The Phantom Menace of Sleep Deprived Doctors - NYTimes.com

The Phantom Menace of Sleep Deprived Doctors - NYTimes.com

Drospirenone Associated With Increased Risk for VTE

Drospirenone Associated With Increased Risk for VTE

April 26, 2011 Women without risk factors for venous thromboembolism (VTE) who are taking the third-generation oral contraceptive drospirenone have an increased risk for nonfatal VTE compared with women taking the second-generation contraceptive levonorgestrel, according to the findings of 2 new case-control studies. Susan S. Jick, Dsc, from the Boston Collaborative Drug Surveillance Program at the Boston School of Medicine, in Massachusetts, and colleagues reported their findings in 2 separate articles published online April 21 in the BMJ.

According to the researchers, a series of case reports beginning in 2002 first raised concerns about an increased risk for VTE in users of oral contraceptives containing drospirenone. This risk has since been assessed in several studies that included women with risk factors for VTE. However, the risk attributable to oral contraceptives in the absence of other causes was unknown. In the current studies, one conducted in the United Kingdom and the other in the United States, the study populations, both consisting of women aged 15 to 44 years, was restricted to patients with idiopathic VTE, each matched with up to 4 control case patients by age and calendar time of drug exposure.

Data for the UK cohort came from the UK General Practice Research Database, which contains data from more than 3 million people. Data for the US cohort were acquired from the PharMetrics database, which contains prescription data on 55 million people reaching back to 1995. The UK study included 61 cases of idiopathic VTE among current users of drospirenone and levonorgestrel; these patients were matched with 215 control patients. All patients were receiving oral contraceptives containing 30 μg of estrogen in combination with either drospirenone or levonorgestrel. The US study included 186 cases of idiopathic VTE; these patients were matched with 681 control patients, with contraceptives including either drospirenone or levonorgestrel.

Although the absolute risk was low, both studies showed a 2- to 3-fold increased risk for nonfatal VTE with drospirenone compared with levonorgestrel. The UK study showed an odds ratio (OR) of 3.3 (95% confidence interval [CI], 1.4 - 7.6), and the US study showed an OR of 2.4 (95% CI, 1.7 - 3.4). In the UK study, the incidence rates for idiopathic VTE were 23 (95% CI, 13.4 - 36.9) per 100,000 woman/years with drospirenone and 9.1 (95% CI, 6.6 - 12.2) per 100,000 woman/years with levonorgestrel. The corresponding incidence rates in the US study were 30.8 (95% CI, 25.6 - 36.8) per 100,000 woman/years with drospirenone and 12.5 (95% CI, 9.61 - 15.9) per 100,000 woman/years with levonorgestrel.

These results would add to emerging data that suggest the use of the oral contraceptive containing drospirenone is associated with a higher risk of [VTE] than are preparations containing levonorgestrel. Since no clear evidence exists to show that the use of the drospirenone pill confers benefits above those of other oral contraceptives in preventing pregnancy, treating acne, alleviating premenstrual syndrome, or avoiding weight gain, prescribing lower risk levonorgestrel preparations as the first line choice in women wishing to take an oral contraceptive would seem prudent.

Medscape Medical News

Letter from CAP

Concern over HPV vaccines

(Fri, 24 Dec 2010) 

THE Consumers Association of Penang is aghast that the relevant authorities, particularly the Health Ministry, have kept silent over the raging controversies on the rush to get young girls vaccinated against cervical cancer. There are many areas of concern over the human papillomavirus (HPV) vaccine which is said to prevent infection against certain species of human papillomavirus associated with cervical cancer, genital warts and some less common cancers.

Many countries are going slow on this vaccine because of many doubts raised. However, Malaysia is rushing into it. HPV vaccines, given in a series of three shots, are to make the body’s immune system produce antibodies against HPV types 16 and 18, which cause seven out of 10 cases of cervical cancer. The antibodies supposedly protect one from getting infected with HPV.

And yet the authorities are not giving the people any details. Even the type of vaccine used seems to be top secret. Two HPV vaccines are in the market: Gardasil and Cervarix. Which one is Malaysia using? And experts tell us that the regular Pap smear screening must be continued to be done even after vaccination because the vaccine only covers some high-risk types of HPV.

The World Health Organisation warned late last year that those vaccinated and do not continue with screening, such as Pap smear because they wrongly believe they are protected against cervical cancer, can raise the death figures, especially with the vaccine protection waning over time.

Some concerns have been raised by the US Centers for Disease Control and Prevention:

As of Sept 1, 2009, there were 15,037 Vaccine Adverse Event Reporting System (VAERS) cases of adverse events following Gardasil vaccination in the US. Of these reports, 93% were reports of events considered to be non-serious, and 7% were reports of events considered to be serious.

Reports on non-serious adverse events after Gardasil vaccination have included fainting, pain and swelling at the injection site (the arm), headache, nausea and fever.

VAERS defines serious adverse events as those that involve hospitalisation, permanent disability, life-threatening illnesses and death.

As of Sept 1, 2009, there have been 44 reports of death among females in the US who have received the vaccine.

CAP calls on the authorities to stop the vaccine programme until the people are clear about it. In September 2009, when the government announced its intention to vaccinate some 300,000 13-year-old-schoolgirls, we voiced our objections. We reiterate that inoculating schoolgirls with the vaccine is a symptomatic and simplistic solution to the problem of cervical cancer in children who may contract cervical cancer due to early sexual activity when instead, the root cause for contracting HPV - sexual relations with multiple partners; should be countered by education.

S.M. Mohamed Idris
President
Consumers Association of Penang

Menopausal hormone therapy association with breast cancer strengthened

In 2002, the Women's Health Initiative (WHI) randomized trial of placebo vs hormone therapy with estrogen and progestin was stopped early because of evidence of harm.¹ Sales of combined estrogen-progestin plummeted 32% between the period immediately before the study's release and the analogous period 1 year later, as the WHI trial had shown that hormone therapy increased a woman's risk of breast cancer and myocardial infarction.² The finding contradicted decades of case-control and observational cohort studies that had suggested that hormone therapy was associated with strong protective effects on the cardiovascular system. The WHI results also undermined a long and successful campaign by hormone replacement advocates to present hormone therapy as a panacea against heart disease, loss of femininity, and other perils of aging. In addition, the WHI documented numerous other negative effects of hormone therapy, including an increased risk of stroke and pulmonary embolism,¹ which are not strongly associated with the timing of hormone therapy initiation. Ultimately, the only long-term benefit of hormone therapy that the US Food and Drug Administration (FDA) allows the manufacturer to claim is reduction of risk of osteoporotic fractures.³

That breast cancer rates in the WHI increased among women receiving hormone therapy was not surprising. Epidemiological and biological studies had anticipated the effect,⁴ although the magnitude of risk was not known until the WHI, which showed that the effect of hormone therapy on breast cancer risk was about the same as the deleterious effect on cardiovascular health. Several years after use of hormone therapy plummeted in the United States, breast cancer incidence also declined.⁵

Chlebowski et al⁶ report results of an 11-year follow-up of WHI estrogen-progestin trial participants that address many of these questions. The authors found that hormone therapy increases the frequency of breast cancer and that the breast cancers are on average more advanced and may be larger. The authors found no evidence that the cancers had favourable prognostic features, such as more frequently being estrogen receptor positive or lacking HER2 /neu gene amplification. If anything, the results suggest a trend in the direction of less favourable cancers. In addition, the authors found strong evidence that the rate of breast cancer death is increased by hormone therapy. It is also probable that the increase in breast cancer deaths due to hormone therapy has been underestimated in the current study and that with longer follow-up, the deleterious effect will appear larger. This suggestion is based on several observations: the mortality curves appear to still be separating at the end of the current follow-up (Figure 4A in the article); the difference in cumulative breast cancer incidence between women in the hormone therapy and placebo groups is widening (Figure 2 in the article), which will ultimately lead to more deaths; and the breast cancers diagnosed among women who received hormone therapy are associated with a poorer prognosis.

Based on present data, the authors project that approximately 1.3 additional deaths from breast cancer per 10 000 person-years of follow-up have already occurred among the women who received hormone therapy in the study. Since this number is relatively small, clinicians might conclude that a brief period of hormone therapy for relief of menopausal symptoms is safe. Such a view would be consistent with some professional guidelines⁷ and with the FDA-approved label for combined estrogen-progestin therapy.³ However, the study by Chlebowski et al⁶ does not address the effect of short periods of hormone therapy on breast cancer risk (or other disease risk), and the current estimate of the deleterious effects of hormone therapy may be underestimated.

Therefore, the available data dictate caution in the current approach to use of hormone therapy, particularly because one of the lessons from the WHI is that physicians are ill-equipped to anticipate the effect of hormone therapy on long-term health. Clinicians who prescribe brief courses of hormone therapy for relief of menopausal symptoms should be aware that this approach has not been proven in rigorous clinical trials and that the downstream negative consequences for their patients are of uncertain magnitude. Given the substantial population of women who seek relief from menopausal symptoms and the large potential burden of disease that could be created if medications given to alleviate symptoms today cause cancer and other deaths tomorrow, it seems that additional randomized trials are needed specifically to determine whether lower doses or shorter durations of hormone therapy could alleviate menopausal symptoms without increasing cancer risk.

References

1. Rossouw JE, Anderson GL, Prentice RL; et al, Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.

2. Majumdar SR, Almasi EA, Stafford RS. Promotion and prescribing of hormone therapy after report of harm by the Women's Health Initiative. JAMA. 2004;292(16):1983-1988.

3. US Food and Drug Administration. Prempro prescribing information. 2009. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020527s045lbl.pdf

4. Key TJA, Pike MC. The role of oestrogens and progestagens in the epidemiology and prevention of breast cancer. Eur J Cancer Clin Oncol. 1988;24(1):29-43. 

5. Chlebowski RT, Kuller LH, Prentice RL; et al, WHI Investigators. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med. 2009;360(6):573-587.

6. Chlebowski RT, Anderson GL, Gass M; et al, WHI Investigators. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA.2010;304(15):1684-1692.  

7. US Preventive Services Task Force. Hormone therapy for the prevention of chronic conditions in postmenopausal women: recommendations from the US Preventive Services Task Force. Ann Intern Med. 2005;142(10):855-860.

Edited by Hanifullah Khan from  Bach PB. Postmenopausal Hormone Therapy and Breast Cancer: An Uncertain Trade-off. JAMA  2010;304(15):1719-1720. doi:10.1001/jama.2010.1528

Two Cervical Cancer Vaccines

1. Two prophylactic HPV vaccines, Cervarix™ (GlaxoSmithKline) and Gardasil™ (Merck) have been licensed for use. Both have been tested in large randomised placebo-controlled trials involving thousands of women from different countries across the world.
2. Impressive protection against persistent vaccine-specific HPV infection has been demonstrated over short- to medium-term follow-up periods. Long-term follow-up data are still required to answer the question of longevity of immune protection and whether booster vaccination(s) will be necessary, and at what time interval.
3. Because of ethical and consent issues, efficacy cannot be determined among pre-adolescent girls, but is assumed by extrapolating data from the young women involved in the original vaccination trials. These suggest higher immune responses following vaccination among young adolescent girls (and boys) when compared with young adults, suggesting that vaccination at this younger age may result either in longer sustained immunity, improved long-term clinical efficacy, or both.
4. It is difficult to assess the impact of an immunisation strategy when many factors are still unknown. 
5. The coverage for the third dose is critical as the vaccine is locally painful and girls may be reluctant to complete the course.
6. The vaccines remain prohibitively expensive - universal HPV vaccination is unlikely in resource-poor countries lacking organised screening programmes, where cervical cancer remains a major cause of cancer-related death in women, and vaccination would be most beneficial. Those countries providing HPV vaccination at the moment have more efficient cervical screening programmes and lower cervical cancer rates than those yet to introduce it.
7. Merck was the first of two pharmaceutical companies to license its vaccine in October 2006, giving it a commercial head start. This quadrivalent vaccine confers immunity against the two oncogenic strains of HPV responsible for 70% of cervical cancers (HPV 16 and 18), as well as two strains that together cause 90% of genital warts (HPV 6 and 11). To many, a vaccine that protects against four strains has appeared to be inherently ‘better’ than one protecting against two strains.15 The bivalent vaccine Cervarix did not become available until almost a year later, in September 2007. Cervarix protects against HPV types 16 and 18, but does not prevent genital warts.
8. Insofar as Cervarix does not prevent genital warts, its use may amount to a ‘missed opportunity’. Genital warts are a very common sexually transmitted viral infection responsible for unsightly lesions that are both difficult and costly to treat. Women with genital warts also risk spread of the infection to the respiratory tract of their newborn infant during childbirth. Recurrent respiratory papillomatosis is a rare, but chronic, debilitating disease characterised by hoarseness, stridor and respiratory distress in the newborn, and requires lifelong repeated surgical intervention and prolonged hospital stays, even causing death in a minority of cases.
9. Published data do not distinguish either vaccine as superior in terms of clinical effectiveness or toxicity. However, recent data released by GlaxoSmithKline from their head-to-head comparison of the two vaccines reported that Cervarix induced significantly higher HPV 16 and 18 serum neutralising antibody titres, as well as higher levels of neutralising antibodies in cervicovaginal secretions and circulating HPV 16 and 18-specific memory B-cells. These results would suggest that a longer duration of protection against HPV infection may be conferred by Cervarix. Declining antibody levels post-vaccination may not, however, indicate a loss of protection, as immunological memory may persist at low levels, and is difficult to measure. Natural viral challenge may be sufficient to ‘boost’ declining serological responses, although booster vaccination is superior.
10. Future cervical screening. Cervical cancer develops after an infection period of a decade or more, and up to 30% of cervical cancers are caused by HPV types not included in either vaccine. Although some degree of cross-protection against similar high-risk HPV types has been presumed from trial data, vaccinated women are still clearly at risk of contracting other oncogenic HPV types that can cause cervical cancer, and cervical screening will still be necessary, even for vaccinated women.
11. Safety scares. In general, both Cervarix and Gardasil appear to be safe and well tolerated. Injection site adverse events, including pain, swelling and redness, have been reported more frequently by women receiving the vaccine, compared with those receiving placebo in clinical trials. Cervarix is recognised to be a more painful inoculation than Gardasil, but even so, most side effects disappear within the first day or two.
12. There have been no deaths attributable to either vaccine in any of the clinical trials to date. Pregnancy and congenital anomaly data have been reported for Gardasil, but not for Cervarix. Higher rates of congenital anomalies unrelated to type have been observed.
13. Maintaining high vaccine coverage. Interim results for the uptake of the third dose has shown a drop in coverage from 83% at the first dose to 74% for dose 3. Whether girls who receive only the first two doses of the vaccine will show sufficient immunity against HPV to prevent subsequent infection remains unclear.
14. The effect of mistimed doses is not fully understood. Data from hepatitis B vaccination studies suggest that longer intervals between second and third doses of the HPV vaccine may not be detrimental to the strength of the immunity generated, presumably as long as HPV exposure does not occur during the delay.

No benefit from GnRH analogue pretreatment for hysteroscopic submucous fibroid resection

Uterine fibroids are the most common benign tumours of the female reproductive tract. On the basis of their location, they can be divided into submucous, intramural or subserosal. Fibroids tend to grow in an estrogenic environment as evidenced by the reduction in size during menopause or in a medically induced hypoestrogenic state, such as with Gonadotrophin Releasing Hormone (GnRH) analogue therapy. Hysterectomy remains the only method of definitive treatment for symptomatic fibroids. However, conservative treatment may be desirable in many instances, chief among which would be the maintenance of child-bearing capability. Other reasons for keeping one’s uterus include better sexual functioning and avoidance of surgery, whether by choice or clinical reasoning.

This conservatism has lead to a proliferation of less invasive methods pursuing management of fibroids without recourse to surgery. Medical therapy provides only temporary relief of variable duration with repeat treatments a nuisance. Amongst the various radiological interventions, uterine artery embolization is an effective procedure, though not an ideal solution if future fertility is desired.(1) Hysteroscopic resection is quite feasible for treatment of submucosal fibroids, and the subject of our current attention.

Whether surgical or otherwise, all these methods can be hampered by complications such as bleeding, obstructed views and inadequate resection during the procedure. In order to minimize these risks, shrinking the fibroids to a more manageable size prior to the procedure offers a logical and practical proposition. GnRH analogue therapy has been advocated as a means to this end for some time now. Advantages of such pretreatment include reduction of fibroid size, bleeding and operating time and visual improvement during the procedure. Disadvantages, it has been said, include non-identification of tumour and tumour recurrence post-procedure. Many investigations in the past have set out to settle this issue once and for all but no definitive data has yet emerged.

The latest study to address this issue involved 47 reproductive-aged women with symptomatic submucosal fibroids randomly assigned to receive 3 months of depot goserelin or placebo injections prior to hysteroscopic resection (2). Sample size was calculated on the basis of an expected complete resection rate of about 50% without pretreatment and an improvement in resection rate to 92% with use of GnRH analogue. The primary outcome measure was the rate of complete resection of the fibroids.

Baseline characteristics and the number and size of submucous fibroids were well balanced in the study groups. Overall, 75% of the women had complete fibroid resection; this frequency was similar in both groups. Fibroid size and degree of intramural involvement were negatively associated with the frequency of successful complete resection. The duration of the procedure, the amount of distention fluid used, and the complication rates (excessive fluid deficit, bleeding, and perforation) were similar in the 2 groups. A similar proportion of women reported symptom improvement, and the need for second surgeries was not different between the 2 groups. On the basis of their findings, Mavrelos and colleagues concluded that preoperative use of GnRH analogues does not improve the outcome of hysteroscopic resection of submucous fibroids.

Evaluation of the outcomes of such trials requires the consideration of many factors. Although the study design seems sturdy, the number of patients involved in this case is not life-defining. A much larger number is required to provide significance. Surgical expertise plays an important part and a fairly high complete resection rate in the placebo arm might reflect the presumed above-average experience of the single surgeon involved. Results might differ with less experienced surgeons or in patients who truly benefit from GnRH analogue pretreatment. Since this study only evaluated women with submucous fibroids, the results obviously cannot be applied to fibroids of other persuasions. Thus, although this study did not find a benefit with GnRH therapy prior to hysteroscopic fibroid resection, use of this therapy should still be considered on an individual basis.

References

1. Freed MM, Spies JB. Uterine artery embolization for fibroids: a review of current outcomes. Semin Reprod Med. 2010;28:235-241. 

2. Marvelos D, Ben-Nagi J, Davies A et al. The Value of Pre-operative Treatment With GnRH Analogues in Women With Submucous Fibroids: A Double-Blind, Placebo-Controlled Randomized Trial. Hum Reprod. 2010;25:2264-2269

FDA approves novel folate OCP

The US Food and Drug Administration (FDA) on 25 September 2010 approved a novel oral contraceptive that is formulated to provide both contraception and reduce the risk for neural tube defects in their offspring if and when they give birth. The new contraceptive, Beyaz (Bayer HealthCare Pharmaceuticals), contains levomefolate calcium, a metabolite of folic acid. Prepregnancy folate supplementation has been associated with a decreased risk of fetal neural tube defects. Thus arises the recommendation that women of childbearing age supplement their diet with folate. This is a logical step since women may become pregnant during oral contraceptive use or shortly after discontinuation. The approval is based on the already-approved oral contraceptive drospirenone/ethinyl estradiol (Yaz, Bayer HealthCare Pharmaceuticals), which contains the same doses of estrogen and progestin.

Apart from the primary indication of contraception, Beyaz is also approved for the treatment of symptoms of premenstrual dysphoric disorder (PMDD), acne vulgaris and the prevention of fetal neural tube defects in women who choose an oral contraceptive as their method of contraception.

According to the FDA (www.fda.gov), the primary efficacy study for Beyaz was a multicenter, double-blind, randomized, controlled U.S. trial in 379 healthy women aged 18 to 40 who were treated with Beyaz or YAZ alone for up to 24 weeks. Beyaz was found to increase folate levels in women. In a German study of Beyaz, folate levels remained elevated for several weeks following discontinuation of Beyaz.  Safety and efficacy data for contraception, PMDD, and acne indications were obtained from previous YAZ clinical trials.

The clinical trials of Beyaz did not yield any findings that would suggest it differs from Yaz in terms of its overall safety profile. It is expected that the most common adverse events for Beyaz will be the same as those for Yaz. Adverse effects most frequently reported by users of combined oral contraceptives are irregular uterine bleeding, nausea, breast tenderness, and headaches.