Archive for October, 2011

HPV Vaccine for Boys

Wednesday, October 26, 2011 // Uncategorized

Gardasil has been in use for several years for preventing HPV in women.  Human papilloma virus causes cervical cancer and cancer of the head and neck.  It also causes venereal warts.  There was a lot of controversy when it was released, but we give other vaccines for diseases that cause cancer like Hepatits B.  There has been considerable interest in preventing HPV in young men by immunizing them with Gardasil.  It was approved by the FDAin 2009, but many insurances don’t cover it because there was not a strong recommendation to give it.  Now the Advisory Committee on Immunization Practices has recommended it.  The articlebelow  deals with the announcement, but focuses on it’s effectiveness (published today in The New England Journal of Medicine) in preventing anal cancer.  I have given the first two doses  to my son and will make sure he gets the third dose.  My concern is about preventing venereal warts as well as preventing cancer of the head and neck.  Previously these types of cancer which include tongue, tonsils, esophagus and others was caused by smoking and alcohol.  Now most of these cancers are caused by HPV.  I also plan to give the vaccine to my daughter.

Panel recommends that 11- and 12-year-old boys get the HPV vaccine; now given to girls

By Associated Press, Published: October 25

ATLANTA — A government panel wants young boys as well as girls to get the controversial HPV vaccine, in part to prevent them from spreading the sexually transmitted virus to girls.

The HPV vaccine has been recommended for young girls to protect them against cervical cancer and genital warts for the last five years. But the vaccine has been slow to catch on — only about a third of adolescent girls have gotten all three shots.

Experts say the HPV vaccine could protect boys against genital warts and some kinds of cancers. But they also say vaccinating 11- and 12-year old boys could help prevent them from spreading the human papilloma virus to girls.

The Advisory Committee on Immunization Practices made the recommendation Tuesday in a unanimous vote. Federal health officials usually adopt what the panel says and asks doctors and patients to follow the recommendations.

The vaccine has been licensed for use in boys for two years but Tuesday’s vote was the first to strongly recommend routine vaccination. Officials acknowledged the disappointing rate in girls encouraged them to take a new, hard look.

But if the expensive HPV vaccine has been a tough sell to the parents of girls, it may be even tougher for boys.

Last year, just 49 percent of adolescent girls had gotten at least the first of the recommended three HPV shots. Only a third had gotten all three doses.

“Pretty terrible,” said Dr. Anne Schuchat, a U.S. Centers for Disease Control and Prevention administrator who oversees the agency’s immunization programs.

She attributed the low rates for girls to confusion or misunderstanding by parents that they can wait until their daughter becomes sexually active. It only works if the shots are given before a girl begins having sex.

The vaccine is approved for use in boys and girls ages 9 to 26; but it is usually given to 11- and 12-year olds when they are scheduled to get other vaccines.

The committee also recommended the vaccination for males 13 through 21 years who have not been vaccinated previously or who have not completed the three-dose series.

Tuesday’s vote follows recent studies that indicate the vaccine prevents anal cancer in males. A study that focused on gay men found it to be 75 percent effective. But while anal cancer has been increasing, it’s still a fairly rare cancer in males, with only about 7,000 cases in the U.S. each year that are tied to the strains of viruses targeted in the HPV vaccine. In contrast, about vaccine-preventable 15,000 cervical cancers occur annually.

Some feel it’s unlikely that most families will agree to get their sons vaccinated primarily to protect girls. The threat of genital warts hasn’t been persuasive yet, either: Some data suggest that less than 1.5 percent of adolescent males have gotten the vaccine.

Its use against anal cancer may not be much of a selling point, said Dr. Ranit Mishori, a family practice doctor in Washington, D.C., and an assistant professor at the Georgetown University School of Medicine.

Some parents may say “’Why are you vaccinating my son against anal cancer? He’s not gay! He’s not ever going to be gay!’ I can see that will come up,” said Mishori, who supports the committee’s recommendation.

There are two vaccines against HPV, but Tuesday’s vote applies only to Merck & Co.’s Gardasil, which costs $130 a dose. The other vaccine wasn’t tested for males.

An estimated 50 percent to 80 percent of men and women are infected with HPV in their lifetimes, although most clear the infection without developing symptoms or illness, according to the CDC.

___

Online:

HPV info: http://www.cdc.gov/hpv/

Copyright 2011 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

 

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Two More Strikes Against Supplements

Thursday, October 13, 2011 // Uncategorized

Health doesn’t come in a pill.  The first of the latest two studies deals with mortality in women who take supplements from The Archives of Internal Medicine.  The second is the risk of prostate cancer in men taking Vitamin E and their risk of prostate cancer from JAMA.  Bottom Line: Supplements are not a substitute for a healthy diet and taking dietary supplements is not risk free.

LESS IS MORE
Dietary Supplements and Mortality Rate in Older Women

The Iowa Women’s Health Study

Jaakko Mursu, PhD; Kim Robien, PhD; Lisa J. Harnack, DrPH, MPH; Kyong Park, PhD; David R. Jacobs Jr, PhD

Arch Intern Med. 2011;171(18):1625-1633. doi:10.1001/archinternmed.2011.445

Background Although dietary supplements are commonly taken to prevent chronic disease, the long-term health consequences of many compounds are unknown.

Methods We assessed the use of vitamin and mineral supplements in relation to total mortality in 38 772 older women in the Iowa Women’s Health Study; mean age was 61.6 years at baseline in 1986. Supplement use was self-reported in 1986, 1997, and 2004. Through December 31, 2008, a total of 15 594 deaths (40.2%) were identified through the State Health Registry of Iowa and the National Death Index.

Results  In multivariable adjusted proportional hazards regression models, the use of multivitamins (hazard ratio, 1.06; 95% CI, 1.02-1.10; absolute risk increase, 2.4%), vitamin B6(1.10; 1.01-1.21; 4.1%), folic acid (1.15; 1.00-1.32; 5.9%), iron (1.10; 1.03-1.17; 3.9%), magnesium (1.08; 1.01-1.15; 3.6%), zinc (1.08; 1.01-1.15; 3.0%), and copper (1.45; 1.20-1.75; 18.0%) were associated with increased risk of total mortality when compared with corresponding nonuse. Use of calcium was inversely related (hazard ratio, 0.91; 95% confidence interval, 0.88-0.94; absolute risk reduction, 3.8%). Findings for iron and calcium were replicated in separate, shorter-term analyses (10-year, 6-year, and 4-year follow-up), each with approximately 15% of the original participants having died, starting in 1986, 1997, and 2004.

Conclusions  In older women, several commonly used dietary vitamin and mineral supplements may be associated with increased total mortality risk; this association is strongest with supplemental iron. In contrast to the findings of many studies, calcium is associated with decreased risk.

This is a summary from Journal Watch followed by the article from JAMA.

Vitamin E Associated with Increased Prostate Cancer Risk
Vitamin E supplements may significantly increase the risk for prostate cancer, according to a JAMA follow-up to a 2008 study.
To test the efficacy of dietary supplements in preventing prostate cancer, researchers originally randomized over 35,000 relatively healthy men to one of four daily regimens: vitamin E (400 IU), selenium, both, or placebo. When no apparent benefit for prostate cancer risk was found, the data monitoring committee recommended stopping the study supplements. The researchers continued following the participants, however, and after roughly 7 years’ total follow-up, men randomized to vitamin E alone showed a 17% relative increase in cancer risk over those on placebo (absolute risk with vitamin E vs. placebo: 10.9 vs. 9.3 cancers per 1000 person-years).
The authors find no apparent biological explanation for the increased risk, and express concern about the widespread use of high-dose vitamin E in the U.S.

Original Contribution
JAMA. 2011;306(14):1549-1556. doi: 10.1001/jama.2011.1437

Vitamin E and the Risk of Prostate Cancer

The Selenium and Vitamin E Cancer Prevention Trial (SELECT)

  1. Eric A. Klein, MD;
  2. Ian M. Thompson, Jr, MD;
  3. Catherine M. Tangen, DrPH;
  4. John J. Crowley, PhD;
  5. M. Scott Lucia, MD;
  6. Phyllis J. Goodman, MS;
  7. Lori M. Minasian, MD;
  8. Leslie G. Ford, MD;
  9. Howard L. Parnes, MD;
  10. J. Michael Gaziano, MD, MPH;
  11. Daniel D. Karp, MD;
  12. Michael M. Lieber, MD;
  13. Philip J. Walther, MD, PhD;
  14. Laurence Klotz, MD;
  15. J. Kellogg Parsons, MD, MHS;
  16. Joseph L. Chin, MD;
  17. Amy K. Darke, MS;
  18. Scott M. Lippman, MD;
  19. Gary E. Goodman, MD;
  20. Frank L. Meyskens, Jr, MD;
  21. Laurence H. Baker, DO

[+] Author Affiliations


  1. Author Affiliations: Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio (Dr Klein); Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio (Dr Thompson); SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington (Drs Tangen and Crowley and Mss Goodman and Darke); Department of Pathology, University of Colorado Health Science Center, Aurora (Dr Lucia); Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland (Drs Minasian, Ford, and Parnes); Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, and the Brigham and Women’s Hospital, Division of Aging, Boston, Massachusetts (Dr Gaziano); Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center/University of Texas, Houston (Drs Karp and Lippman); Department of Urology, Mayo Clinic, Rochester, Minnesota (Dr Lieber); Department of Urology, Duke University Medical Center, Durham, North Carolina (Dr Walther); Department of Urology, Sunnybrook Medical Center, North York, Ontario, Canada (Dr Klotz); Department of Surgery, Moores Cancer Center, University of California San Diego, La Jolla (Dr Parsons); London Health Sciences Center, London, Surgical Oncology, Ontario, Canada (Dr Chin); Swedish Medical Center Cancer Institute, Medical Oncology, Seattle, Washington (Dr Goodman); University of California at Irvine, Department of Medicine, Orange (Dr Meyskens); and University of Michigan, Division of Hematology/Oncology, Ann Arbor (Dr Baker). Dr Karp’s previous affiliation was Beth Israel Deaconess Medical Center, Medical Oncology, Boston, Massachusetts.
  1. Corresponding Author: Eric A. Klein, MD, Glickman Urological and Kidney Institute, Cleveland Clinic, Desk Q10-1, 9500 Euclid Ave, Cleveland, OH 44195 ([email protected]).

More author information

Abstract

Context The initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a statistically nonsignificant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer.

Objective To determine the long-term effect of vitamin E and selenium on risk of prostate cancer in relatively healthy men.

Design, Setting, and Participants A total of 35 533 men from 427 study sites in the United States, Canada, and Puerto Rico were randomized between August 22, 2001, and June 24, 2004. Eligibility criteria included a prostate-specific antigen (PSA) of 4.0 ng/mL or less, a digital rectal examination not suspicious for prostate cancer, and age 50 years or older for black men and 55 years or older for all others. The primary analysis included 34 887 men who were randomly assigned to 1 of 4 treatment groups: 8752 to receive selenium; 8737, vitamin E; 8702, both agents, and 8696, placebo. Analysis reflect the final data collected by the study sites on their participants through July 5, 2011.

Interventions Oral selenium (200 μg/d from L-selenomethionine) with matched vitamin E placebo, vitamin E (400 IU/d of all rac-α-tocopheryl acetate) with matched selenium placebo, both agents, or both matched placebos for a planned follow-up of a minimum of 7 and maximum of 12 years.

Main Outcome Measures Prostate cancer incidence.

Results This report includes 54 464 additional person-years of follow-up and 521 additional cases of prostate cancer since the primary report. Compared with the placebo (referent group) in which 529 men developed prostate cancer, 620 men in the vitamin E group developed prostate cancer (hazard ratio [HR], 1.17; 99% CI, 1.004-1.36, P = .008); as did 575 in the selenium group (HR, 1.09; 99% CI, 0.93-1.27; P = .18), and 555 in the selenium plus vitamin E group (HR, 1.05; 99% CI, 0.89-1.22, P = .46). Compared with placebo, the absolute increase in risk of prostate cancer per 1000 person-years was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination.

Conclusion Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men.

Trial Registration Clinicaltrials.gov Identifier: NCT00006392

Lifetime risk of prostate cancer in the United States is currently estimated to be 16%.1 Although most cases are found at an early, curable stage, treatment is costly and urinary, sexual, and bowel-related adverse effects are common.2 Even men who choose active surveillance as an initial management strategy face anxiety, uncertain prognosis, and a measurable risk of sepsis with follow-up biopsies,3 and more than one-third of those who initially defer therapy are ultimately treated.4,5 With such a high prevalence, risk of morbidity from treatment, and treatment-related costs, primary prevention of prostate cancer is an attractive option.

With considerable preclinical and epidemiological evidence that selenium and vitamin E may reduce prostate cancer risk, we conducted and reported the results of a prospective randomized trial examining the effect of these 2 agents for prostate cancer prevention.6 Coordinated by SWOG, a federally funded cancer research cooperative group, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) began accrual on August 22, 2001, and randomized 35 533 men into 4 groups: selenium with matching placebo, vitamin E with matching placebo, both agents, or placebo.

Based on a preplanned interim analysis, the independent data and safety monitoring committee met on September 15, 2008, and recommended the early discontinuation of study supplements because of lack of efficacy for risk reduction and because futility analysis demonstrated no possibility of benefit to the planned degree with additional follow-up.6

As reported in the initial article,6 with a median follow-up of 5.5 years, the numbers of prostate cancers detected were 473 (hazard ratio [HR], 1.13; 99% CI, 0.95-1.35) for vitamin E; 432 (HR, 1.04; 99% CI, 0.87-1.24) for selenium; 437 (HR, 1.05; 99% CI, 0.88-1.25) for selenium plus vitamin E; and 416 (HR, 1.0) for placebo. Although these results were not statistically significant, the data and safety monitoring committee expressed concern about the increased risk of prostate cancer observed in the vitamin E plus placebo group, which approached statistical significance (P = .06) and a statistically nonsignificant increased risk of type 2 diabetes mellitus in the selenium plus placebo group (P = .16).

Since that time, participant follow-up has continued, allowing observation of additional events. On May 20, 2011, the data and safety monitoring committee reviewed trial data and recommended reporting the finding regarding increased risk of prostate cancer with vitamin E. This recommendation was based on final data collection from the study sites and coincided with the preplanned final analysis at 7 years after the last participant was randomized.

Trial Registration Clinicaltrials.gov Identifier: NCT00006392

Lifetime risk of prostate cancer in the United States is currently estimated to be 16%.1 Although most cases are found at an early, curable stage, treatment is costly and urinary, sexual, and bowel-related adverse effects are common.2 Even men who choose active surveillance as an initial management strategy face anxiety, uncertain prognosis, and a measurable risk of sepsis with follow-up biopsies,3 and more than one-third of those who initially defer therapy are ultimately treated.4,5 With such a high prevalence, risk of morbidity from treatment, and treatment-related costs, primary prevention of prostate cancer is an attractive option.

With considerable preclinical and epidemiological evidence that selenium and vitamin E may reduce prostate cancer risk, we conducted and reported the results of a prospective randomized trial examining the effect of these 2 agents for prostate cancer prevention.6 Coordinated by SWOG, a federally funded cancer research cooperative group, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) began accrual on August 22, 2001, and randomized 35 533 men into 4 groups: selenium with matching placebo, vitamin E with matching placebo, both agents, or placebo.

Based on a preplanned interim analysis, the independent data and safety monitoring committee met on September 15, 2008, and recommended the early discontinuation of study supplements because of lack of efficacy for risk reduction and because futility analysis demonstrated no possibility of benefit to the planned degree with additional follow-up.6

As reported in the initial article,6 with a median follow-up of 5.5 years, the numbers of prostate cancers detected were 473 (hazard ratio [HR], 1.13; 99% CI, 0.95-1.35) for vitamin E; 432 (HR, 1.04; 99% CI, 0.87-1.24) for selenium; 437 (HR, 1.05; 99% CI, 0.88-1.25) for selenium plus vitamin E; and 416 (HR, 1.0) for placebo. Although these results were not statistically significant, the data and safety monitoring committee expressed concern about the increased risk of prostate cancer observed in the vitamin E plus placebo group, which approached statistical significance (P = .06) and a statistically nonsignificant increased risk of type 2 diabetes mellitus in the selenium plus placebo group (P = .16).

Since that time, participant follow-up has continued, allowing observation of additional events. On May 20, 2011, the data and safety monitoring committee reviewed trial data and recommended reporting the finding regarding increased risk of prostate cancer with vitamin E. This recommendation was based on final data collection from the study sites and coincided with the preplanned final analysis at 7 years after the last participant was randomized.

METHODS

Detailed descriptions of the rationale, design, conduct, and initial results of SELECT have been previously published.6​,7 The study enrolled healthy men at average risk of prostate cancer based on a baseline prostate-specific antigen (PSA) of ≤4 ng/mL and normal digital rectal examination (DRE) commencing at age 50 years for black men or at age 55 years for all others. Men were randomized into 1 of 4 groups: selenium (200 μg/d from L-selenomethionine) with matching vitamin E placebo, vitamin E (400 IU/d of all rac -α-tocopherol acetate) with matching selenium placebo, both agents, or matching placebo (Figure 1).

Figure 1.Patient Flow DiagramaSince the primary publication, there was additional review and 1 additional participant was found to have had prior prostate cancer.

 

Participants without prostate cancer were monitored every 6 months with an annual limited physical examination including blood pressure, weight, and smoking status; participants who developed prostate cancer during the study were monitored annually thereafter. Participants were recommended to undergo PSA and DRE testing and prostate biopsy based on the standard of care in their community and in accordance with the participant’s preference. To facilitate adherence, a multivitamin containing no selenium or vitamin E was offered. All participants were required to provide written informed consent and the local institutional review board of each study site approved the study.

At study visits, men were asked about new medical events in the previous 6 months. The primary end point of the study was prostate cancer incidence as determined by routine clinical management and confirmed by central pathology review. Blinded follow-up continued until October 23, 2008, at which time participants discontinued use of study supplements. Prostate cancer status was determined by self-report at each 6-month study visit. Medical records were obtained thereafter and clinical stage and diagnostic method were abstracted. The pathology report and tissue were forwarded to the SELECT central pathology laboratory for confirmation of diagnosis and for assignment of Gleason score. Median baseline and follow-up plasma vitamin E and selenium levels are included in the original report.6

Follow-up continued in an unblinded fashion at study sites from October 2008 until July 2011. The final study site visits included follow-up for study end points and a blood sample from participants diagnosed with prostate cancer. An independent data and safety monitoring committee met yearly commencing with study inception, reviewing data on safety, adherence, and prostate and other cancer diagnoses. On September 15, 2008, the committee recommended reporting initial results related to the lack of efficacy of the agents on prevention of prostate cancer. Since that time the committee has continued to meet yearly via teleconference.

Statistical Analysis

The primary end point was prostate cancer incidence resulting from routine community care. Cancers not centrally confirmed (17% of the total) are included in the analysis. Five prespecified comparisons of the 4 study groups were conducted: selenium vs placebo, vitamin E vs placebo, selenium plus vitamin E vs placebo, selenium vs selenium plus vitamin E, and vitamin E vs selenium plus vitamin E. Although a 1-sided significance level of .005 was specified to test for the preventive effect for each supplement comparison and thus 99% confidence intervals are reported, we have reported 2-sided P values throughout because the comparison of prevention vs increased risk of cancer is a 2-sided question.6

A proportional hazards model was used to compare prostate cancer and other cancer incidence between placebo and each of the 3 study groups with active agents. Men without the end point of interest were censored at their last contact date. An additional analysis was performed on all the data using a variable for selenium supplementation, a variable for vitamin E supplementation, and an interaction term. In all cases, the proportional hazards assumption was evaluated by assessing each study group × time interaction. The cumulative incidence curves for prostate cancer were generated accounting for the competing risk of death.8 A χ2 test was used to test the difference in the relative risk of diabetes. Data were analyzed using SAS version 9.2 (SAS Institute Inc, Cary, North Carolina).

RESULTS

The current report includes data as of July 5, 2011. There are 54 464 additional person-years of follow-up since the primary report, an increase of 23%. A summary of baseline characteristics is displayed in Table 1 and an updated flow diagram in Figure 1. The frequency of use of DRE and PSA is displayed in Table 2; there were no differences between groups in the intensity of PSA testing, absolute PSA levels, PSA change from study entry to year 1, nor rates of testing following study unblinding.

Table 1. Baseline Participant Characteristics

 

Table 2. Diagnostic Testing

 

A total of 521 additional prostate cancers have been diagnosed since the initial report: 113 in the placebo group, 147 in the vitamin E group, 143 in the selenium group, and 118 in the combination group (Table 3). The rate of prostate cancer detection was greater in all treatment groups when compared with placebo but was statistically significant only in the vitamin E alone group (HR, 1.17; 99% CI, 1.004-1.36; P = .008; Table 3). After adjustment for the marginal effects of vitamin E and selenium, the interaction between vitamin E and selenium was statistically significant (P = .02), indicating no increased risk of prostate cancer when vitamin E and selenium were taken together. The risk of Gleason 7 or greater disease was higher for all 3 interventions (vitamin E: HR, 1.16 [99% CI, 0.86-1.58]; selenium: HR, 1.21 [99% CI, 0.90-1.63]; combination: HR, 1.23 [99% CI, 0.91-1.66]) but did not reach statistical significance for any group (Table 3). The elevated risk estimate for vitamin E was consistent across both low- and high-grade disease.

Table 3. Number and Risk of Prostate Cancers

 

The cumulative incidence curves of prostate cancer by supplement group compared with placebo are presented in Figure 2. The difference in rates of prostate cancer between vitamin E and placebo became apparent during the participants’ third year in the trial, at which point the HR was 1.10, and increased slightly each year thereafter. The proportional hazards assumption was reasonable for each study group (all P ≥ .17). The unadjusted absolute increase in risk of cases of prostate cancer per 1000 person-years compared with placebo was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination.

Figure 2.Cumulative Incidence of Prostate Cancer

 

Virtually all men with prostate cancer were without metastases at diagnosis (Table 4). Gleason 6 was the most common grade over all. For those with more aggressive disease, Gleason 7 was the most common score. Stage and grade distributions were similar among groups.

Table 4. Clinical and Pathological Characteristics of Incident Prostate Cancers

 

In the initial SELECT report a statistically nonsignificant increased risk of type 2 diabetes mellitus (as defined by self-report or new use of glitazone medications) was observed in the selenium supplementation group (HR, 1.07). In the updated results the HR is 1.04 and is not statistically significant (P = .34; Table 5). Table 5 also displays updated data on the prespecified secondary end points of lung, colorectal, and total other cancers, deaths, and grade 4 cardiovascular events. There are no statistically significant differences in the HRs between groups, suggesting neither benefit nor harm from dietary supplementation with selenium or vitamin E for these end points.

Table 5. Secondary End Points

 

COMMENT

Prevention of prostate cancer remains an important public health goal because of the relatively high incidence and the high likelihood of curative-intent treatment of this cancer even when indolent disease is present,9 and treatment related costs and morbidity. Although 2 large randomized trials have demonstrated that 5α-reductase inhibitors reduce prostate cancer risk by 20% to 25%,10​,11 the use of these agents is controversial because of concerns related to an observed increased risk of high-grade disease.12 SELECT was designed to assess the effect of selenium and vitamin E alone and in combination as supplements to a normal diet on their ability to prevent prostate cancer in men at average risk. Other randomized studies have shown no benefit to dietary supplementation with selenium, lycopene, or soy in reducing the risk of invasive cancer in men with high-grade prostatic intraepithelial neoplasia on biopsy.13,14

In this article, we report an observation of important public health concern that has emerged with continued follow-up of SELECT participants. With primary end point ascertainment based on contemporary community practice across the United States, Canada, and Puerto Rico using PSA and DRE as indications for biopsy, the risk of prostate cancer at 7 years of median follow-up was increased by 17% in men randomized to supplementation with vitamin E alone, a difference that started to appear about 3 years after randomization. Although there is debate about how to best handle accumulating results after the publication of primary findings and the appropriate threshold for statistical significance, the increased rate of prostate cancer in the vitamin E group was seen as early as 2006 and continued until the present analysis (HRs ranged from 1.12 to 1.17) suggesting that the current results are not an outlier observation due to multiple looks at the data. Extended follow-up with additional events has resulted in narrowed confidence intervals.

A biological explanation for the observed increased risk of prostate cancer in the vitamin E arm is not apparent from these data. The risk does not appear to be due to an increased biopsy rate prompted by changes in DRE, PSA, or unblinding. There was not a statistically significant increased risk of prostate cancer in the vitamin E and selenium combination group (HR, 1.05; P = .46), suggesting that selenium may have a protective effect by dampening the increased risk associated with vitamin E alone, a hypothesis reinforced by the P value (.02) of the interaction term in the marginal analysis. Tests of this hypothesis and other potential explanations for the results will be addressed by analysis of the effects of baseline plasma vitamin E levels and their interaction with baseline plasma and toenail selenium levels from samples collected from participants at study entry. Despite the lack of a mechanistic explanation, the findings show that vitamin E supplementation in the general population of healthy men significantly increases the risk of being diagnosed with prostate cancer.

The current findings of SELECT differ from findings from other large randomized intervention trials that examined the effects of vitamin E supplementation on prostate cancer risk. The Alpha-Tocopherol, Beta Carotene (ATBC) trial reported a 35% risk reduction for prostate cancer in men taking 50 mg/d of vitamin E for a median of 6.1 years,15 although there are important differences with SELECT: (1) the participants of ATBC were all long-term smokers (36 years on average) compared with 43% who had never smoked and 8% current smokers in SELECT; (2) prostate cancer was a secondary end point in ATBC; and (3) men in ATBC were not screened so that prostate cancer was diagnosed at more advanced stages than in SELECT. In the Physicians Health Study II (PHS II) conducted contemporaneously with SELECT, intervention with 400 IU of vitamin E every other day for a median of 8 years had no effect on the incidence of prostate cancer (HR, 0.97; 95% CI, 0.85-1.09; P = .58), although like SELECT there was no effect on total cancer incidence (HR, 1.04; 95% CI, 0.95-1.13; P = .41) or overall mortality (HR, 1.08; 95% CI, 0.98-1.19).16

Furthermore, both ATBC and PHS II were designed and analyzed as factorial trials, so the reported effect of vitamin E is estimated across the secondary factor (beta carotene or vitamin C, respectively). In contrast, SELECT was designed as a 4-group trial because of concerns about the potential interaction of vitamin E and selenium, for which a statistically significant interaction between these agents was indeed observed.

Given that more than 50% of individuals 60 years or older are taking supplements containing vitamin E and that 23% of them are taking at least 400 IU/d17 despite a recommended daily dietary allowance of only 22.4 IU for adult men,18 the implications of our observations are substantial. Consistent with the original SELECT report, longer follow-up did not demonstrate a benefit for selenium or vitamin E supplementation on risk of colorectal or lung cancer or cardiovascular events.

Although modest benefits for vitamin E supplementation have been observed in a limited number of randomized clinical trials for Alzheimer disease19 and (as 1 part of a combination of oral antioxidants) for age-related macular degeneration,20 no benefits were demonstrated for prevention of cardiac events or mortality,21,22​,23 colorectal adenomas,24 respiratory infections in elderly individuals,25 pre-eclampsia in women with type 1 diabetes,26 or prevention or progression of cataracts or macular degeneration.27,28 Moreover, the increased incidence of prostate cancer seen in SELECT, the previously reported increased incidence of lung cancer with high-dose beta carotene in both ATBC15 and the Beta-Carotene and Retinol Efficacy Trial (CARET),29 and the increased risk of colon polyps seen in a trial administering high-dose folate,30 suggest that caution should be used when recommending or studying high doses of micronutrients. As opposed to synthetic pharmaceuticals, these naturally occurring dietary constituents are part of normal physiology, and a U -shaped-dose response curve may exist where either deficiency or supraphysiological doses are harmful.

The findings of SELECT, ATBC, and CARET emphasize the importance of large-scale, population-based, randomized trials in accurately assessing the benefits and harms of micronutrients as dietary supplements. Because a statistically significant interaction was observed between vitamin E and selenium, we believe that caution should be used when designing factorial prevention trials in the future. Although factorial designs are appealing because of their statistical efficiency, interactions can make it difficult to evaluate the underlying effects of each treatment component.31

Furthermore, the fact that the increased risk of prostate cancer in the vitamin E group of participants in SELECT was only apparent after extended follow-up (allowing for additional events) suggests that health effects from these agents may continue even after the intervention is stopped, emphasizing the need for long-term follow-up even in trials closed before the planned intervention period is completed. Consenting SELECT participants have the opportunity to transition to a centralized follow-up study where annual updates to general health and cancer status are obtained either via a mailed questionnaire or data entered by the participant on the SELECT participant Web site, which will allow additional follow-up to further address these issues.

CONCLUSION

Extended follow-up of SELECT participants shows that healthy men with average risk of prostate cancer subjected to contemporary community standards of screening and biopsy who took a common dose and formulation of vitamin E (400 IU/d) have a significantly increased risk of prostate cancer. The observed 17% increase in prostate cancer incidence demonstrates the potential for seemingly innocuous yet biologically active substances such as vitamins to cause harm. The lack of benefit from dietary supplementation with vitamin E or other agents with respect to preventing common health conditions and cancers or improving overall survival, and their potential harm, underscore the need for consumers to be skeptical of health claims for unregulated over-the-counter products in the absence of strong evidence of benefit demonstrated in clinical trials.

Author Information


  1. Author Affiliations: Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio (Dr Klein); Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio (Dr Thompson); SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington (Drs Tangen and Crowley and Mss Goodman and Darke); Department of Pathology, University of Colorado Health Science Center, Aurora (Dr Lucia); Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland (Drs Minasian, Ford, and Parnes); Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, and the Brigham and Women’s Hospital, Division of Aging, Boston, Massachusetts (Dr Gaziano); Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center/University of Texas, Houston (Drs Karp and Lippman); Department of Urology, Mayo Clinic, Rochester, Minnesota (Dr Lieber); Department of Urology, Duke University Medical Center, Durham, North Carolina (Dr Walther); Department of Urology, Sunnybrook Medical Center, North York, Ontario, Canada (Dr Klotz); Department of Surgery, Moores Cancer Center, University of California San Diego, La Jolla (Dr Parsons); London Health Sciences Center, London, Surgical Oncology, Ontario, Canada (Dr Chin); Swedish Medical Center Cancer Institute, Medical Oncology, Seattle, Washington (Dr Goodman); University of California at Irvine, Department of Medicine, Orange (Dr Meyskens); and University of Michigan, Division of Hematology/Oncology, Ann Arbor (Dr Baker). Dr Karp’s previous affiliation was Beth Israel Deaconess Medical Center, Medical Oncology, Boston, Massachusetts.

Corresponding Author: Eric A. Klein, MD, Glickman Urological and Kidney Institute, Cleveland Clinic, Desk Q10-1, 9500 Euclid Ave, Cleveland, OH 44195 ([email protected]).

Author Contributions: Dr Tangen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Klein, Thompson, Tangen, Crowley, P. Goodman, Minasian, Ford, Parnes, Lieber, Walther, Klotz, Lippman, G. Goodman, Baker.

Acquisition of data: Klein, Thompson, Tangen, Crowley, Lucia, P. Goodman, Parsons, Chin.

Analysis and interpretation of data: Klein, Thompson, Tangen, Crowley, P. Goodman, Minasian, Ford, Karp, Klotz, Darke, Lippman, G. Goodman, Meyskens.

Drafting of the manuscript: Klein, Thompson, Tangen, P. Goodman, Lieber, Klotz, G. Goodman, Baker.

Critical revision of the manuscript for important intellectual content: Klein, Thompson, Tangen, Crowley, Lucia, P. Goodman, Minasian, Ford, Parnes, Karp, Walther, Parsons, Chin, Darke, Lippman, Meyskens, Baker.

Statistical analysis: Tangen, Crowley, P. Goodman, Darke.

Obtained funding: Klein, Thompson, Lippman, Baker.

Administrative, technical, or material support: Klein, Thompson, Lucia, Minasian, Parnes, Lieber, Walther, Parsons, Chin, Lippman.

Study supervision: Thompson, Crowley, P. Goodman, Minasian, Ford, Klotz, Lippman, G. Goodman, Baker.

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The New Language of Medicine

Wednesday, October 12, 2011 // Uncategorized

Dr. Hartzband and Dr. Groopman have just published a new book, Your Medical Mind which I have mentioned in previous blogs.  This editorial is from tomorrow’s New England Journal of Medicine.  It reminds me of when I went from being a doctor/physician to a PCP or primary care provider.

The New Language of Medicine

Pamela Hartzband, M.D., and Jerome Groopman, M.D.

N Engl J Med 2011; 365:1372-1373October 13, 2011

Article
References

During our first year of medical school, we spent countless hours learning new words, memorizing vocabulary as if we were studying a foreign language. We discovered that some words that sounded foreign actually represented the familiar: rubeola was measles, pruritus meant itching. Now, we find ourselves learning a new language of medicine filled with words that seem familiar yet feel foreign. Patients are no longer patients, but rather “customers” or “consumers.”1 Doctors and nurses have been transmuted into “providers.” These descriptors have been widely adopted in the media, medical journals, and even on clinical rounds. Yet the terms are not synonymous. The word “patient” comes from patiens, meaning suffering or bearing an affliction. Doctor is derived from docere, meaning to teach, and nurse from nutrire, to nurture. These terms have been used for more than three centuries.

What precipitated the increasing usage of this new vocabulary in medicine? We are in the midst of an economic crisis, and efforts to reform the health care system have centered on controlling spiraling costs. To that end, many economists and policy planners have proposed that patient care should be industrialized and standardized.2 Hospitals and clinics should run like modern factories, and archaic terms such as doctor, nurse, and patient must therefore be replaced with terminology that fits this new order.

The words we use to explain our roles are powerful. They set expectations and shape behavior. This change in the language of medicine has important and deleterious consequences. The relationships between doctors, nurses, or any other medical professionals and the patients they care for are now cast primarily in terms of a commercial transaction. The consumer or customer is the buyer, and the provider is the vendor or seller. To be sure, there is a financial aspect to clinical care. But that is only a small part of a much larger whole, and to people who are sick, it’s the least important part. The words “consumer” and “provider” are reductionist; they ignore the essential psychological, spiritual, and humanistic dimensions of the relationship — the aspects that traditionally made medicine a “calling,” in which altruism overshadowed personal gain. Furthermore, the term “provider” is deliberately and strikingly generic, designating no specific role or type or level of expertise. Each medical professional — doctor, nurse, physical therapist, social worker, and more — has specialized training and skills that are not recognized by the all-purpose term “provider,” which carries no resonance of professionalism. There is no hint of the role of doctor as teacher with special knowledge to help the patient understand the reasons for his or her malady and the possible ways of remedying it, no honoring of the work of the nurse as a nurturer with unique expertise whose close care is essential to healing. Rather, the generic term “provider” suggests that doctors and nurses and all other medical professionals are interchangeable. “Provider” also signals that care is fundamentally a prepackaged commodity on a shelf that is “provided” to the “consumer,” rather than something personalized and dynamic, crafted by skilled professionals and tailored to the individual patient.

Business is geared toward the bottom line: making money. A customer or consumer is guided by “caveat emptor” — “let the buyer beware” — an adversarial injunction and hardly a sentiment that fosters the atmosphere of trust so central to the relationship between doctor or nurse and patient. Reducing medicine to economics makes a mockery of the bond between the healer and the sick. For centuries, doctors who were mercenary were publicly and appropriately castigated, the subjects of caustic characterization in plays by Moliere and stories by Turgenev. Such doctors betrayed their calling. Should we now be celebrating the doctor whose practice, like a successful business, maximizes profits from “customers”?

Beyond introducing new words, the movement toward industrializing and standardizing all of medicine (rather than just safety and emergency protocols) has caused certain terms that were critical to our medical education to all but disappear. “Clinical judgment,” for instance, is a phrase that has fallen into disgrace, replaced by “evidence-based practice,” the practice of medicine based on scientific data. But evidence is not new; throughout our medical education beginning more than three decades ago, we regularly examined the scientific evidence for our clinical practices. On rounds or in clinical conferences, doctors debated the design and results of numerous research studies. But the exercise of clinical judgment, which permitted assessment of those data and the application of study results to an individual patient, was seen as the acme of professional practice. Now some prominent health policy planners and even physicians contend that clinical care should essentially be a matter of following operating manuals containing preset guidelines, like factory blueprints, written by experts.2 These guidelines for care are touted as strictly scientific and objective. In contrast, clinical judgment is cast as subjective, unreliable, and unscientific. But there is a fundamental fallacy in this conception. Whereas data per se may be objective, their application to clinical care by the experts who formulate guidelines is not. This truth, that evidence-based practice codified in clinical guidelines has an inescapable subjective core, is highlighted by the fact that working with the same scientific data, different groups of experts write different guidelines for conditions as common as hypertension and elevated cholesterol levels3 or for the use of screening tests for prostate and breast cancers.4 The specified cutoffs for treatment or no treatment, testing or no testing, the weighing of risk versus benefit — all necessarily reflect the values and preferences of the experts who write the recommendations. And these values and preferences are subjective, not scientific.5

What impact will this new vocabulary have on the next generation of doctors and nurses? Recasting their roles as those of providers who merely implement prefabricated practices diminishes their professionalism. Reconfiguring medicine in economic and industrial terms is unlikely to attract creative and independent thinkers with not only expertise in science and biology but also an authentic focus on humanism and caring.

When we ourselves are ill, we want someone to care about us as people, not as paying customers, and to individualize our treatment according to our values. Despite the lip service paid to “patient-centered care” by the forces promulgating the new language of medicine, their discourse shifts the focus from the good of the individual to the exigencies of the system and its costs. Marketplace and industrial terms may be useful to economists, but this vocabulary should not redefine our profession. “Customer,” “consumer,” and “provider” are words that do not belong in teaching rounds and the clinic. We believe doctors, nurses, and others engaged in care should eschew the use of such terms that demean patient and professional alike and dangerously neglect the essence of medicine.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Source Information

From Beth Israel Deaconess Medical Center and Harvard Medical School — both in Boston.

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Insights into the 1918 Influenza Pandemic

Tuesday, October 11, 2011 // Uncategorized

Here is a summary of an article in Journal Watch which analyzes tissue from soldiers who died during the 1918 pandemic.

Why Was the 1918 Influenza Pandemic So Lethal?

In a case series of influenza-related deaths during and just before the pandemic, all 68 cases had histopathological evidence of severe bacterial pneumonia.

The worldwide influenza epidemic in 1918–1919 caused about 50 million deaths. In an effort to understand why the mortality rate was so high, investigators reexamined preserved lung tissue, stained slides, and records from 68 soldiers stationed at U.S. Army training camps who had died from probable influenza between May and October 1918.

The men had a median age of 27 (range, 18–32), and nine of them had died during the 4 months before the pandemic was identified. Pneumonia or bronchopneumonia with or without influenza had been diagnosed in all 59 men for whom medical records were available.

The 68 cases showed a spectrum of histopathological changes, including features of bronchitis (4/4 with available bronchial tissue), bronchiolitis (39/68), primary influenza viral pneumonia with diffuse alveolar damage (36/68), acute edema (41/68), acute hemorrhage (27/68). In addition, all 68 cases had evidence of severe acute bacterial pneumonia, and bacteria — predominantly gram-positive organisms morphologically consistent with Streptococcus pneumoniae, Streptococcus pyogenes, or Staphylococcus aureus — were found in recut tissue specimens from 63 of 67 cases. These results were concordant with bacterial lung-culture results recorded in 1918 for 44 of the cases. Influenza viral antigens were identified in alveolar lining cells, apical cells of bronchial epithelium, and hyaline membrane material, with no difference between prepandemic and pandemic cases. Analysis of influenza viral RNA from a subset of cases showed a shift from mixed “avian-like” and “human-like” glycan binding specificity in prepandemic cases to “human-like” specificity in pandemic cases.

Comment: These data provide several key insights. First, the pandemic virus was circulating in the U.S. for at least 4 months before the pandemic was recognized. Second, the overall characteristics of influenza infection in the cases studied here were quite similar to those seen in fatal 2009 H1N1 influenza cases and were not suggestive of more-severe viral disease. Finally, mortality was universally associated with concurrent severe bacterial pneumonia, which today should be preventable with immunization or treatable with readily available antibiotics.

Richard T. Ellison III, MD

Published in Journal Watch Infectious Diseases October 5, 2011

Citation(s):

Sheng Z-M et al. Autopsy series of 68 cases dying before and during the 1918 influenza pandemic peak. Proc Natl Acad Sci U S A2011 Sep 27; 108:16416.

So most people died of secondary infections.  The virus was not some lethal supervirus.  We would be able to treat these secondary infections now preventing many deaths.

 

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A Tale of Two Statins

Sunday, October 2, 2011 // Uncategorized

Lipitor (atorvastatin) should soon become generic.  The most potent statin, Crestor (rosuvastatin), is still protected by patent.  If it is not more effective than generic Lipitor, physicians will be pressured to prescribe the less expensive generic. Reduction in the volume of plaque is just one measure of efficacy.

A manufacturer sponsored trial failed to show a greater reduction  reduction in plaque volume by Crestor compared with Lipitor. This is a summary from Journal Watch.

Rosuvastatin Fails to Outperform Atorvastatin in High-Risk Patients
Rosuvastatin (Crestor) is not significantly better than atorvastatin (Lipitor) in slowing the progression of atherosclerosis, according to results from the SATURN trial.
The 2-year trial, conducted by rosuvastatin’s manufacturer, included some 1300 patients with coronary artery disease randomized to daily rosuvastatin (40 mg) or atorvastatin (80 mg). The study’s primary endpoint — change in atheroma volume on intravascular ultrasound — did not differ significantly between the groups, the manufacturer said in a press release, although the absolute numbers favored rosuvastatin.
The findings come in anticipation of generic atorvastatin hitting the market in November, the Wall Street Journal reports.

The following is the manufacturer’s press release.

AstraZeneca announces top-line results from SATURN study

Friday, 2 September 2011

AstraZeneca today announced top-line results from SATURN (Study of Coronary Atheroma by InTravascular Ultrasound: Effect of Rosuvastatin Versus AtorvastatiN). SATURN was designed to measure the impact of CRESTOR (rosuvastatin) 40 mg and atorvastatin 80 mg on the progression of atherosclerosis in high risk patients.

The results for the primary efficacy measure, which was change from baseline in percent atheroma volume (PAV) in a ≥40 mm segment of the targeted coronary artery as assessed by intravascular ultrasound (IVUS), demonstrated a numerically greater reduction in favour of CRESTOR versus atorvastatin but did not reach statistical significance.

For the secondary IVUS measure, which was change from baseline in total atheroma volume (TAV) within the targeted coronary artery, CRESTOR demonstrated a statistically significant reduction compared with atorvastatin.

Tolerability and efficacy of CRESTOR seen in SATURN were in line with previous studies and approved product labelling.

Further data and analyses will be presented by the study’s academic investigators at the American Heart Association Scientific Sessions (AHA) on Tuesday, 15 November.

NOTES TO EDITORS

About SATURN

SATURN is a 104-week, randomized, double-blind, parallel group, multi-center Phase IIIb study of approximately 1,300 patients, investigating the effects of treatment with rosuvastatin 40 mg and atorvastatin 80 mg on atherosclerotic disease burden as measured by IVUS in patients with coronary artery disease.

About PAV and TAV

Percent atheroma volume (PAV) and total atheroma volume (TAV) can be estimated as part of an intravascular ultrasound examination of a coronary artery. PAV and TAV are two different derivatives of the same measurements taken with a tiny ultrasound probe that is inserted inside the coronary artery. In effect, they take the same ultrasound data, but look at the volume of plaques, or fatty deposits, in different ways to represent what is happening in the patient’s artery.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialisation of prescription medicines for gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca.com

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Too Much Care? Newer Treatment for Smoking Cessation

Saturday, October 1, 2011 // Uncategorized

So, actually 52% of physicians thought their patients were getting the right amount of care.

 

Need a Real Sponsor here

  • September 26, 2011, 4:19 PM ET

Many Physicians Feel They’re Delivering Too Much Care

Your doctor may secretly think you’re making too many office visits and getting too many drugs and tests.

A survey of primary-care doctors conducted in 2009 finds that 42% of the 627 respondents believed the patients in their own practice were getting too much care. Just 6% of doctors believed their patients were getting too little care. (The rest thought the level of care was just right.)

And 28% of the doctors thought they themselves were practicing more aggressively than they would prefer to.

The response rate to the mailed survey was 70%, suggesting this is a topic of interest for doctors — as well as for a health-care system struggling to control costs while helping to improve people’s health.

The survey, the results of which were published in the latest Archives of Internal Medicine, found 76% of doctors blamed malpractice worries for their over-aggressive care. The impact of defensive medicine has been debated, but “it is certainly the most widely endorsed external factor cited by physicians,” says Brenda Sirovich, an author of the study and a staff physician and research associate in the Outcomes Group at the VA Medical Center in White River Junction, VT.

Sirovich, also an associate professor of medicine at the Dartmouth Institute for Health Policy and Clinical Practice, notes that 83% of physicians thought they could easily be sued for failure to order a test that was indicated, but only 21% thought they could be sued for ordering a test that wasn’t indicated.

The incentives point toward “when in doubt, do more,” she says.

Some 52% of physicians cited clinical-performance measures, which gauge how closely doctors or institutions adhere to recommended protocols for a certain disease or condition, as a reason for excessive care. “Almost universally, they’re in place to make sure you’re doing enough” for the patient, says Sirovich. Rarely do they attempt to make sure physicians aren’t doing too much.

And 40% of doctors surveyed said inadequate time to spend with patients led them to order tests or refer patients to specialists rather than use other, less-aggressive ways of addressing patients’ issues.

Financial incentives were also cited, but “most thought they affected other physicians,” the study found. Only 3% said financial considerations influenced their own care decisions while 39% said they affected other primary-care doctors and 62% thought they affected sub-specialist physicians.

While the notion that our health-care system delivers too much care to some people is often framed as a cost issue, there’s plenty of reason to believe it can also cause harm, says Sirovich. (Read our Q&A with an author of “Overdiagnosed.” Two of its co-authors, Lisa Schwartz and Steven Woloshin, are also authors of this study.)

Given that so many of these incentives are tied up with the very structure of the malpractice, reimbursement and quality-measurement systems, what can be done? “I don’t think every change has to be sweeping,” says Sirovich. Almost half (45%) of the doctors surveyed estimated that at least 10% of the patients they see on a typical day could be dealt with using an alternative to a full physician’s visit such as a visit with a nurse or an email or phone consultation.

Better reimbursement for those less-intensive ways of following up would help, she says.

And Sirovich notes that “as a profession and as a society, it’s good for us to think about doing a better job of educating patients and the public that more care isn’t necessarily better,” she says. “There’s such a thing as too much.”

Cytisine a Possible Cheaper Approach to Smoking Cessation
Cytisine, a partial nicotine agonist extracted from acacia seeds, sustains smoking cessation better than placebo, according to a New England Journal of Medicine study.
Researchers randomized 740 smokers to 25 days’ treatment with cytisine or matching placebo. The primary outcome, biochemically confirmed smoking cessation at 1 year, was 8.4% with cytisine and 2.4% with placebo.
Gastrointestinal side effects — stomachache, dry mouth, dyspepsia, and nausea — occurred more often with cytisine.
The authors conclude that cytisine’s low cost (about $15 for a course of therapy) “may make it an attractive treatment option for smokers in low-income and middle-income countries.”

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Original Article

Placebo-Controlled Trial of Cytisine for Smoking Cessation

Robert West, Ph.D., Witold Zatonski, M.D., Magdalena Cedzynska, M.A., Dorota Lewandowska, Ph.D., M.D., Joanna Pazik, Ph.D., M.D., Paul Aveyard, Ph.D., M.D., and John Stapleton, M.Sc.

N Engl J Med 2011; 365:1193-1200September 29, 2011

 

Background

Cytisine, a partial agonist that binds with high affinity to the α4β2 nicotinic acetylcholine receptor, is a low-cost treatment that may be effective in aiding smoking cessation. This study assessed the efficacy and safety of cytisine as compared with placebo.

 

Methods

We conducted a single-center, randomized, double-blind, placebo-controlled trial. Participants were randomly assigned to receive cytisine or matching placebo for 25 days; participants in both groups received a minimal amount of counseling during the study. The primary outcome measure was sustained, biochemically verified smoking abstinence for 12 months after the end of treatment. Of 1542 adult smokers screened, 740 were enrolled and 370 were randomly assigned to each study group.

 

Results

The rate of sustained 12-month abstinence was 8.4% (31 participants) in the cytisine group as compared with 2.4% (9 participants) in the placebo group (difference, 6.0 percentage points; 95% confidence interval [CI], 2.7 to 9.2; P=0.001). The 7-day point prevalence for abstinence at the 12-month follow-up was 13.2% in the cytisine group versus 7.3% in the placebo group (P=0.01). Gastrointestinal adverse events were reported more frequently in the cytisine group (difference, 5.7 percentage points; 95% CI, 1.2 to 10.2).

 

Conclusions

In this single-center study, cytisine was more effective than placebo for smoking cessation. The lower price of cytisine as compared with that of other pharmacotherapies for smoking cessation may make it an affordable treatment to advance smoking cessation globally. (Funded by the National Prevention Research Initiative and others; Current Controlled Trials number, ISRCTN37568749.)

 

Supported by a grant from the United Kingdom National Prevention Research Initiative (to Dr. West), which included contributions from the British Heart Foundation, Cancer Research UK, Chief Scientist Office of the Scottish Government Health Directorates, Department of Health, Diabetes UK, Economic and Social Research Council, Research and Development Office of Health and Social Care in Northern Ireland, Medical Research Council, and Welsh Assembly; and by grants from Cancer Research UK (to Dr. West and Mr. Stapleton) and the National Institute for Health Research (to Dr. Aveyard).

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank the members of the Trial Steering Committee (Michael Ussher, Lindsay Stead, Elspeth Lee, Robert Hewings, Martin Edwards, and Dorota Olszak); the members of the Data Monitoring and Ethics Committee (Peter Hajek, Ann McNeill, and Lesley Owen); the doctors (Ewelina Bobek-Pstrucha, Joanna Jonska, Elzbieta Karpinska, Marzena Piasecka, Joanna Surowinska, Ewelina Sliwka, Olga Tronina, and Ewa Wazna), nurses (Teresa Kankiewicz, Mirosława Kleszcz, Katarzyna Marczyk, Elzbieta Milkowska, Malgorzata Pokorska, Dorota Sadowska, and Magdalena Starosciak), psychologists and therapists (Anna Blogosz, Anna Debska, Justyna Koziorowska, Marta Porebiak, Irena Przepiorka, and Agnieszka Smolinska), and secretarial staff (Halina Gaj, Joanna Szwechowicz, and Ewa Tarnowska) who assisted with the conduct of the trial; Ognyan Donev of Sopharma for performing the randomization and providing study medication; and Prof. Piotr Tutka for his help and advice before and during the study.

While this may not seem like an effective treatment, the success of other forms of treatment are similarly dismal( around 23% at 52 weeks for Chantix).  However, if this works for 10% of smokers who try this, the total number is huge and the cost is minimal with few side effects.

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