol cigarettes have had a profound adverse impact on public health in the United States, resulting in more smoking and more death and disease from tobacco use. It also leaves no doubt that the tobacco industry is directly responsible for the harm caused by menthol cigarettes because of its targeted marketing of children and African-American and other communities, and its manipulation of menthol cigarettes to appeal to specific target markets.

We applaud and thank the Tobacco Products Scientific Advisory Committee for its thorough review of the scientific evidence regarding menthol cigarettes and its carefully considered and science-based recommendation. The committee has done exactly what Congress directed when it enacted the 2009 law granting the FDA authority over tobacco products. Now the FDA must act expeditiously and implement the committee’s recommendation.

Senate Bill 355 and House Bill 670 propose a Texas statewide smoke-free workplace law

AUSTIN, March 3, 2011 /PRNewswire/ — This week, smoke-free workplace bills were heard in the Texas Senate Committee on Health and Human Services and the Texas House Committee on Public Health. Both committees left the bills pending, which is common in the legislative process.

From my perspective as a researcher in the field of public health, I understand the need for a statewide smoke-free workplace law not only for the sake of customers and employees, but for the Texas economy,” said Phil Huang, MD, MPH, in both hearings. “This statewide law could truly make a positive health and economic impact on our state.”

Senate Bill 355 and House Bill 670, authored by Sen. Rodney Ellis (D-Houston) and Rep. Myra Crownover (R-Denton) respectively, are a result of bipartisan consensus reached after several years of collaboration among many lawmakers and stakeholders.

“I’ve never smoked a cigarette in my life, nor does anyone in my household, but I got lung cancer because of secondhand smoke exposure in the jobs I worked during and after college,” said Trena Stafford, Texas Parent Teacher Association volunteer, in both hearings. “Secondhand smoke has truly hurt me and my family.”

Secondhand smoke kills 46,000 Americans due to heart disease and 3,400 Americans due to lung cancer every year. In fact, it is the third leading cause of preventable death in the U.S. and is a known cause of lung cancer, heart disease, premature birth and low birth weight and other health problems. Texas lawmakers now have the opportunity to decrease the impact of these health problems for all Texans.

Momentum for this important legislation continues to grow as the Legislative Session progresses. A 2011 statewide poll indicates 70 percent of Texas voters surveyed support a statewide smoke-free workplace law and a new secondhand smoke economic study shows $404 million in savings to the Texas economy over the biennium. Nearly two-thirds of Republican primary voters surveyed support a statewide smoke-free workplace law.

“Having been a professional musician for the past 40 years, the most difficult aspect of my job has always been the noxious smoke so ubiquitous in nightclubs and bars,” wrote Natalie Zoe, professional musician. “I look so forward to the day I can book gigs anywhere and everywhere in Texas with impunity knowing I can manage to go out and make a living doing what I do without endangering my delicate and precious lungs. What a miserable trade off it has been trading my ability to breathe for my ability to make a living.”

It is important to note that more than 5.5 million Texans living in unincorporated or rural areas of the state cannot be covered by smoke-free legislation because they live in areas of the state that do not have a local government that can pass or enforce this type of legislation. A comprehensive statewide smoke-free workplace law is the only way to protect all Texas employees and customers from secondhand smoke exposure.

Smoke-free workplace legislation has proven to either have no impact or a positive impact on businesses in Texas and throughout the U.S. A 2003 study that provided a comprehensive evaluation of all available studies on the economic impact of smoke-free workplace legislation concluded that these studies report no impact or a positive impact on sales or employment.

“A statewide smoke-free workplace law would benefit businesses all around the state,” said John Korioth, owner of SIX Lounge and Hanger Bar in Austin at a Smoke-Free Texas event last week. “The law would positively impact employees’ morale and productivity, and customers will appreciate going home wearing clothes that don’t stink of cigarette smoke.”

Twenty-nine other states and 34 Texas cities have enacted comprehensive smoke-free legislation similar to Senate Bill 355 and House Bill 670. A statewide smoke-free workplace law would provide clean indoor air to all 25 million Texans: 5.6 percent of the U.S. population.

“A statewide smoke-free workplace law would improve the health of Texas employees and customers,” said Joel Romo, senior director of government relations for American Heart Association. “Without a statewide law, millions of Texans will remain susceptible to the dangers of secondhand smoke exposure, and business owners and employees will miss out on the economic benefits the law would bring.”