Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes: The Star-2 Trial (JAMA, June 21, 2006) September 30, 2006
Posted by rajkmd in Women's Health.3 comments
The Big Picture
- According to CDC, in women, breast cancer is the most commonly diagnosed cancer after skin cancer and the second leading cause of death after lung cancer.
- In 2002, 182,000 women were diagnosed and 41,000 women died from breast cancer.
- American women of European ancestry are more likely to be diagnosed from the disease, while African American women have the highest rates of death from breast cancer.
- Annually, it is estimated more than $7 billion ( in 2000 dollars) is spent on the diagnosis and treatment of breast cancer
- Raloxifene was first discovered and patented by Ely Lilly and sold under the trade name Evista. It was approved in 1997 for the prevention of osteoporosis
- According to the prnewswire, Evista has annual sales of around $635 million
- Ely Lilly plead guilty in 2005 for illegally promoting Evista in prevention of invasive breast cancer and is currently paying fines as part of its settlement with the government.
- There was patent dispute between Barr Labrotories and Ely Lilly in 2001
- Tamoxifen
- Went off patent in 2002
- More than half a million women annually take the drug
- According to IMS Health, while on patent, it had more $1 billion in sales, but after the drug went off patent and other classes of drugs have been found to be more effective sales have slumped to $53 million in 2004
- To read article about this study in the nytimes click here
Background
- Tamoxifen is a selective estrogen receptor modulator (SERM)
- It has been used to treat both early and advanced breast cancer for more than 3 decades
- Raloxifene is a second generation SERM
- Studies have shown that it decreases the development of breast cancer and reduces the risk of invasive breast cancer
- It is also used in the treatment of osteoporosis
- The STAR-2 trial was funded by National Surgical Adjuvant Breast and Bowel Project (NSABP), which is an arm of the CDC
- The study was completely publicly funded
- Some of the authors, though, did have relationship with the drug manufacturers
Methods
- The trial was double blinded
- There was no placebo group
- Patient Characterisitcs
- At least a 5 year predicited predicited breast cancer risk of 1.66% based on the Gail Model (for a breast cancer risk assessment tool based on the Gail Model, click here)
- At least 35 yo
- Post menopausal
- No taking tamoxifen, raloxifene, hormone therapy, oral contraceptives, or androgens in the previous three months to enrollment
- Not taking warfarin or cholestyramine
- No h/o of stroke, pulm embolism, DVT,
- No h/o of malignancy diagnosed less than 5 years before randomization except basal or squamous cell cancer of the skin or carcinoma in situ of the cervix
- No uncontrolled atrial fibrillation, hypertension, diabetes, or psychiatric condition
- Post menopausal women 35 yo or older with a history of lobular in situ (LCIS) could be enrolled as long as they had been treated with local excision alone
- Study flow
- A total of 184,460 were screened
- 93,368 had a 5 yr risk greater or equal to 1.66%
- 19,747 were actually randomized
- 9,872 recieved tamoxifen and 9,875 recieved raloxifene
- Of these, 9,726 in the tamoxifen arm and 9,745 in the raloxifene arm were included in the primary analysis
- Eligible women were assigned to recieve ramoxifen or raloxifene for a max of 5 yrs
- Patient Characterisitics
- Mean age – 58.5
- More than 93% were women of European decent, 2.5% were African American, 2% were Hispanic, and the remainder were other ethnic groups
- 9 percent had a history of LCIS
- 22 percent had a history of breast biopsy results before randomization that showed either atypical ductal or lobular hyperplasia
- Mean follow-up was 3.9 years
- There was a nonadherence rate of 9.2 percent
- Primary endpt was invasive breast cancer
- Secondary enpt
- endomertrial cancer
- in situ breast cancer
- CV disease
- Pulm embolism
- DVT
- TIA
- Cataracts
- Death
- Quality of life
- Randomization occured by stratifiying pts by age, race/ethnicity, history of LCIS, and 5 yr breast cancer risk
- Pt’s were followed every 6 months for 5 years
Results
- There was no difference between the effect of tamoxifen or raloxifene on the incidence of invasive breast cancer
- Moreover, there was also no difference within in the groups even after taking into account age, history of LCIS, history of atypical hypreplasia, 5 year predicted breast cancer risk, or family history
- There was also no difference between the types of breast cancer or the size of the cancers that developed.
- There was a difference, albiet not statistically significant (p<.052), in the development of noninvasive breast cancers between the tamoxifen and raloxifene groups
- There were 57 incident cases of noninvasive breast cancers in the tamoxifen group and 80 in the raloxifene group
- There was a trend for decrease in uterine cancer in the raloxifene group that was not sig statistic (p= .07)
- But there was a statistifically significant difference in the incidence of uterine hyperplasia, as pts treated with raloxifene were 84% less likely to develop hyperplsia than the tamixifen group
- Also pt’s on raloxifene underwent a fewer hysterectomies compared to the tamoxifen group
- No statistically significant difference in other invasive malignancies.
- Raloxifene group had fewer DVT and pulmonary embolism, which was statisticall significant (RR 0.70 95% CI 0.54-0.91)
- No difference in the number of fractures between both groups
- Decreased cataracts in the raloxifene group.
- Mortalility was similar in both groups
Conclusion
- Raloxifene does not provide additional protection against the risk of invasive breast cancer when compared to tamoxifen in patients with an elevated GAIL score and LCIS
- Raloxifene does, however, have decreased incidence of thromboembolic disease and uterine hyperplasia when compared to tamoxifen.
- Of note, more than half the patients in this study were s/p hysterectomy
THE BOTTOM LINE: In 1,000 high risk (as defined by the study design) women, without treatment 40 women would develop invasive breast cancer over next five years. If all 1,000 were treated, then this number drops to 20 regardless if you use raloxifene to tamoxifen. This means you would treat 980 women who would not benefit from the treatment to prevent 20 cases of invasive breast cancer. Also, all treated women would be at increased risk of developing a pulmonary embolism or DVT, but the patients treated with raloxifene will develop fewer thromboemblic complications when compared to tamoxifen.
Dr. Greg Mints on Isosorbide and Hydralazine September 27, 2006
Posted by healthweb in Uncategorized.5 comments
This post is in response to the article Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure (NEJM, Nov. 11, 2004)
One of the most interesting and controversial aspects of this paper is how to interpret the racial aspect of it. I wish to make the following comments:
1. There is currently no proof that members of other racial groups would not enjoy the same benefits from the Tx. Previous studies suggesting that AA may gain more benefit from this combo Tx were post hoc analyses and therefore “hypothesis generating” only.
2. There is no proof that in AA hydralazine-nitro combo is better than ACE-BB-aldo inhibitor cocktail. The present study design obviously does not allow for this conclusion. Previous studies, again, were post hoc analyses.
3. Essentially all the existing clinical data available was derived from predominantly Caucasian patients. This has not prevented us, the clinicians, from using the studied interventions in other ethnic groups. Similarly, until proven otherwise, it is not reasonable to withhold a treatment with NNT of 7 from our, say, Hispanic patients. In my practice, I do give hydralazine-nitro to all patients whose BP allows another agent after ACE/ARB, BB, and aldosterone inhibitors have been added
Methicillin-Resistant S. aureus Infections among Patients in Emergency Department (NEJM, August 17th, 2006) September 20, 2006
Posted by healthweb in Infectious Disease.2 comments
by Raj Khandwalla
Background
- Methicillin-resistant staphylococcus aureus (MRSA) emerged in the 1960 primarily in hospitilized patients
- More recently, community acquired MRSA has been identified in prisoners, IV drug users, athletes, military trainees, and men who have sex with men
- It is usually associated with skin and soft tissue infections, but it has also been associated with sepsis and necrotizing pneumonia
- Compared hospitlized MRSA, community acquired MRSA is less resistant, produces different toxins, and has a different gene complex that confers methicillin resistant, named staphylococcus cassette chromosome mec (SCCmec)
- This study set out to determine the prevelance of skin infection caused by MRSA in several geographically diverse, metropolitan areas in the United States
Methods
- A prospective prevalance study involving adult patients with skin and soft tissue infections to emergency departments in Albuquerque, Atlanta, Charlotte, Kansas City, Los Angeles, Minneapolis New Orleans, New York, Philadephia, Phenoix, and Portland
- Inclusion criteria: 18 years or older presenting in August 2004 with purulent skin and soft tissue infections of less than one week’s duration
- Pt’s with perirectal abscesses were excluded
- Management decisions were left up to the physicians taking care of the patients
- Follow-up data were obained by telephone approx. two to three weeks after enrollment
- Specimens were obtained from the single largest area of infection with the use of sterile swabs
Results
- A total of 422 patients with skin and soft tissue infections wer enrolled
- Baseline Characteristics
- Race
- 49 percent of pts were non Hispanic African Americans
- 25 percent were non Hispanic individuals of European origin
- 22 percent were Hispanic
- 4 percent belonged to other groups
- Infections were located
- upper extremities – 29 percent
- lower extremities – 27 percent
- torso – 17 percent
- perineum - 14 percent
- head and neck – 13 percent
- Infections were classfied as an abscess in 81 percent of patients, an infected wound in 11 percent, and as a cellulitis with purulent exudate in 8 percent
- Race
- S aureus was isolated from skin and soft tissue infections in 320 patients (76 percent) and of these 249 pts (78 percent) were MRSA
- The prevelance of MRSA ranged from 15 to 74 percent, and MRSA was the most common identifiable cause of skin and soft tissue infections in 10 of 11 emergency departments
- MRSA isolated in
- 61 percent of abscesses
- 53 percent of purulent wounds
- 47 percent of cases of cellulutis with purulent exudate
- Seventeen percent of isolates were meticillin sensitive staph aureus (MSSA)
- Seven percent of isolates were streptococcal species
- MRSA susceptibilities
- 100 percent to Bactrim and Rifampin
- 95 percent clindamycin
- 92 percent to tetracycline
- 60 percent to fluroquinolones
- 6 percent to erythromycin
- People with MRSA were more likely to
- have used antibiotics in the month before enrollment
- had an abscess
- lesion attributed to a spider bite at enrollment
- history of MRSA infection
- recent history of close contact with someone with a similar skin infection
- Treatment
- 19 percent were treated with incision and drainage
- 10 percent received antibiotics alone
- 66 percent were treated with I&D and antibiotics
- 21 percent underwent neither I&D nor antibiotics
- Of 422 patients 59 percent were contacted 15 to 21 days after their visit to the er
- Of these, 96 percent reported that their infectionhad resolved or improved
- There was no significant difference in the outcome between patients infected with MRSA, MSSA, or any other isolate
Discussion
- MRSA is the most common skin and soft tissue infection in the hospital centers studied
- Eighty percent of patients with MRSA received antimicrobial therapy for their infection
- Interestingly, the isolated bacteria was resistant to the prescribed antibiotics in 57 percent of patients
- Perhaps empiric treatment of infection needs to be reconsidered
- Despite the lack of susceptibility in the majority of cases , there was no difference in outcomes when comparing patients prescribe antibiotics that were or were not effective in killing the cultured bacteria
-
- This is consistent with the known literature and suggests that simple skin abscesses can be treated with simple drainage
- The findings of this study show that there has been a dramatic increase in the incidence of MRSA
- Prescribing antibiotics that are not indicated will only decrease their effectiveness in the future
- Clinicians should consider culturing MRSA isolates and modifying standard empirical therapy when indicated
In response to Dr. Orna Kleiman’s questions September 14, 2006
Posted by healthweb in Cardiology, Uncategorized.3 comments
In the comments section….
Can you comment on the other endpoints, ie: did the treatment group also have a significant reduction in LV wall thickness or EF that would go along with the proposed mechanism of the drugs in question reducing myocardial hypertrophy and remodeling? second, just to confirm, all these people were still on beta blocker, ace, +/- arb, and even spironolactone, all the while they were on hydral+nitrate, right? kinda expensive and a tough regimen to maintain as an outpatient…
In the study, Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure (NEJM, Nov. 11, 2004), despite listing change in LV ejection fraction and LV wall thickness as secondary endpts at six months, the study does not report these results in the text or any of its tables.
To be involved in the study patients had to be receiving standard therapy as determined by their physician including beta blockers, ACE inhibitors, diuretics, digoxin, ARBs, and spironolactone. In fact, an interesting aspect of this trial is that almost 70% of patients in both placebo and experimental arms were on ACE inhibitors and more than 70% of patients were on beta blockers.
To apply the findings of the study, then, pt should be maximized on standard therapy before being started on the combination of isosorbide and hydralizine
Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure (NEJM, Nov. 11, 2004) September 6, 2006
Posted by healthweb in Cardiology, Uncategorized.4 comments
by Raj Khandwalla
The Big Picture
- An estimated 4.9 million Americans are being treated with heart failure with 550,000 new cases diagnosed each year
- The prevelence increased with age affecting 1-2 percent of persons age 45 to 54 years and up to 10 percent of indiviudals older than 75 yo
- Heart failure is the leading discharge diagnosis in persons 65 years or older with average length of stay around 5.3 days .
- $3.5 billion dollars was spent on Medicare beneficiares for the in-hospital management of heart failure
- The cost of hospitilizations for heart failure is twice that for all forms of cancer and myocardial infarction combined
- This study was funded by the company NitroMed
- Between July, 2004 and November, 2004 (the month this study was published ), NitroMed’s stock increased from $5.9 per share to $25.8 per share – an increase of more than 400%. Currently, the stock is $2.84 per share with a market capitilization of $500 million.
Background
- Neurohormonal inhitibors, such as beta blockers and ACE inhibitors, have been shown to reduce the rates of death and complications associated with heart failure
- Increasing nitric oxide levels in the heart may help slow or reverese the progression of heart disease
- Vasodilator Heart Failure Trial demonstrated benefit of combining nitric oxide donor, isosorbide dinitrate and hydralizine in patients with mild to severe heart failure
- Studies have shown that persons who identify themselves as black on average have a less active renin angiotensin system and lower levels of bioavailability compared to self identified whites
Methods
- A randomized, placebo controlled, double blinded trial
- Study was sponsered by NitroMed
- Inclusion criteria
- pts 18 yo or older, self described as black (defined as of African descent)
- pts NYHA class III or IV heart failure for at least three months were eligible
- pts required to have receiving standard therapy for heart failure as determined appropriate by their physicians
- such therapy included ACE inhibitors, ARBs, beta-blockers, spironolactone, digoxin, and diuretics for at least three months before randomization
- Pt’s also had evidence of LV dysfunction within six months preceding randomization as defined by echo
- Excluson criteria
- acute MI, acute coronary syndrome, or stroke within the preceding three months
- cardiac surgery or PCI within the preceding three months or the likelihood of a requirement of such a procedure within the study period
- presence of sig valvular dysfunction
- presence of hypertrophic or restrictive cardiomyopathy
- uncontrolled hypertension
- requiring inotropes or potential need for cardiac transplantation.
Randomization Procedure
- Initial dose was one tablet containing either placebo alone or hydralazine 37.5 mg 3xdaily combined with isorsobide 20 mg 3 x daily
- The dose was increased to two tablets three times daily for a total daily dose of 225 mg of hydralzine and 120 mg of isosorbide
- Pts were followed for 18 m with assessment of LV EF, LV internal diastolic dimension, LV wall thickness, and level of BNP at 6 months. Quality assessments were completed every 6 months
Outcome Measures
- The primary efficacy end pt was a composite score outlined below
- Death (at any time of trial) -3
- Survival to end of the trial 0
- First hospitilization for heart failure -1
- Change in quality of life at 6 mo (as measured by the Minnesota Living with Heart Failure questionaire)
- Improvement by >10 units +2
- Imoprovement by 5-9 units +1
- Change by <5 units 0
- Worsening by 5-9 -1
- Worsening by >10 -2
- Change in quality of life at 6 mo (as measured by the Minnesota Living with Heart Failure questionaire)
- Secondary end points
- included individual components of aggregate score
- death from cardiac causes
- total number of hospitilizations for heart failure
- total number of hospitilization of any cause
- total number of days of hospitilization
- overall quality of life
- change in BNP
- change in EF
- need for cardiac transplantation
Results
- This trial was stopped owing to a significantly higher motrality rate in the placebo group compared to the isorsorbide and hydralazine
- At the time the trial was halted 54 pts had died in the placebo (10.2 percent) and 32 patients had died in the combination therapy group
- Baseline Characteristics – the significant differences
- combination pill group was less likely to be male 55.8% vs 63.9%
- combination pill group was more likely to have diabetes 44.8% vs 37%
- combination pill group had increased diatolic pressure and slightly better Minnesota Living Scale
Discussion
- 43 percent reduction in the mortality rate in the group given combination pill
- An absolute reduction of mortality of 4% and a number needed to treat of 25 patients for every life saved
- Adverse effects
- the placebo group had significantly higher rates of CHF exacerbations
- the combination pill group had significantly higher rates of headache and dizziness
- All of these pts were on optimal medical therapy and the benefit may may be consistent with the existence of an alternative mechanism of controlling heart failure
- Isorsobide dinitrate is a nitric oxide donor and hydralazine confers protection against the degradation of nitric oxide
- Proposed mechanisms
- nitric oxide regulates cardiovascular processes including myocardial hypertrophy and remodeling as well as helping endothelial dysfxn
