Some anticonvulsants may be linked to increased risk of suicide
Data of an analysis of prescription and clinical claims suggests that the use of certain anticonvulsant medications may be associated with an increased risk of suicide, attempted suicide or violent death.
Anticonvulsant medications are a primary therapeutic approach for patients with epilepsy, but labeled indications also include bipolar disorder, mania, neuralgia, migraine and neuropathic pain.
In 2008, the FDA ( Food and Drug Administration ) mandated warning labeling for anticonvulsant medications regarding the increased risk of suicidal thoughts and behaviors. The decision was based on a meta-analysis not sufficiently large to investigate individual drugs.
Elisabetta Patorno, of Brigham and Women's Hospital and Harvard Medical School, Boston, and colleagues evaluated whether there was an increased risk of attempted or completed suicide, and combined suicidal acts or violent death associated with a range of individual anticonvulsant medications and within patient subgroups.
The Researchers analyzed data for 14 states from the HealthCore Integrated Research Database for patients 15 years and older who began taking an anticonvulsant between July 2001 and December 2006.
The study identified 827 suicidal acts ( 801 attempted suicides and 26 completed suicides ) and an additional 41 violent deaths ( 868 combined suicidal acts or violent deaths ) in 297,620 new episodes of treatment with an anticonvulsant.
The Researchers found that the risk of suicidal acts was increased for Gabapentin ( Neurontin ), Lamotrigine ( Lamictal ), Oxcarbazepine ( Trileptal ), Tiagabine ( Gabitril ), and Valproate ( Depakote ), compared with Topiramate ( Topamax ).
The analyses including violent death produced similar results.
Gabapentin users had increased risk in subgroups of younger and older patients, patients with mood disorders, and patients with epilepsy or seizure when compared with Carbamazepine ( Tegretol ).
Source: JAMA, 2010
anticonvulsants - suicide
Dutasteride reduces risk of prostate carcinoma diagnosis in high-risk men
Dutasteride ( Avodart ) has shown to reduce the risk of a prostate cancer diagnosis by 23 percent in men with an increased risk of the disease.
The results are reported in the New England Journal of Medicine ( NEJM ).
The four-year study found that Dutasteride significantly reduced the chances that men would be diagnosed with the tumors that are most often treated excessively: those that fall in the mid-range of aggressiveness. These tumors, which account for the majority of all prostate cancers, grow unpredictably. This uncertainty leads many men to opt for surgery or radiation therapy, treatments that can lead to incontinence and impotence.
"Dutasteride may potentially offer many thousands of men a way to reduce their risk of being diagnosed with prostate cancer," says the study's lead author Gerald Andriole, MD, chief of urologic surgery at Washington University School of Medicine in St. Louis. "This means more men could avoid unnecessary treatment for prostate cancer along with the costs and harmful side effects that can occur with treatment."
The REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial has been conducted at 250 sites in 42 countries. It is the first to evaluate chemoprevention for prostate cancer in men at increased risk of disease.
The trial involved 8,231 men ages 50-75, who were randomly assigned to receive a placebo or a daily 0.5 mg dose of Dutasteride, a drug that is known to shrink the prostate. Men in the study were considered to be at increased risk for prostate cancer because they had elevated PSA levels ( 2.5-10 ng/ml ) but no evidence of tumor on biopsies performed within six months of enrolling in the trial.
The investigators performed scheduled biopsies on the men two years after they enrolled in the study and again after four years. Over all, 659 men ( 19.9% ) taking Dutasteride were diagnosed with prostate cancer, compared to 858 men ( 25.1% ) taking a placebo. None of the men in the study died of prostate carcinoma.
Among men with a family history of prostate cancer, the drug reduced the relative risk of a prostate cancer diagnosis by 31.4 percent.
According to Gerald Andriole, at Washington University School of Medicine in St. Louis, the most likely explanation for the study's results is that Dutasteride is keeping tumors small or even shrinking them to the point that they are unlikely to be detected by a biopsy.
Dutasteride was most effective at reducing the risk of medium-grade tumors, defined as 5-6 on the Gleason scale. The Gleason scoring system measures tumor aggressiveness based on biopsy results and can range from 1-10, with 10 being the most aggressive. Over the study's four years, 70 percent of all men diagnosed with prostate cancer had Gleason 5-6 tumors, roughly the same percentage doctors see in clinical practice. These included 617 men ( 18.1% ) taking a placebo and 437 men ( 13.2% ) taking Dutasteride, a statistically significant difference.
Dutasteride was approved by the FDA ( Food and Drug Administration ) in 2001 for the treatment of benign prostatic hyperplasia ( BPH ). The condition causes frequent urination that is difficult or painful because the swollen prostate gland blocks urine flow. Dutasteride is not approved for prostate cancer prevention.
The investigators found no significant increase in aggressive, high-grade tumors ( defined as a Gleason score 7-10 ) among men who took Dutasteride over four years. There were 220 men ( 6.7% ) on Dutasteride with aggressive, high-grade tumors, compared with 233 men ( 6.8% ) on a placebo. However, they noted a disparity in the most aggressive tumors ( defined as a Gleason score 8-10 ) among men taking Dutasteride in years three and four of the study: 12 such tumors were detected in the Dutasteride group versus one in the placebo group.
The study was designed so that men were withdrawn after they had a positive tumor biopsy. But it's likely that if the men in the placebo group who were diagnosed with Gleason score 5-7 tumors in years one and two had remained in the study and been biopsied again, some of their tumors likely would have been upgraded to a Gleason 8-10 in study years three and four. This so-called tumor upgrading has been observed in other studies.
Moreover, it is well recognized that Gleason scores based on biopsies are more accurate in men on Dutasteride or the similar benign prostatic hyperplasia drug Finasteride ( Proscar ), who have smaller prostates, than in men with larger, growing prostates, where a needle biopsy is more likely to miss a tumor and to underestimate the true Gleason score.
The observation regarding high-grade tumors parallels that in the earlier Prostate Cancer Prevention Trial, which evaluated Finasteride in men with no increased risk of the disease. While Finasteride was found to lower overall prostate cancer risk, there were more aggressive tumors detected by biopsies in men taking that drug. Later analyses adjusting for prostate size at the time biopsies were performed showed no increase in high-grade tumors.
When researchers in the current study accounted for prostate size at the time of biopsy, their analysis also indicated fewer aggressive cancers among men receiving Dutasteride. Despite these considerations, the investigators could not completely rule out that some of the most aggressive tumors were due, in part, to Dutasteride.
Like Finasteride in the Prostate Cancer Prevention Trial, Dutasteride also improved the accuracy of the PSA test to detect prostate cancer, particularly when tumors are aggressive. Dutasteride is known to reduce PSA levels by 50 percent.
According Andriole, if PSA levels started to rise even slightly in a man taking Dutasteride, he had an increased chance of being diagnosed with prostate cancer, compared with men in the placebo group who tended to have PSA levels that naturally fluctuated.
Dutasteride blocks two forms of the enzyme 5-alpha reductase, which converts the hormone testosterone into dihydrotestosterone. In contrast, Finasteride inhibits only one form of the enzyme. Dihydrotestosterone is known to drive benign prostate growth and the development of prostate cancer.
Last year, both the American Society of Clinical Oncology and the American Urological Association issued guidelines suggesting that healthy older men who already are taking a 5-alpha reductase inhibitor for BPH or undergoing regular prostate cancer screening tests discuss with their doctors long-term use of the drug for prostate cancer prevention.
The REDUCE investigators also found that Dutasteride reduced the risk of urinary retention, urinary tract infection and the need for surgery to alleviate BPH, compared with the placebo.
The two most common side effects associated with Dutasteride were low rates of erectile dysfunction and decreased libido, which are consistent with earlier studies of the drug.
While rare, the investigators also noted more occurrences of cardiac failure among men taking Dutasteride, compared with those taking a placebo. Thirty ( 0.7 percent ) men on Dutasteride and 16 ( 0.4 percent ) men on a placebo received a diagnosis of cardiac failure. There was no significant difference between the two groups in the occurrence of deaths from cardiovascular causes.
Supplemental data to the NEJM article indicated that cardiac failure was more likely to occur in men taking both alpha-blockers and Dutasteride. Alpha-blockers are used to treat a range of conditions, including high blood pressure and benign prostatic hyperplasia.
Among United States men, prostate cancer is the second most deadly cancer after lung cancer. About 192,000 cases are diagnosed annually and some 27,300 die of the disease, according to the American Cancer Society.
Source: Washington University School of Medicine, 2010
REDUCE trial: Dutasteride in the prevention of prostate tumor
An editorial about REDUCE ( Reduction by Dutasteride of Prostate Cancer Events ) trial by Fritz H Schröder and Monique J Roobol has been published in the European Urology.
The final report of the REDUCE trial appeared in the New England Journal of Medicine ( NEJM ) together with a commentary entitled Chemoprevention of prostate cancer by Patrick Walsh.
What were the noteworthy items of the editorial ?
? The REDUCE trial, contrary to the Prostate Cancer Prevention Trial ( PCPT ), is performed in men who would have been candidates for biopsy anyway because of PSA values of 2.5-10 ng/ml, making the reduction of the chance of a positive biopsy of 23% clinically relevant.
? The mechanism of Dutasteride is not primarily prevention but the inhibition of growth of small, well differentiated cancers as a result of the intracellular reduction of 5-alpha-dihydrotestosterone ( DHT ). This mechanism which results in the prevention of disease progression is called tertiary prevention and in this setting can be seen as treatment of minimal disease. This effect is seen in spite of the simultaneous, up to 40 times increase in testosterone. It remains unclear why the rise in testosterone does not prevent the effect of the reduction in DHT.
? The report indicates a small difference in cardiovascular side effects in disadvantage of Dutasteride. The long-term general health effects obviously remain unknown at this time.
? Unanswered issues: is Dutasteride useful in reducing unnecessary biopsies and does it help to selectively identify aggressive disease ? The reported data show that in men with an indication of periodic biopsies the reduction in the detection of potentially over-diagnosed cancers is 28.2%.
? More detailed analyses are warranted. Extended follow-up to monitor, for example, the outcome of relevant endpoints such as delayed diagnosis of aggressive cancers, progression to metastatic disease and disease-specific mortality in comparison to the control population will be of great scientific value in spite of the unblinding of the trial and should therefore have top priority.
Source: European Association of Urology, 2010
Multiple sclerosis: blood flow insufficiency not found to contribute to development of disease
Two important new studies challenge the controversial hypothesis that venous congestion, chronic cerebrospinal venous insufficiency ( CCSVI ), contributes to the development of multiple sclerosis. This theory has resulted in many multiple sclerosis patients receiving experimental endovascular angioplasty, a treatment for multiple sclerosis unproven by clinical trials.
For nearly 150 years it has been known that focal multiple sclerosis lesions tend to develop around cerebral veins that are thought to the portal by which inflammatory cells targeting myelin enter the brain. However, a 2009 study by Zamboni et al offered an alternative theory suggesting that chronically impaired venous drainage from the central nervous system - a term that he labeled Chronic Cerebrospinal Venous Insufficiency or CCSVI - leads to multiple sclerosis development.
Zamboni et al. also claimed that endovascular angioplasty was markedly effective in multiple sclerosis patients.
According Stephen L Hauser, at the University of California, San Francisco, and editor-in-chief of the Annals of Neurology, these two papers should add a note of caution for multiple sclerosis patients and physicians who are contemplating interventions for possible venous abnormalities based on the findings of Zamboni. At this time, the theory must be considered unconfirmed and unproven. Such interventions carry risk, and several people have already been harmed by the inappropriate application of venous angioplasty and stenting for multiple sclerosis. A previously published review of the evidence in the Annals by Khan et al noted that treatment procedures, based upon these findings, have included placing stents in the jugular veins of multiple sclerosis patients which led to serious injury in some cases.
Florian Doepp and colleagues in Germany performed an extended extra- and trans-cranial color-coded sonography study on 56 multiple sclerosis patients ( 36 female; 20 male ) and 20 control subjects ( 12 female; 8 male ). The analysis included extra-cranial venous blood volume flow ( BVF ), internal jugular vein ( IJV ) flow analysis during Valsalva maneuver, as well as tests included in the CCSVI criteria.
Results showed that blood flow direction was normal in all participants, excluding one subject with relapsing-remitting multiple sclerosis. Furthermore, the research team noted that blood volume flow in both groups were equal in the supine body position. In summary, the researchers determined that none of the study participants fulfilled more than one criterion for CCSVI.
Researchers did not find supporting evidence that cerebral venous congestion plays a significant role in the development of multiple sclerosis.
A second study by researchers at Umeå University in Sweden also concluded that CCSVI does not contribute to the development of multiple sclerosis. The Swedish research team led by Peter Sundström, tested the vital component of the CCSVI theory - the obstructed IJV flow- in 21 multiple sclerosis patients and 20 healthy controls using magnetic resonance imaging with phase contrast ( PC-MRI ).
Using PC-MRI, investigators were not able to reproduce the findings by Zamboni et al which suggest CCSVI contributes to the development of multiple sclerosis. The researchers found no significant differences between the multiple sclerosis group and control group relating to total IJV blood flow.
Multiple sclerosis is an inflammatory disease of the central nervous system in which lesions ( plaques ) form in the white matter of the brain and destroy the myelin sheath around nerve fibers. Initial symptoms of multiple sclerosis - typically blurred or double vision, muscle weakness, sensory changes, or difficulty with balance -usually appear between the ages of 20 and 40. The course can be relapsing-remitting or relentlessly progressive, and if untreated results in permanent neurologic disability in most affected individuals.
Multiple sclerosis affects 2.5 million individuals worldwide, making it one of the most common neurological disorders and causes of disability in young adults.
Source: Annals of Neurology, 2010
Acute coronary syndromes: Ticagrelor, a better option than Clopidogrel for patients undergoing invasive procedures
A new research has shown that Ticagrelor ( Brilinta ) reduces death rates without increasing bleeding compared with the current standard treatment of Clopidogrel ( Plavix ) for patients with myocardial infarction. This new analysis of the PLATO trial is published in The Lancet.
Clopidogrel is an antiplatelet drug that is used in combination with Acetylsalicylic acid ( Aspirin ) in patients with acute coronary syndrome, in order to prevent clots forming, thus reducing the risk of further myocardial infarction, stroke, and death. Ticagrelor is an antiplatelet drug that has a greater and more consistent antiplatelet effect than does Clopidogrel, with a faster onset and offset of action.
In this study, Researchers compared the two drugs in patients with acute coronary syndromes patients who were planned to undergo invasive procedures ( such as angioplasty and stenting of the coronary artery ).
At the beginning of the study, an invasive strategy was planned for 13,408 (72?0%) of 18,624 patients hospitalised for acute coronary syndromes. Patients were randomly assigned in a one-to-one ratio to Ticagrelor and placebo ( 180 mg loading dose followed by 90 mg twice a day ), or to Clopidogrel and placebo (300-600 mg loading dose or continuation with maintenance dose followed by 75 mg per day ) for 6-12 months. All patients were given Acetylsalicylic acid.
The primary endpoint was any of cardiovascular death, myocardial infarction, or stroke.
Patients in the Ticagrelor group were 16% less likely to experience the primary endpoint than those in the Clopidogrel group. The endpoint of cardiovascular death, heart attack, or stroke occurred in fewer patients in the Ticagrelor group than in the Clopidogrel group ( event rate at 360 days 9.0% vs 10.7% ).
The risk of death was also significantly reduced from 5% ( Clopidogrel ) to 3.9% ( Ticagrelor ), a reduction in the risk of dying over one year of around one fifth.
Blood clots developing inside heart stents were also significantly reduced. On the other hand, there was no statistically significant difference between Clopidogrel and Ticagrelor groups between Clopidogrel and Ticagrelor groups in the rates of total major bleeding ( 12% each group ), or severe bleeding ( 3% both groups ).
The Authors have commented that patients given Ticagrelor had significant and clinically relevant reductions in cardiovascular and total deaths, myocardial infarction, and stent thrombosis, without an increase in risk of major bleeding. The benefits with respect to clinical events and stent thrombosis were consistent whether or not patients were given standard or higher loading doses of Clopidogrel, as advocated for patients undergoing invasive strategies. Thereby, Ticagrelor has important advantages, and improves the early invasive and long-term management of patients with acute coronary syndromes.
According to Authors, the use of Ticagrelor instead of Clopidogrel for 1 year in 1000 patients with acute coronary syndromes and who are planned to undergo an invasive strategy at the start of drug treatment would lead to 11 fewer deaths, 13 fewer myocardial infarctions, and 6 fewer cases of stent thrombosis without an increase in the rates of major bleeding or transfusion.
According to Gregg W Stone, Columbia University Medical Center, these results support Ticagrelor as a new standard of care in acute coronary syndromes. However, a personalised approach to drug selection should be used wherein each patient's individualised risk of ischaemia versus bleeding is considered. Clopidogrel might still be appropriate for selected patients who are at relatively low risk of myocardial infarction or stent thrombosis and/or high risk of major bleeding, and/or for whom non-compliance with Ticagrelor because of cost or other considerations ( eg, twice daily dosing ) is a concern.
Source: Lancet, 2010
Children with autism spectrum disorders frequently receive psychotropic drugs
Behavioral interventions typically are the first line of treatment to manage unwanted behaviors in children with autism spectrum disorders ( ASDs ). If behaviors do not improve, medications frequently are added to the mix.
Research conducted by Autism Speaks' Autism Treatment Network ( ATN ) has shown that use of psychotropic drugs is common among children with ASD, with 27 percent of those enrolled in the network registry receiving at least one medication to manage their behavior. The most common reasons for medication use were hyperactivity, repetitive behaviors, irritability and attentional concerns.
An estimated one in 110 US children has autism, a group of complex developmental brain disorders that affect behavior, social skills and communication.
Although the FDA ( Food and Drug Administration ) has approved only two medications to treat certain symptoms seen in autism spectrum disorders, many other drugs are used to treat a variety of symptoms exhibited by these children.
ATN researchers sought to identify which medicines are prescribed for children on the autism spectrum and how frequently they are used. The ATN, which includes 14 Centers in the United States and Canada, enrolls patients ages 2-18 years with a diagnosis of autism, Asperger's syndrome or pervasive developmental disorder-not otherwise specified ( PDD-NOS ).
Medication data were available for 415 children in the registry. Results showed that 112 ( 27% ) were receiving at least one psychotropic drug for their behavior. Of these 112 children, 46% were taking two or more medications.
In addition, medication use was more common in older children: 60 percent of youths ages 11 and older took at least one medication compared to 44 percent of children ages 6-10 years, 11 percent of those ages 3-5 and 4 percent of children younger than 3.
The most common medications prescribed were stimulants, which are used to treat attention-deficit/hyperactivity disorder ( ADHD ). Symptoms of ADHD are among the most common problem behaviors reported by parents of children on the autism spectrum.
Risperidone ( Risperdal ), an atypical antipsychotic, also was prescribed frequently. The FDA has approved Risperidone for the treatment of irritability, including aggression, temper tantrums, self-injurious behavior and quickly changing moods associated with autism spectrum disorders.
Source: American Academy of Pediatrics, 2010
psychotropic drugs - children
psychotropic drugs - autism spectrum disorders
Increase in the risk of diabetes and cardiovascular diseases in men treated with GnRH agonists
GnRH ( Gonadotropin-Releasing Hormone ) agonists, a class of drugs primarily used to treat men with prostate cancer, have been associated with a small increased risk for diabetes, myocardial infarction, stroke, and sudden death.
At this time, FDA ( Food and Drug Administration ) has not made any conclusions about whether GnRH agonists cause an increase in the risk of diabetes and heart disease in patients receiving one of these medications to treat prostate carcinoma.
Agents in the GnRH class are marketed under the brand names Eligard, Lupron, Synarel, Trelstar, Vantas, Viadur, and Zoladex. There are also several generic products available.
The prostate gland is part of the male reproductive system. Prostate cancer is the second most common type of cancer among men in the United States, behind skin cancer, and usually occurs in older men. This year an estimated 203,415 new cases of prostate cancer will be diagnosed and about 28,372 men will die from the disease, according to the Centers for Disease Control and Prevention ( CDC ).
GnRH agonists are drugs that suppress the production of testosterone, a hormone that is involved in the growth of prostate cancer. This type of treatment is called androgen deprivation therapy. Suppressing testosterone has been shown to shrink or slow the growth of prostate cancer.
Some GnRH agonists are also used in women to help manage the pain caused by endometriosis, to improve anemia associated with uterine fibroids prior to hysterectomy and in some cases for palliative treatment of advanced breast cancer. Use of these products should not exceed one year for women except in treating breast cancer. There are no known comparable studies that have evaluated the risk of diabetes and heart disease in women taking GnRH agonists.
Some GnRH agonists are also used in children to treat central precocious puberty. There are no known studies that have evaluated the risk of diabetes and heart disease in children taking GnRH agonists.
Based on initial findings, FDA advises:
Health care professionals should be aware of these potential risks and carefully weigh the benefits and risks of GnRH agonists when determining a treatment for patients with prostate cancer;
Patients receiving a GnRH agonist should be monitored for the development of diabetes and cardiovascular disease;
Cardiovascular risk factors such as smoking and increases in blood pressure, cholesterol, blood sugar and weight should be managed according to current clinical practice;
Patients should not stop treatment with a GnRH agonist unless instructed to do so by a health care professional.
Source: FDA: 2010
Zyprexa: use in adolescents and safety informations
The FDA ( Food and Drug Administration ) has approved the use of oral Zyprexa ( Olanzapine ) in adolescents ( ages 13-17 ).
Information from the Indications and Usage section and Patient Counseling Information of the US product label are shown below:
Schizophrenia - Oral Zyprexa is indicated for the treatment of schizophrenia. Efficacy was established in three clinical trials in adult patients with schizophrenia: two 6-week trials and one maintenance trial. In adolescent patients with schizophrenia ( ages 13-17 ), efficacy was established in one 6-week trial.
Bipolar I disorder ( manic or mixed episodes ) - Monotherapy: oral Zyprexa is indicated for the acute treatment of manic or mixed episodes associated with bipolar 1 disorder and maintenance treatment of bipolar 1 disorder. Efficacy was established in three clinical trials in adult patients with manic or mixed episodes of bipolar I disorder: two 3-to 4-week trials and one monotherapy maintenance trial. In adolescent patients with manic or mixed episodes associated with bipolar I disorder ( ages 13-17 ), efficacy was established in one 3-week trial.
When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential ( in adolescents as compared with adults ) for weight gain and hyperlipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents.
Special considerations in treating pediatric schizophrenia and bipolar I disorder - Pediatric schizophrenia and bipolar I disorder are serious mental disorders; however, diagnosis can be challenging. For pediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, pediatric patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia and bipolar I disorder should be part of a total treatment program that often includes psychological, educational and social interventions.
Use in specific populations, pediatric use - Zyprexa is indicated for treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adolescents 13 to 17 years of age. Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin, and hepatic transaminase levels. Patients should be counseled about the potential long-term risks associated with Zyprexa and advised that these risks may lead them to consider other drugs first. Safety and effectiveness of Zyprexa in patients under 13 years of age have not been established. Safety and effectiveness of Zyprexa and Fluoxetine in combination in patients less than 18 years of age have not been established.
Need for comprehensive treatment program in pediatric patients - Zyprexa is indicated as an integral part of a total treatment program for pediatric patients with schizophrenia and bipolar disorder that may include other measures ( psychological, educational, social ) for patients with the disorder. Effectiveness and safety of Zyprexa have not been established in pediatric patients less than 13 years of age. Atypical antipsychotics are not intended for use in the pediatric patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders. Appropriate educational placement is essential and psychosocial intervention is often helpful. The decision to prescribe atypical antipsychotic medication will depend upon the physician?s assessment of the chronicity and severity of the patient?s symptoms.
The recommended starting dose in adolescents is lower than that in adults. Although no studies were conducted comparing adolescent and adult patients, safety information from adolescent studies was compared to safety information from adult studies. The types of adverse events observed in adolescents were similar to those seen in adult patients. However, the magnitude and frequency of some events were greater in adolescents than in adults. Compared to patients from adult clinical trials, adolescents were likely to gain more weight and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic transaminase levels, and sedation. Prescribers should review the following safety information and the enclosed full prescribing information and Medication Guide and carefully consider the individual risk-benefit assessment for each adolescent.
Hyperglycemia - Increases in fasting glucose were similar in adolescents and adults treated with Olanzapine; however, the difference between Olanzapine and placebo groups was greater in adolescents compared to adults.
In adolescents, as in adults, physicians should consider the risks and benefits when prescribing Olanzapine to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose levels ( fasting: 100-126 mg/dL, non-fasting: 140-200 mg/dL ). Patients taking Olanzapine should be monitored regularly for worsening of glucose control. Patients starting treatment with Olanzapine should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
Hyperlipidemia - In adolescents, as in adults, undesirable alterations in lipids have been observed with Olanzapine use. Clinically significant, and sometimes very high ( greater than 500 mg/dL) elevations in triglyceride levels have been observed with Olanzapine use. Modest increases in total cholesterol have also been seen.
Increases in fasting total cholesterol, LDL cholesterol, and triglycerides were generally greater in adolescents than in adults treated with Olanzapine.
Clinical monitoring, including baseline and periodic follow-up lipid evaluations is recommended.
Weight gain - As in adults, potential consequences of weight gain should be considered prior to starting Olanzapine in adolescents. Patients receiving Olanzapine should have their weight monitored regularly.
In Olanzapine-treated adolescent patients, both the magnitude of weight gain and the proportion of patients who had clinically significant weight gain were greater than in adult patients with comparable exposures. The percentages of adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure ( greater than or equal to 24 weeks) were 89%, 55%, and 29%, respectively. Discontinuation due to weight gain occurred in 2.2% of Olanzapine-treated adolescent patients following at least 24 weeks of exposure.
Hyperprolactinemia - Adolescents treated with Olanzapine had a higher incidence of elevated prolactin levels compared with adults. There was also a greater incidence of galactorrhea and gynecomastia in adolescents compared to adults.
Sedation - Sedation-related adverse events ( defined as hypersomnia, lethargy, sedation, and somnolence ) occurred at higher frequencies in adolescents compared to adults.
Because Olanzapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Olanzapine therapy does not affect them adversely.
Hepatic transaminase levels - Compared to adult patients in clinical trials, adolescents were more likely to have greater increases in hepatic transaminases.
In adolescents, as in adults, caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs.
Source: FDA, 2010
Zyprexa - adolescents
Zyprexa - safety
HIV infection: Saquinavir in combination with Ritonavir linked to abnormal heart rhythm
The FDA ( Food and Drug Administration ) is reviewing clinical trial data about a potentially serious effect on the heart from the use of Invirase ( Saquinavir ) in combination with Norvir ( Ritonavir ). The data suggest that together the two drugs may affect the electrical activity of the heart.
The changes to the electrical activity of the heart possibly associated with these drugs, known as prolonged QT or PR intervals, can be seen on an electrocardiogram ( EKG ). A prolonged QT interval can increase the risk for abnormal heart rhythms, including a serious abnormal rhythm called torsades de pointes. A prolonged PR interval can cause the electrical signal responsible for generating a heart beat to slow or even stop; this is known as heart block and can affect how fast the heart is able to beat.
Saquinavir and Ritonavir are antiviral medications given together to treat HIV infection. Ritonavir is given at a low dose with Saquinavir in order to increase the level of Saquinavirin the body. This is a process known as boosting.
FDA's analysis of these data is ongoing. However, healthcare professionals should be aware of this potential risk for changes to the electrical activity of the heart. Invirase and Norvir should not be used in patients already taking medications known to cause QT interval prolongation such as Class IA ( such as Quinidine ) or Class III ( such as Amiodarone ) antiarrhythmic drugs; or in patients with a history of QT interval prolongation.
Patients should not stop taking their prescribed antiviral medications. Patients who are concerned about possible risks associated with using Invirase and Norvir should talk to their healthcare professional.
The study data were submitted by Roche, the manufacturer of Invirase, based on FDA's request that all manufacturers of protease inhibitors, including Invirase, conduct a thorough QT study to evaluate the effect these drugs have on the QT and PR intervals.
The preliminary data has shown that when Invirase boosted with Norvir ( 1000 mg / 100 mg) was given to healthy patients, ages 18 to 55 years, there was a dose-dependent prolongation of the QT and PR intervals. The magnitude of the effect and clinical implications of QT and PR interval prolongation are still being reviewed by FDA.
These findings suggest that some patients using Invirase boosted with Norvir may be at an increased risk for developing abnormal heart rhythms. In particular, this risk may be increased in patients using other medications known to cause QT interval prolongation such as Class IA and Class III antiarrhythmic drugs or in patients with a history of QT interval prolongation.
Source: FDA, 2010
HIV infection - Saquinavir Ritonavir
Saquinavir Ritonavir - abnormal heart rhythm
Meridia is contraindicated in patients with history of cardiovascular disease or uncontrolled hypertension
The FDA ( Food and Drug Administration ) has reviewed additional data that indicate an increased risk of myocardial infarction and stroke in patients with a history of cardiovascular disease using Sibutramine ( Meridia ).
The Sibutramine drug label already includes warnings against the use of Sibutramine in patients with cardiovascular disease. However, based on the serious nature of the review findings, FDA requested to add a new contraindication to the Sibutramine drug label.
Sibutramine is contraindicated in patients with a history of cardiovascular disease, including: history of coronary artery disease ( e.g., myocardial infarction, angina ), history of stroke or transient ischemic attack ( TIA ), history of heart arrhythmias, history of congestive heart failure, history of peripheral arterial disease, uncontrolled hypertension ( e.g., > 145/90 mmHg ).
Patients currently using Sibutramine should talk with their healthcare professional to determine if continued use of Sibutramine is appropriate and discuss any questions they may have about their treatment.
Healthcare professionals should regularly monitor the blood pressure and heart rate of patients using Sibutramine and if sustained increases in blood pressure and/or heart rate are observed, Sibutramine should be discontinued. Additionally, Sibutramine should be discontinued in patients who do not lose at least 5% of their baseline body weight within the first three to six months of treatment, as continued treatment is unlikely to be effective and exposes the patient to unnecessary risk.
The Sibutramine Cardiovascular Morbidity/Mortality Outcomes in Overweight or Obese Subjects at Risk of a Cardiovascular Event ( SCOUT ) study was designed to show that weight loss with Sibutramine and standard care was more effective in reducing the number of cardiovascular events compared to weight loss from a placebo and standard care. Patients included in the study were 55 years of age or older, overweight or obese, and had a history of cardiovascular disease or type 2 diabetes plus one additional cardiovascular risk factor. Patients who recently had a heart attack or stroke, or had poorly controlled congestive heart failure were not included in the study. Approximately 10,000 patients enrolled in the study.
The November 2009 Early Communication from FDA described preliminary results from the SCOUT study indicating cardiovascular events occurred in 11.4% of patients using Sibutramine compared to 10% of patients using a placebo. This difference was higher than expected, suggesting that Sibutramine was associated with an increased cardiovascular risk in the study population.
The additional data from the SCOUT study reviewed by FDA indicate that the increased risk for cardiovascular events with Sibutramine occurred only in patients with a history of cardiovascular disease.
Source: FDA, 2010
Meridia - cardiovascular disease
Meridia - hypertension
Acute myeloid leukaemia: Pfizer has voluntarily withdrawn Mylotarg
Pfizer has announced the voluntary withdrawal from the US market of the drug Mylotarg ( Gemtuzumab ozogamicin ) for patients with acute myeloid leukemia ( AML ). The company took the action at the request of the FDA ( Food and Drug Administration ) after results from a recent clinical trial raised new concerns about the product?s safety and the drug failed to demonstrate clinical benefit to patients enrolled in trials.
Mylotarg was approved in May 2000 under the FDA?s accelerated approval program. This program allows the agency to approve a drug to treat serious diseases with an unmet medical need based on a surrogate endpoint ? a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that directly measures how a patient feels, functions, or survives.
Under accelerated approval, the company is required to conduct additional clinical trials after approval to confirm the drug?s benefit. If those trials fail to confirm clinical benefit to patients, or if the company does not pursue the required confirmatory trials with due diligence, the FDA can withdraw the drug from the market using expedited procedures.
Mylotarg was approved to treat patients ages 60 years and older with recurrent acute myeloid leukemia who were not considered candidates for other chemotherapy. The initial approval was based on the surrogate endpoint of response rate ( i.e., the percentage of patients whose leukemia decreased or disappeared in laboratory tests ), observed in 142 patients with acute myeloid leukemia across three clinical trials.
A confirmatory, post approval clinical trial was begun by Wyeth ( now Pfizer ) in 2004. The trial was designed to determine whether adding Mylotarg to standard chemotherapy demonstrated an improvement in clinical benefit ( survival time ) to patients with acute myeloid leukemia. The trial was stopped early when no improvement in clinical benefit was observed, and after a greater number of deaths occurred in the group of patients who received Mylotarg compared with those receiving chemotherapy alone.
At initial approval, Mylotarg was associated with a serious liver condition called veno-occlusive disease, which can be fatal. This rate has increased in the postmarket setting.
Source: FDA, 2010
acute myeloid leukaemia ? Mylotarg
Angiotensin receptor blockers linked to tumor: FDA is conducting a safety review
The FDA ( Food and Drug Administration ) is conducting a review of the class of medications known as angiotensin receptor blockers ( ARBs ) after a recently published study suggested they may be associated with a small increased risk of tumor.
FDA's review is ongoing and the Agency has not concluded that ARBs, also known as sartans, increase the risk of cancer.
At this time, FDA believes that the benefits of these medicines continue to outweigh their potential risks.
FDA recommends that these drugs continue to be used as recommended in their approved labels.
Sartans are used in patients with high blood pressure and other conditions. Brand names include Atacand ( Candesartan ), Avapro ( Irbesartan ), Benicar ( Olmesartan ), Cozaar ( Losartan ), Diovan ( Valsartan ), Micardis ( Telmisartan ), and Teveten ( Eprosartan ). ARBs are also sold in combination with other medications: Atacand HCT ( Candesartan and Hydrochlorothiazide ), Avalide ( Irbesartan and Hydrochlorothiazide ), Azor ( Olmesartan and Amlodipine ), Benicar HCT ( Olmesartan and Hydrochlorothiazide ), Diovan HCT ( Valsartan and Hydrochlorothiazide ), Exforge ( Valsartan and Amlodipine ), Exforge HCT ( Valsartan, Amlodipine, and Hydrochlorothiazide ), Hyzaar ( Losartan and Hydrochlorothiazide ), Micardis HCT ( Telmisartan and Hydrochlorothiazide ), Teveten HCT ( Eprosartan and Hydrochlorothiazide ), Twynsta ( Telmisartan and Amlodipine ), Valturna ( Valsartan and Aliskiren ).
The Agency plans to review the available data on these medications, and evaluate additional ways to better assess a possible link between use of sartans and cancer.
The published study was a meta-analysis combining cancer-related findings from several clinical trials. The study found a small increased risk of reported new tumors in patients taking an angiotensin receptor blocker compared to those not taking an ARB. No statistically significant difference in the number of cancer deaths was observed.
These clinical trials were not designed to study the effects of sartans on cancer risk. The findings need close examination for more detailed information about the patients who were reported to have tumor so that it can be determined whether this cancer was in fact new. Angiotensin receptor blockers have been shown to provide significant benefit in many patients with certain heart-related conditions such as high-blood pressure and heart failure.
The meta-analysis included data from over 60,000 patients in several long-term, randomized, controlled clinical trials evaluating angiotensin receptor blockers for which adverse events related to cancer were captured during the study. The mean duration of follow-up ranged from 1.7 to 4.8 years.
The study reported the frequencies of new cancer occurrence to be 7.2% for patients receiving sartans compared to 6.0% for those not receiving sartans ( risk ratio, RR= 1.08 ). No statistically significant difference in cancer deaths was noted.
The meta-analysis had several limitations that make it difficult to determine the validity of the findings without further examination of the underlying data. The limitations include: a) the analysis included data from trials where there was no adjudication of cancer-related adverse events. In these trials, there was no way to determine whether the events represented new diagnoses of cancer, or events related to a preexisting cancer. Thus, the actual number of new cancer occurrences is unknown; b) the analysis may not have included all relevant clinical trials of sartans; c) the analysis is not based on patient-level data. Knowledge of the specific timing and nature of events in individual patients would aid in interpretation of the findings; d) the majority of patients included in the studies reviewed were receiving the Telmisartan; therefore the applicability of the cancer-related findings to all sartans is uncertain; e) the meta-analysis was planned to examine a hypothesis raised by cancer-related trends in three outcome studies. Because the meta-analysis included two of these studies, the results of the meta-analysis do not provide a fully independent confirmation of the hypothesis raised by the earlier studies.
Source: FDA, 2010
angiotensin receptor blockers ? tumor
Olmesartan linked to cardiovascular events
The FDA ( Food and Drug Administration ) is evaluating data from two clinical trials in which patients with type 2 diabetes taking the blood pressure medication, Benicar ( Olmesartan ) had a higher rate of death from a cardiovascular cause compared to patients taking a placebo.
FDA's review is ongoing and the Agency has not concluded that Olmesartan increases the risk of death. FDA currently believes that the benefits of Olmesartan in patients with high blood pressure continue to outweigh its potential risks.
The Agency plans to review the primary data from the two studies of concern, ROADMAP and ORIENT, and is considering additional ways to assess the cardiovascular effects of Olmesartan.
ROADMAP and ORIENT are both long-term clinical trials. In both trials, patients with type 2 diabetes were given either Olmesartan or placebo to determine if treatment with Olmesartan would slow the progression of kidney disease. An unexpected finding observed in both trials was a greater number of deaths from a cardiovascular cause ( myocardial infarction, sudden death, or stroke ) in the Olmesartan-treated patients compared to placebo.
Olmesartan is in the class of drugs called angiotensin II receptor blockers ( ARBs or sartans ). These drugs and a closely related group of drugs called angiotensin-converting enzyme inhibitors ( ACEIs ) have been evaluated in many studies involving thousands of patients at high-risk for cardiovascular events, such as patients who had a previous myocardial infarction or had heart failure. No increased risk of cardiovascular-related death has been reported in these trials and, in fact, some of these studies indicate ARBs and ACEIs are useful as treatments for certain patients at high-risk for cardiovascular events.
In the United States, Olmesartan is also sold in combination with Hydrocholorothiazide as Benicar HCT for the treatment of hypertension.
Source: FDA, 2010
Olmesartan - cardiovascular events
High-dose Simvastatin associated with increased risk of muscle injury
Based on review of data from a large clinical trial and data from other sources, the FDA ( Food and Drug Administration ) has informed the public about an increased risk of muscle injury in patients taking the highest approved dose of the cholesterol-lowering medication, Zocor ( Simvastatin ) 80 mg, compared to patients taking lower doses of Simvastatin and possibly other statins.
The clinical trial data being reviewed is from the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine ( SEARCH ) trial. The Agency is also reviewing data from other clinical trials, observational studies, adverse event reports, and data on prescription use of Simvastatin to better understand the relationship between high-dose Simvastatin use and muscle injury.
The muscle injury, also called myopathy, is a known side effect with all statin medications. Patients with myopathy generally have muscle pain, tenderness or weakness, and an elevation of a muscle enzyme in the blood ( creatine kinase ). The higher the dose of statin used, the greater the risk of developing myopathy. The risk of myopathy is also increased when Simvastatin, especially at the higher doses, is used with certain drugs.
The most serious form of myopathy is called rhabdomyolysis. It occurs when a protein ( myoglobin ) is released as muscle fibers break down. Myoglobin can damage the kidneys. Patients with rhabdomyolysis may have dark or red urine and fatigue, in addition to their muscle symptoms. Damage to the kidneys from rhabdomyolysis can be so severe that patients may develop kidney failure, which can be fatal.
Known risk factors for developing rhabdomyolysis include age ( greater than 65 years ), hypothyroidism, and poor kidney function. Myopathy and rhabdomyolysis are listed as possible side effects in the Simvastatin and other statin drug labels.
The SEARCH trial evaluated over 6.7 years the number of major cardiovascular events ( myocardial infarction, revascularization, and cardiovascular death ) in 6031 patients taking 80 mg of Simvastatin compared to 6033 patients taking 20 mg of Simvastatin. All patients in the study had previously had a myocardial infarction.
Preliminary SEARCH trial results revealed that more patients in the Simvastatin 80 mg group developed myopathy compared to patients in the Simvastatin 20 mg group ( 0.9% compared to 0.02% ). Further, FDA's preliminary analyses of the primary data suggest that 11 ( 0.2% ) of the patients in the Simvastatin 80 mg group developed rhabdomyolysis compared to no patients in the Simvastatin 20 mg group.
In 2008, the Agency alerted the public about an increased risk of developing rhabdomyolysis when doses greater than 20 mg of Simvastatin are given with Amiodarone.
In March 2010, FDA approved a labeling revision for Simvastatin based on interim results from an ongoing clinical trial ? the Heart Protection Study 2 (HPS2). The revised label states that patients of Chinese descent should not receive Simvastatin 80 mg with cholesterol-modifying doses of niacin-containing products. Further, the revised label recommends caution when such patients are treated with Simvastatin 40 mg or less in combination with cholesterol-modifying doses of niacin-containing products. The interim HPS2 results showed that the incidence of myopathy was higher in patients of Chinese descent (0.43%) compared with patients not of Chinese descent ( 0.03% ) taking 40 mg Simvastatin plus cholesterol-modifying doses ( greater than or equal to 1 g/day ) of a Niacin-containing product. It is not known if the increased risk for myopathy observed in these patients applies to other patients of Asian descent.
Moreover, FDA has requested that the sponsor of Simvastatin change the product labeling to instruct healthcare professionals to avoid prescribing Simvastatin doses greater than 40 mg daily when patients are taking the medication Diltiazem, due to an increased risk for myopathy.
A 2010 review of prescription drug use data conducted by FDA found that, despite dose limitations and drug-drug interaction precautions included in the Simvastatin drug label, patients are continuing to be prescribed higher doses of Simvastatin with other medications that are known to increase the risk for rhabdomyolysis.
It is important for healthcare professionals to consider the potential risks and known benefits of Simvastatin compared to other cholesterol-lowering therapies when deciding to use Simvastatin. Healthcare professionals should also carefully review patients' medications for potential drug-drug interactions before prescribing or dispensing Simvastatin.
Simvastatin dose limitations
These limitations apply to all patients taking Simvastatin.
A) Do not use Simvastatin with these medications: Itraconazole, Ketoconazole, Erythromycin, Clarithromycin, Telithromycin, HIV protease inhibitors, Nefazodone;
B) Do not use more than 10 mg of Simvastatin with these medications: Gemfibrozil, Cyclosporine, Danazol;
C) Do not use more than 20 mg of Simvastatin with these medications: Amiodarone, Verapamil;
D) Do not use more than 40 mg of Simvastatin with this medication: Diltiazem.
Source: FDA, 2010
Sartans linked to risk of cancer
Angiotensin-receptor blockers ( also known as sartans ) are a widely used drug class approved for treatment of hypertension, heart failure, diabetic nephropathy, and for cardiovascular risk reduction.
Experimental studies implicate the renin-angiotensin system, particularly angiotensin II type-1 and type-2 receptors, in the regulation of cell proliferation, angiogenesis, and tumour progression.
Researchers at Case Western Reserve University School of Medicine, Cleveland, have evaluated whether sartans affect cancer occurrence, and carried out a meta-analysis of randomised controlled trials of these drugs.
Randomised controlled trials with an Angiotensin-receptor blocker given in at least one group, with a follow-up of at least 1 year, and that enrolled at least 100 patients were included in the analysis.
New-cancer data were available for 61,590 patients from five trials. Data on common types of solid organ cancers were available for 68,402 patients from five trials, and data on cancer deaths were available for 93,515 patients from eight trials.
Telmisartan ( Micardis ) was the study drug in 30,014 ( 85·7% ) patients who received sartans as part of the trials with new cancer data.
Patients randomly assigned to receive Angiotensin-receptor blockers had a significantly increased risk of new cancer occurrence compared with patients in control groups ( 7·2% vs 6·0%, risk ratio [RR] 1·08; p=0·016 ).
When analysis was limited to trials where cancer was a prespecified endpoint, the RR was 1·11 ( p=0·001 ).
Among specific solid organ cancers examined, only new lung-cancer occurrence was significantly higher in patients randomly assigned to receive sartans than in those assigned to receive control ( 0·9% vs 0·7%, RR 1·25; p=0·01 ).
No statistically significant difference in cancer deaths was observed ( 1·8% vs 1·6%, RR 1·07; p=0·183 ).
This meta-analysis of randomised controlled trials suggests that Angiotensin-receptor blockers are associated with a modestly increased risk of new cancer diagnosis. Given the limited data, it is not possible to draw conclusions about the exact risk of cancer associated with each particular drug.
Source: Lancet Oncology, 2010
Parkinson's disease: Stalevo linked to possible development of prostate carcinoma
The FDA ( Food and Drug Administration ) is evaluating clinical trial data that may suggest that patients taking Stalevo, a Parkinson's disease medication, may be at an increased risk for developing prostate cancer. In this trial, patients taking Stalevo were compared to those taking Carbidopa and Levodopa ( Sinemet ).
At this time, no new conclusions or recommendations about the use of this drug have been made.
Stalevo contains a combination of the active ingredients Entacapone, Carbidopa, and Levodopa. Entacapone is also available as a single-ingredient ( Comtan ). Both Stalevo and Comtan are used to treat symptoms of Parkinson's disease.
The data being reviewed are from a long-term clinical trial called STRIDE-PD ( Stalevo Reduction in Dyskinesia Evaluation ? Parkinson's Disease ).
STRIDE-PD evaluated the time to onset of dyskinesia ( difficulty controlling voluntary movement ) in patients with Parkinson's disease taking Stalevo compared to those taking Sinemet. An unexpected finding in the trial was that a greater number of patients taking Stalevo were observed to have prostate cancer compared to those taking the combination of Carbidopa and Levodopa.
The Agency is exploring additional ways to better understand if Stalevo actually increases the risk of prostate carcinoma. Previous controlled clinical trials of shorter duration evaluating Stalevo in Parkinson's disease have not found an increased risk of prostate tumor, and prostate cancer is most commonly diagnosed in men who are of the same age as men included in the STRIDE-PD trial.
Healthcare professionals should be aware of this possible risk and follow current guidelines for prostate cancer screening. Patients should not stop taking their medication unless directed to do so by their healthcare professional.
The STRIDE-PD trial was a double blind, randomized, parallel group, controlled clinical trial conducted at 77 centers in 14 countries, including 31 sites in the United States, between September 2004 and November 2008.The purpose of the trial was to evaluate the time to onset of dyskinesia in patients with Parkinson's disease taking Stalevo or Sinemet. A total of 745 patients with Parkinson's disease were enrolled in the trial and 541 completed treatment. Of the patients who completed treatment, 265 patients received Stalevo and 276 received Sinemet. Treatment lasted between 2.6 years and 4 years ( mean duration: 2.7 years ). The average age of patients in the trial was approximately 60 years. The majority of subjects were Caucasian ( 95.2% ) and male ( 62.7% ).
A total of 467 men received randomized treatment in the trial. Among those who received treatment, there was a higher number of cases of prostate cancer in patients in the Stalevo group compared those in the Carbidopa / Levodopa group. Specifically, 9 out of 245 males ( 3.7% ) had prostate cancer in the Stalevo group compared to the 2 out of 222 males ( 0.9% ) in the Sinemet group. The incidence rate of prostate cancer was 14 cases/1,000 patient years for Stalevo and 3.2 cases/1,000 patient years for Sinemet. The odds ratio for the occurrence of prostate cancer in males taking Stalevo was 4.19. Duration of therapy prior to diagnosis of prostate cancer in the Stalevo-treated group ranged from 148 days to 949 days ( mean: 664 days ).
STRIDE-PD is the first long-term clinical trial evaluating Stalevo in Parkinson's disease. Previous clinical trials with Stalevo did not find an increased risk for prostate cancer. Most of these trials evaluating this drug were conducted for less than a year, whereas STRIDE-PD was conducted over a 4 year period, with a mean duration of exposure of 2.7 years.
Source: FDA, 2010
EMA: positive benefit-risk balance of topical formulations of Ketoprofen
Following a review of topical formulations of Ketoprofen, the European Medicines Agency?s Committee for Medicinal Products for Human Use ( CHMP ) has concluded that the benefit-risk balance of these medicines continues to be positive. However, the Committee recommended that physicians should inform patients on how to use these medicines appropriately to prevent the occurrence of serious skin photosensitivity reactions.
Ketoprofen is a non-steroidal anti-inflammatory drug ( NSAID ). Topical formulations of Ketoprofen are used to treat minor trauma, tendonitis, small-joint osteoarthritis, acute low-back pain and phlebitis.
The review of these medicines had been initiated further to concerns over the risk of skin photosensitivity reactions, including photoallergy, and a new risk of co-sensitisation with Octocrylene ( a chemical sun filter included in several cosmetic and care products ).
Having reviewed all available safety data, including data from EU member states? databases and data provided by involved manufacturers, the CHMP has concluded that the risk of serious photoallergic reactions was very low ( 1 case per 1 million patients treated ) and that this risk could be minimised by harmonised risk-minimisation measures.
The Committee has recommended that topical Ketoprofen should only be used when prescribed by a physician. The CHMP has also recommended strengthening the contraindications and warnings on sun exposure and a warning on the risk of co-sensitisation when used together with Octocrylene-containing products.
Source: EMA, 2010
Modified-release oral opioids of the WHO level III scale for the management of pain: benefits of most of these medicines outweigh risks
The EMA ( European Medicines Agency ) has finalised a review of modified-release oral opioids of the WHO level III scale for the management of pain. The Agency?s Committee for Medicinal Products for Human Use ( CHMP ) has concluded that the benefits of most of these medicines continue to outweigh their risks, but that the existing warnings on the interaction of these drugs with alcohol should be made consistent across the class.
However, for modified-release oral opioids that contain a polymethacrylate-triethylcitrate controlled-release system the Committee recommended suspension of the marketing authorisations, until the manufacturers have reformulated them so that they are more stable in alcohol.
Modified-release oral opioids of the WHO level III scale for the management of pain are strong painkillers used to treat pain that has not been controlled with other medicines. They release the active substance slowly, often over many hours, to reduce the number of times patients have to take the medicine every day. Included in the class are Morphine and the related medicines Oxycodone and Hydromorphone.
These medicines were reviewed because of concerns that their controlled-release systems may be unstable in alcohol and that the active substance may be released too quickly when patients take them together with alcohol. This effect called dose dumping could put patients at risk of exposure to large doses of the opioid, which may lead to serious side effects such as respiratory depression.
Based on the evaluation of the available data, the CHMP found that around half of the controlled-release systems tested interacted with alcohol, but that this effect was mild and would only have a minor effect on the release of the active substance.
However, for opioids using a polymethacrylate-triethylcitrate controlled-release system, the CHMP found that there was a significant interaction with alcohol and that patients were at risk of dose dumping if they drink alcohol while taking them.
While the Committee noted that the current product information already contraindicates drinking alcohol when using strong opioids, it also noted some studies which show that many patients with severe pain drink alcohol while they are being treated with opioids.
The CHMP therefore recommended the suspension of the marketing authorisation of these medicines until the marketing authorisation holders have developed a more alcohol-stable controlled-release system.
For all other modified-release oral opioids of the WHO level III scale for the management of pain the Committee concluded that the benefits outweigh the risks, but that the existing warnings in the product information on the potential interaction with alcohol, e.g. the increased sedative effects of opioids, should be made consistent across the whole class.
Source: EMA, 2010
EMA: Modafinil for treatment of narcolepsy only
The EMA ( European Medicines Agency ) has recommended restricting the use of Modafinil-containing medicines. The medicine should only be used to treat sleepiness associated with narcolepsy. Physicians and patients should no longer use the medicine for the treatment of idiopathic hypersomnia, excessive sleepiness associated with obstructive sleep apnoea and chronic shift work sleep disorder.
Modafinil is a wakefulness promoting agent, currently licensed in 21 countries in Europe. They are available under the following invented names: Modasomil, Modiodal, Provigil and Vigil, and as generic medicines.
The review by the Agency?s Committee for Medicinal Products for Human Use ( CHMP ) was initiated because of a number of safety concerns, relating to psychiatric disorders, skin and subcutaneous tissue reactions as well as significant off-label use and potential for abuse.
On the basis of the available data the Committee has concluded that the benefits of these medicines only outweighed their risks in the therapeutic indication narcolepsy, a chronic sleep disorder characterised by excessive daytime sleepiness. For all other indications the Committee found that the risk for development of skin or hypersensitivity reactions and neuropsychiatric disorders outweighed the evidence for clinically important efficacy. Therefore, the Committee has concluded that all other indications should be withdrawn from the marketing authorisations of these medicines.
The risk of development of serious skin and hypersensitivity adverse reactions appears to be higher in children than in adults. The Committee concluded that the product information should carry a recommendation saying that Modafinil should not be prescribed to children.
The CHMP also identified particular cardiovascular risks with Modafinil and recommended that the use of the medicine be contraindicated in patients with uncontrolled moderate to severe hypertension and in patients with cardiac arrhythmias.
There are some reports that Modafinil is being used recreationally for performance enhancement. However, the data seen by the Committee did not allow it to make firm recommendations regarding this risk. The CHMP has requested that the marketing authorisation holders continue to provide further information to monitor the potential for abuse.
Source: EMA, 2010
EMA is reviewing benefit-risk balance of Avandia, Avandamet and Avaglim
The EMA ( European Medicines Agency ) is currently reviewing Rosiglitazone to determine the impact of new data from recent publications on the risk of cardiovascular problems on the benefit- risk profile of these medicines. Prescribers in the European Union are reminded to strictly follow the current restrictions in the product information.
Rosiglitazone, commercially known as Avandia, was initially authorised in the European Union in July 2000 as second-line diabetes type-2 treatment to be used when other treatments have either failed or are unsuitable for a patient. Avandia has been contra-indicated in patients with heart failure or a history of heart failure since its first authorisation. It was subsequently approved in combination with Metformin as Avandamet and with Glimepiride as Avaglim. Since then, the use of these medicines has been further restricted several times by new warnings and contra-indications on their use in patients with heart problems.
The current review of Rosiglitazone was initiated on 9 July 2010 on the request of the European Commission following publication of studies questioning the cardiovascular safety of the medicine. At its 19-22 July meeting the Agency?s Committee for Medicinal Products for Human Use ( CHMP ) held preliminary discussions, including with experts in diabetes, cardiovascular diseases and pharmacovigilance and with patients.
The Committee noted that additional new data sets have become available very recently. It will assess these data in depth together with all other available data on the benefits and risks of Rosiglitazone to allow the finalisation of the current review by September 2010.
While the CHMP is reviewing all available evidence on Rosiglitazone, prescribers in Europe are reminded to strictly follow the recommendations in the product information with respect to patients indicated for treatment, defined contraindications and warnings.
Prior to initiation of new treatment and in the ongoing monitoring of patients, physicians should pay particular attention to the following:
a) Rosiglitazone must not be used in patients with current or previous heart failure and in patients with acute coronary syndrome;
b) Rosiglitazone and Insulin should only be used together in exceptional cases and under close supervision;
c) the use of Rosiglitazone is not recommended in patients with ischaemic heart disease or peripheral arterial disease.
Source: EMA, 2010
Atypical antipsychotics among older adults with dementia: FDA warnings linked to reduced use
The use of atypical antipsychotics to treat elderly patients with dementia appears to have decreased following a 2005 FDA ( Food and Drug Administration ) advisory regarding the risks of these medications in this population.
Clozapine ( Clozaril, Leponex ), the first second-generation or atypical antipsychotic medication, was introduced in the United States in 1989. Several additional drugs, including Risperidone ( Risperdal ), Olanzapine ( Zyprexa ) and Paliperidone ( Invega ), followed. Although they are less likely to cause neurological adverse effects associated with conventional or typical antipsychotics, some reports have linked atypical antipsychotics to strokes, diabetes and other severe adverse events.
In April 2005, the FDA issued a public health advisory that asked manufacturers to include a boxed warning regarding the increased risk of death associated with using atypical antipsychotics to treat behavioral symptoms in older patients with dementia ( an off-label use of the drugs ).
E. Ray Dorsey, at the University of Rochester Medical Center, New York, and colleagues analyzed nationally representative data to assess rates of atypical antipsychotic drug use between January 2003 and December 2008. Physicians participating in the national index recorded diagnoses, therapies and patient characteristics for all clinical encounters over a two-day period. The researchers calculated the number of patient-physician interactions during which an antipsychotic was mentioned as a therapy and compared time periods before and after the FDA warning was issued to quantify its effects.
From January 2003 to March 2005, the rate of atypical drug mentions increased 34 percent per year, including a 16 percent increase among patients with dementia. In the year before the FDA advisory, approximately 13.6 million atypical antipsychotic mentions occurred, 0.8 million of which involved patients with dementia.
An overall decline in the use of atypical medications began within one month of the FDA advisory. Mentions of atypical antipsychotics decreased 2 percent overall and 19 percent among those with dementia in the year following the warning; by 2008, monthly drug uses among elderly patients with dementia decreased more than 50 percent.
The use of these medications for both FDA-approved and off-label indications continued decline for all populations through the end of the study period ( December 2008 ). However, despite the uncertain benefits and the decrease in use among elderly patients with dementia, atypical antipsychotics still comprised 9 percent of prescription drug uses for dementia among older adults by the end of 2008.
In conclusion, the residual use in the population at risk and the decrease in the use of atypical antipsychotics in the general population, who were not targeted by the warning, raise the question as to whether the effect and specificity of FDA regulatory actions could be enhanced. Targeting specific segments of patients and physicians ( e.g., high prescribers ) and further customizing and evaluating the impact of regulatory actions may improve their impact at minimizing the risks associated with select prescription medications.
Source: Archives of Internal Medicine, 2010
Routine cessation of Clopidogrel in patients before colonoscopy polypectomy is not necessary
Researchers at the Syracuse Veterans Affairs Medical Center in New York examined postpolypectomy bleeding in patients undergoing colonoscopy on uninterrupted Clopidogrel ( Plavix ) and found that the postpolypectomy bleeding rate is significantly higher in patients undergoing polypectomy while taking Clopidogrel and concomitant Acetylsalicylic acid ( Aspirin ) / nonsteroidal anti-inflammatory drugs ( NSAIDs ), but that the risk is small and the outcome is favorable. This is the first study to evaluate postpolypectomy bleeding in patients on uninterrupted Clopidogrel therapy and concludes that routine cessation of Clopidogrel in patients before colonoscopy polypectomy is not necessary.
The study is published in the Gastrointestinal Endoscopy.
Colonoscopy is recommended as the primary screening method for colorectal cancer because of the ability to diagnose and remove polyps before they become cancer. Polyp removal is also referred to as polypectomy. Bleeding is the most common complication of colonoscopic polypectomy, ranging from 0.3 percent to 3.6 percent per patient. A number of factors contribute to postpolypectomy bleeding ( PPB ), among them, anticoagulants significantly increase the risk of PPB, whereas antiplatelet agents, Acetylsalicylic acid , and other nonsteroidal anti-inflammatory drugs do not. Uninterrupted use of Clopidogrel, a newer antiplatelet agent, is recommended in cardiac patients with drug-eluding stents.
The concern for most endoscopists is the potential increased risk of bleeding after therapeutic interventions, especially polypectomy, in patients whose coagulation status is impaired. The concern for the patient and his or her other treating physicians is the potential for thromboembolic events, which may pose a substantial, even life-threatening, risk to the patient whose anticoagulation therapy is interrupted. Data on the actual risk of the occurrence of these events are limited, particularly for the risks of postpolypectomy bleeding.
The retrospective study included all patients who underwent a colonoscopy with or without a polypectomy on uninterrupted Clopidogrel therapy between January 2002 and October 2007 at the Veterans Affairs Medical Center in Syracuse, New York. Electronic pharmacy records and current procedural terminology codes identified patients receiving Clopidogrel therapy at the time of colonoscopy during the study period. Group A ( cases ) included 142 patients who underwent polypectomy and 77 underwent colonoscopy without a polypectomy. Group B ( controls ) comprised 1,243 randomly selected patients during the same period who had undergone colonoscopic polypectomy but were not receiving Clopidogrel therapy. Patients with acute gastrointestinal bleeding were excluded.
Demographics, clinical parameters, polyp characteristics, polypectomy techniques, and postpolypectomy events in the groups were compared by univariate analysis. Stepwise logistic regression analyses identified independent risk factors associated with PPB. There was no difference in polyp number per patient, location, adenoma detection rate, and polypectomy technique between groups A and B.
Forty-six patients had postpolypectomy bleeding, 8 in group A and 38 in group B. Among the postpolypectomy bleeders, Acetylsalicylic acid / NSAID use was significantly higher in patients taking Clopidogrel ( 8/8 vs. 16/38 not on Clopidogrel ). The intraprocedural bleeding rate was similar in the two groups ( 2.1 percent vs. 2.1 percent ). Delayed postpolypectomy bleeding rate was higher in the group taking Clopidogrel ( 3.5 percent vs. 1.0 percent ). Delayed bleeding of significance requiring hospitalization and transfusion/intervention was also higher in patients taking Clopidogrel ( 2.1 percent vs. 0.4 percent ). The length of hospital stay and interventions for postpolypectomy bleeding were comparable between the two groups. There was no mortality.
Univariate comparison between 46 PPB cases and 1,339 nonbleeders showed that patients with postpolypectomy bleeding were older and had more polyps removed. Use of Clopidogrel alone or Acetylsalicylic acid / NSAIDs alone was comparable between postpolypectomy bleeding patients and nonbleeders, however, the concomitant use of Clopidogrel and Acetylsalicylic acid / NSAID was significantly higher among postpolypectomy bleeding patients. Concomitant use of Clopidogrel and Acetylsalicylic acid / other NSAIDs and the number of polyps removed were the only significant risk factors associated with postpolypectomy bleeding. Clopidogrel alone was not an independent risk factor for postpolypectomy bleeding.
Researchers concluded that the postpolypectomy bleeding rate is significantly higher in patients undergoing polypectomy while taking Clopidogrel and concomitant Acetylsalicylic acid / nonsteroidal anti-inflammatory drugs, but the risk is small and the outcome is favorable. Routine cessation of Clopidogrel in patients before colonoscopy polypectomy is not necessary. This is the first study to show that in patients taking Clopidogrel, postpolypectomy bleeding did not occur without concomitant Acetylsalicylic acid / NSAID use.
Researchers further noted that stopping Clopidogrel in individuals with cardiovascular and atherothrombotic diseases predisposes them to the serious risk of acute ischemic events, especially when Clopidogrel is held within 90 days of initiation of therapy. They support the recommendation to defer elective/screening colonoscopy for the first 6 to 12 months after coronary intervention. Even after 12 months, it is unnecessary to hold Clopidogrel in all individuals undergoing a screening colonoscopy for polyp detection rates of 25 percent to 35 percent.
Source: American Society for Gastrointestinal Endoscopy, 2010
colonoscopy polypectomy - Clopidogrel
Rotarix: porcine circovirus type 1 in the oral vaccine poses no risk to public health, according to EMA
Following a review of the oral vaccine Rotarix, the European Medicines Agency?s Committee for Medicinal Products for Human Use ( CHMP ) has concluded that the vaccine continues to have a positive benefit-risk balance and that the presence of a very small amount of viral particles does not present a risk to public health.
Results from a very large clinical study database, together with safety data from millions of children who have already received the vaccine, show no safety concern with the vaccine.
Rotarix is a vaccine given by mouth to children of 6 weeks and older, to protect against gastroenteritis ( diarrhoea and vomiting ) due to rotavirus infection.
It is prepared from live human rotavirus strains that are manipulated to make them unable to cause the disease, while keeping their ability to trigger an immune response. Rotarix was approved in the European Union ( EU ) in February 2006. It is not usually part of Member States? childhood vaccination schedules, but is approved in all EU Member States. As for many vaccines, Rotarix is given according to official recommendations in line with vaccination programmes in the different Member States. The vaccine is widely used outside of the European Union and is part of the World Health Organization ( WHO ) prequalification programme for vaccines. Some 51,000 children received the vaccine in clinical trials ( out of a total of 91,000 children ) and about 68 million doses have been distributed worldwide to date.
The review of Rotarix was initiated after the unexpected detection of DNA of Porcine circovirus type 1 ( PCV-1 ) in the vaccine. PCV-1 is commonly found in certain meat and other food products, and is not known to cause any disease in either humans or animals.
Data from tests carried out by the manufacturer, GlaxoSmithKline Biologicals, showed that the vaccine contained only very small amounts of live PCV-1. The viral particles may have always been present in the vaccine, and have been found in the raw material used to make the vaccine. Their presence was detected only now because of the emergence of new technology.
The Committee concluded that the detection of PCV-1 did not change the benefit-risk balance of Rotarix, and noted that the vaccine is effective in preventing rotavirus infections which are responsible for half a million deaths each year, mostly in developing countries.
However, since PCV-1 should not be present in the Rotarix vaccine, the manufacturer has proposed measures to manufacture the vaccine free of the virus.
Source: EMA, 2010
Sartans: higher incidence of lung tumor
Sartans, or Angiotensin-receptor blockers, are a class of blood-pressure-lowering drug that is also used for the treatment of heart failure and diabetic nephropathy.
A significant excess of fatal tumors was observed in the CHARM trial with Candesartan ( Atacand ), published in 2003, but that the Researchers concluded this finding was likely due to chance.
Investigators at Case Western Reserve University School of Medicine, Cleveland, have decided to perform a meta-analysis of clinical trials.
New cancer data were available for 61,950 patients from five trials, including only three of the seven FDA-approved sartans; most patients in this meta-analysis ( 85.7% ) received Telmisartan ( Micardis ) as study drug; the other patients received Losartan or Candesartan. The five trials with new cancer data were ONTARGET, PROFESS, LIFE, TRANSCEND, and CHARM-Overall. In addition, data were available for cancer deaths in LIFE, TRANSCEND, VALIANT, and Val-HeFT.
It is unknown whether other sartans, as Irbesartan ( Avapro ), Valsartan ( Diovan ), Olmesartan ( Benicar ), and Eprosartan ( Teveten ), are linked to a higher risk of new cancer incidence.
Given the limited data, it is not possible to draw conclusions about the exact risk of cancer associated with each Angiotensin-receptor blocker.
In the meta-analysis, patients randomly assigned to receive sartans had a significantly increased risk of new cancer occurrence, compared with those in the control groups ( 7.2% vs 6%; risk ratio [RR] 1.08; p=0.016 ).
When analysis was limited to trials where cancer was a prespecified end point, the RR was 1.11 ( p=0.001 ).
Among the malignancies examined ( lung, breast, and prostate ) only new lung-cancer occurrence was significantly higher in those randomly assigned to sartans than in control subjects ( 0.9% vs 0.7%; RR 1.25; p=0.01 ).
It has been seen a weak trend for an increased risk of prostate cancer with Angiotensin-receptor antagonists use.
There was no significant difference in cancer deaths observed in the meta-analysis between those who took Angiotensin-receptor blockers and control subjects ( 1.8% vs 1.6%; RR 1.07; p=0.183 ). But the Researchers noted that tumor death is typically a slow process and, with the present trials, it is not possible to make conclusions regarding the effect of sartans on cancer-related deaths.
Source: Lancet Oncology, 2010
Low-risk patients undergoing elective PCI: platelet function tests may provide modest benefit in predicting cardiac outcomes
An analysis of six tests that are used to measure platelet function and help gauge the effectiveness of antiplatelet drugs for patients undergoing a cardiac procedure such as a coronary stent implantation found that only three of the tests were associated with a modest ability to predict outcomes such as heart attack or death.
Dual antiplatelet therapy with Acetylsalicylic acid ( Aspirin ) and Clopidogrel ( Plavix ) reduces atherothrombotic complications in patients undergoing percutaneous coronary intervention ( PCI ) with stenting. However, the individual response to dual antiplatelet therapy is not uniform. There currently is no consensus regarding the most appropriate method to quantify the magnitude of effect an antiplatelet agent may have on platelet reactivity.
Nicoline J. Breet, of St. Antonius Hospital in Nieuwegein ( Netherlands ), and colleagues conducted a study to evaluate the ability of multiple platelet function tests to predict atherothrombotic events, including stent thrombosis, in 1,069 Clopidogrel-pretreated patients undergoing elective coronary stent implantation. Using blood samples, platelet reactivity was measured in parallel with six platelet function tests. The primary outcome measured was a composite of all-cause death, nonfatal heart attack, stent thrombosis and ischemic stroke.
The researchers found that at 1-year follow-up, the primary outcome occurred more frequently in patients with high platelet reactivity when assessed by the tests light transmittance aggregometry, VerifyNow and Plateletworks, which also had modest ability to discriminate between patients having and not having a primary event. The three other testing methods ( IMPACT-R, Dade PFA collagen/ADP, and Innovance PFA P2Y ) were unable to discriminate between patients with and without the primary outcome. None of the tests identified patients at risk for bleeding.
In conclusion, of the platelet function tests assessed, only light transmittance aggregometry, VerifyNow, and Plateletworks were significantly associated with the primary end point. However, the predictability of these 3 tests was only modest. None of the tests provided accurate prognostic information to identify patients at higher risk of bleeding. Thus, this study does not support the use of platelet function testing to guide clinical practice in a low-risk population of patients undergoing elective PCI.
Source: Journal of American Medical Association, 2010
Olmesartan increases risk of death
The FDA ( Food and Drug Administration ) has not concluded that Olmesartan ( Benicar ) increases the risk of death. In the ROADMAP and ORIENT trials, there were a greater number of cardiovascular-related deaths in the Olmesartan group compared to the placebo group.
Other controlled clinical trials evaluating Olmesartan and other angiotensin II receptor blockers ( also known as sartans ) have not suggested an increased risk of cardiovascular-related death.
The Randomized Olmesartan and Diabetes Microalbuminuria Prevention Study ( ROADMAP ) was a randomized, double-blind, placebo-controlled, multicenter trial conducted in Europe. The trial included 4,447 patients with type 2 diabetes and at least one additional cardiovascular risk factor, but without overt evidence of nephropathy. Patients were randomized to receive either 40 mg of Olmesartan or placebo daily. Patients were permitted to receive other antihypertensive medications, but not angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.
The primary objective was to evaluate whether Olmesartan could delay the onset of microalbuminuria. The majority of patients had 3 to 5 cardiovascular risk factors and 80% of patients were using other antihypertensives. The mean duration of exposure to Olmesartan was 39 months.
There were 15 cardiovascular deaths ( seven cases of sudden death, five fatal myocardial infarctions, two fatal strokes, and one death related to coronary revascularization ) in the Olmesartan group compared with a total of three cardiovascular deaths ( one sudden death and two fatal strokes ) in the control group.
The Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial ( ORIENT ) was a randomized, double-blind, placebo-controlled, multicenter trial conducted in Japan and Hong Kong. Patients ( n= 566 ) with type 2 diabetes and overt nephropathy were randomized to receive Olmesartan 10 mg to 40 mg or placebo daily. Patients were permitted to take additional antihypertensives including angiotensin-converting enzyme inhibitors, but excluding angiotensin II receptor blockers. The primary composite endpoint was the time to first event of doubling of serum creatinine, end stage renal disease, and all cause death.
Of the 10 cardiovascular deaths in the Olmesartan group, five were sudden death, one was a fatal myocardial infarction, three were fatal strokes, and one was of unknown cardiovascular cause. Three patients in the control group died, two from sudden death and one from myocardial infarction.
An unexpected finding in both trials was an increased number of cardiovascular deaths in the patients receiving Olmesartan compared to placebo.
In considering the results of these trials, it is important to remember that numerous clinical trials with Olmesartan as well as trials with other sartans have not suggested an increased risk of cardiovascular-related death.
To evaluate the possible association with Olmesartan and increased cardiovascular-related death, FDA plans to review the primary data from the two trials and the total clinical trial data on Olmesartan. Also, the Agency will evaluate additional ways to understand the findings from ROADMAP and ORIENT, in light of information supporting the use of sartans and ACE inhibitors in certain patients at high risk for cardiovascular events.
Source: FDA, 2010
Olmesartan - death
FDA: new recommendations on the appropriate use of LABAs in the treatment of asthma
Long-acting beta-agonists ( LABAs ), a class of medications used for the treatment of asthma and chronic obstructive pulmonary disease ( COPD ), have new recommendations in their drug label intended to promote their safe use in the treatment of asthma. The new recommendations do not apply to the use of LABAs for the treatment of COPD.
In February 2010, the FDA ( Food and Drug Administration ) announced it was requiring manufacturers to revise their drug labels because of an increased risk of severe exacerbation of asthma symptoms, leading to hospitalizations, in pediatric and adult patients, as well as death in some patients using LABAs for the treatment of asthma.
The new recommendations in the updated labels state:
Use of a LABA alone without use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated in the treatment of asthma.
LABAs should not be used in patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.
LABAs should only be used as additional therapy for patients with asthma who are currently taking but are not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid.
Once asthma control is achieved and maintained, patients should be assessed at regular intervals and step down therapy should begin ( e.g., discontinue LABA ), if possible without loss of asthma control, and the patient should continue to be treated with a long-term asthma control medication, such as an inhaled corticosteroid.
Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA, to ensure adherence with both medications.
FDA believes that when LABAs are used according to the recommendations outlined above and in the approved drug labels, the benefits of LABAs in improving asthma symptoms outweigh their risks of increasing severe asthma exacerbations and deaths from asthma.
Source: FDA, 2010
asthma - LABAs
Ticagrelor more effective than Clopidogrel in myocardial infarction patients
New research has shown that the stronger anticlotting medication Ticagrelor ( Brilinta ) reduces death rates without increasing bleeding compared with the current standard treatment of Clopidogrel for myocardial infarction patients.
Clopidogrel ( Plavix ) is an antiplatelet drug that is used in combination with Acetylsalicylic acid ( Aspirin ) in patients with acute coronary syndrome ( non-ST segment myocardial infarction / unstable angina ), in order to prevent clots forming, thus reducing the risk of further myocardial infarctions, stroke, and death.
Ticagrelor is an antiplatelet drug that has a greater and more consistent antiplatelet effect than does Clopidogrel, with a faster onset and offset of action.
In this study, PLATO researchers compared the two drugs in patients with acute coronary syndromes patients who were planned to undergo invasive procedures.
At the beginning of the study, an invasive strategy was planned for 13,408 (72?0%) of 18,624 patients hospitalised for acute coronary syndromes. Patients were randomly assigned in a one-to-one ratio to Ticagrelor and placebo ( 180 mg loading dose followed by 90 mg twice a day ), or to Clopidogrel and placebo ( 300-600 mg loading dose or continuation with maintenance dose followed by 75 mg per day ) for 6-12 months. All patients were given Acetylsalicylic acid.
The primary endpoint was any of cardiovascular death, myocardial infarction, or stroke.
Patients in the Ticagrelor group were 16% less likely to experience the primary endpoint than those in the Clopidogrel group. The endpoint of cardiovascular death, heart attack, or stroke occurred in fewer patients in the Ticagrelor group than in the Clopidogrel group ( event rate at 360 days 9.0% vs 10.7% ). The risk of death was also significantly reduced from 5.0% ( Clopidogrel ) to 3.9% ( Ticagrelor ), a reduction in the risk of dying over one year of around one fifth. Blood clots developing inside heart stents were also significantly reduced. On the other hand, there was no statistically significant difference between Clopidogrel and Ticagrelor groups between Clopidogrel and Ticagrelor groups in the rates of total major bleeding ( 12% each group ), or severe bleeding ( 3% both groups ).
Patients given Ticagrelor had significant and clinically relevant reductions in cardiovascular and total deaths, myocardial infarction, and stent thrombosis, without an increase in risk of major bleeding. The benefits with respect to clinical events and stent thrombosis were consistent whether or not patients were given standard or higher loading doses of Clopidogrel, as advocated for patients undergoing invasive strategies. Thereby, Ticagrelor has important advantages, and improves the early invasive and long-term management of patients with acute coronary syndromes.
In conclusion, the use of Ticagrelor instead of Clopidogrel for 1 year in 1000 patients with acute coronary syndromes and who are planned to undergo an invasive strategy at the start of drug treatment would lead to 11 fewer deaths, 13 fewer myocardial infarctions, and 6 fewer cases of stent thrombosis without an increase in the rates of major bleeding or transfusion.
Gregg W Stone, Columbia University Medical Center, New York, has commented that these compelling results support Ticagrelor as a new standard of care in acute coronary syndromes. However, a personalised approach to drug selection should be used wherein each patient's individualised risk of ischaemia versus bleeding is considered. Clopidogrel might still be appropriate for selected patients who are at relatively low risk of myocardial infarction or stent thrombosis and/or high risk of major bleeding, and/or for whom non-compliance with Ticagrelor because of cost or other considerations ( eg, twice daily dosing ) is a concern. Nonetheless, the introduction of Ticagrelor, a more potent and effective agent which is as safe as its predecessor, is a landmark event that should redefine the care of patients with acute coronary syndromes.
Source: Lancet, 2010
Epilepsy: Levetiracetam, Topiramate and Vigabatrin may increase risk of suicide
A new study has shown that only certain epilepsy drugs may increase the risk of suicide. The study is published in the Neurology.
Newer drugs with a higher risk of causing depression than other epilepsy drugs, such as Levetiracetam ( Keppra ), Topiramate ( Topamax ) and Vigabatrin ( sabril ), were found to increase the risk of self-harm or suicidal behavior among people with epilepsy.
In contrast, newer drugs that have a low risk of causing depression and conventional epilepsy drugs did not have any increased risk of self-harm or suicidal behavior. These groups include drugs such as Lamotrigine ( Lamictal ), Gabapentin ( Neurontin ), Carbamazepine ( Tegretol ), Valproate ( Depakene ) and Phenytoin ( Dilantin ).
An earlier analysis of data by the FDA ( Food and Drug Administration ) grouped all of the epilepsy drugs together and found an increased risk of suicidal thoughts and behavior.
In an editorial accompanying the article, Josemir Sander, of the University College London in the United Kingdom and the Epilepsy Institute of the Netherlands Foundation and Marco Mula, of the University Hospital Maggiore della Carità in Novara, Italy, noted that some researchers have been concerned that the risks of people stopping taking their epilepsy drugs or not starting to take a drug due to worries about the risk of suicide would be greater than the risk of suicidal behavior.
The study looked at all of the people in the United Kingdom General Practice Research Database who had epilepsy and had at least one prescription for an epilepsy drug from 1989 through 2005. The participants were followed for an average of five and a half years. Of the 44,300 people, 453 had harmed themselves or attempted suicide; 78 people died at the time or within four weeks of the initial attempt. The 453 people were compared to 8,962 in the larger group who had not harmed themselves or attempted suicide.
People who were currently using the newer drugs with a higher risk of depression, such as Levetiracetam, Topiramate and Vigabatrin, were three times more likely to harm themselves or attempt suicide than those who were not currently taking any epilepsy drugs. A total of six of the 453 people, or 1.3 percent, who harmed themselves or attempted suicide were taking the newer drugs with the higher risk of depression, compared to 45 of the 8,962 people, or 0.5 percent, of those who did not harm themselves.
According to the Authors, the number of people taking some of the drugs was small, so the results need to be confirmed by additional studies. People should not abruptly stop or change their epilepsy medication based on the findings of this study but should discuss this issue with their physician.
Source: American Academy of Neurology, 2010
epilepsy - Levetiracetam,
epilepsy - Topiramate
epilepsy - Vigabatrin
Levetiracetam - risk suicide
Topiramate ? risk suicide
Vigabatrin - risk suicide
Everolimus-eluting stent better than paclitaxel-eluting stent in unselected patients
The Everolimus-eluting stent is better than the second generation Paclitaxel-eluting stent in unselected patients undergoing percutaneous coronary intervention (PCI)*in terms of safety and efficacy, concludes the COMPARE study, published Online First (www.thelancet.com) and in an upcoming edition of the Lancet. On the basis these findings, the authors suggest that paclitaxel-eluting stents should no longer be used in everyday clinical practice. The Article is written by Dr Pieter Cornelis Smits, Dr. Elvin Kedhi, and Dr. Eugene McFadden, Department of Cardiology, Maasstad Ziekenhuis, Rotterdam, the Netherlands, and colleagues.
Compared with the currently available first-generation drug-eluting stents, second-generation drug-eluting stents have been designed with the goal of improving safety, efficacy, and device performance. Everolimus, a semisynthetic sirolimus analogue, is released from a thin coating of biocompatible fluoropolymer on an open cell, thin strut, cobalt-chromium frame. A significant reduction in serious adverse cardiac events was noted in patients with the everolimus-eluting stent compared with those who had the first-generation paclitaxel-eluting stent. This first-generation stent has been superseded in Europe by the new-generation paclitaxel-eluting stent since September, 2005. Whether such differences persist with a new-generation paclitaxel-eluting stent that consists of the same polymer but has a different stent platform is not known.
The COMPARE study randomly assigned 1800 consecutive patients (aged 18? years) undergoing PCI at one centre to treatment with everolimus-eluting and second-generation paclitaxel-eluting stents. The primary endpoint was a composite of safety and efficacy (all-cause mortality, heart attack, and target vessel revascularisation**) within 12 months.
Follow-up was completed in 1797 patients. The primary endpoint occurred in 56 (6%) patients in the everolimus-eluting stent group versus 82 (9%) in the paclitaxel-eluting stent group (relative risk of primary endpoint occurring was 31% lower for the everolimus group). The difference was attributable to a lower rate of stent thrombosis (6 [<1%] vs 23 [3%]), heart attack (25 [3%] vs 48 [5%]), and target vessel revascularisation (21 [ 2%] vs 54 [6%]). Cardiac death, non-fatal myocardial infarction, or target-lesion revascularisation occurred in 44 [5%] patients in the everolimus-stent group versus 74 [8%] patients in the paclitaxel-stent group.
The authors say: "The use of second-generation everolimus-eluting stents, compared with paclitaxel-eluting stents, was associated with a significant reduction in the risk of major adverse cardiac events at 1 year. This difference was a result of reduction in the rate of myocardial infarction, a safety component of the primary endpoint, and reduction in repeat revascularisation of the target vessel."
They conclude: "The everolimus-eluting stent is better than the second generation paclitaxel-eluting stent in unselected patients in terms of safety and efficacy. On the basis of our results, we suggest that paclitaxel-eluting stents should no longer be used in everyday clinical practice."
FDA has received reports of malignancies in children using TNF antagonists
The FDA ( Food and Drug Administration ) has received reports of malignancies in children using tumor necrosis factor alpha ( TNF ) blockers, raising concerns of an associated risk and prompting an investigation. Researchers from the FDA set out to identify all reports of malignancy in children using Infliximab ( Remicade ), Etanercept ( Enbrel ), and Adalimumab ( Humira ).
The FDA has approved 3 TNF blockers for use in children: Etanercept to treat juvenile idiopathic arthritis ( JIA ); Infliximab to treat Crohn's disease; and Adalimumab to treat JIA. Data suggest that certain adult populations may be at an increased risk of malignancy with TNF blocker therapy. The immunosuppressive properties of TNF blockers may also increase the risk of malignancy in children, but to what extent is unclear.
Cancer is very rare in children. According to the National Cancer Institute's Surveillance, Epidemiology, and End-Results ( SEER ) database, the United States annual incidence rate for all cancers in children ages 0-18 years was 16.8/100,000 compared with the rate of 469.7/100,000 for all cancers in adults, age adjusted to the year 2000 U.S. population. When 48 incidences of malignancy were identified among pediatric patients treated with TNF blockers, there was cause for concern.
According the study leader Peter Diak, the number and rare types of malignances reported in these cases are worrisome given the underreporting of adverse events in the Adverse Event Reporting System ( AERS ) database, the long latency period of malignancy, and the relatively small number of pediatric patients treated with TNF blockers.
The study team searched the AERS database for all reports of malignancy in children using Infliximab, Etanercept, and Adalimumab who initiated therapy between the ages of 0 and 18 years. The 48 cases identified included 31 following Infliximab use, 15 following Etanercept use, and 2 following Adalimumab use. The reporting rates for Infliximab and Etanercept were compared with the background cancer rate in the general pediatric population. Reporting rates were not calculated for Adalimumab because only 2 cases were reported, and previous use of other TNF blockers was reported in both cases. Most of the children evaluated received TNF blocker therapy for a prolonged period, a median of 30 months, suggesting these cases were not preexisting malignancies that were misdiagnosed as a rheumatic condition.
The analysis showed the reporting rate for U.S. cases of malignancy in children for Infliximab was 66 per 100,000 patient years, 4 times the estimated background rate for the general U.S. pediatric population. For lymphomas in children, the reporting rate was 44 per 100,000 patient years, 18 times the background rate. If cases of hepatosplenic T cell lymphoma are excluded from the calculation, the reporting rate for lymphomas with Infliximab drops to 22 per 100,000 patient years but still exceeds the background rate by 9 times. For Etanercept, the reporting rate for U.S. cases of malignancy in children was 22 per 100,000 patient years and approximated the background rate. However, for lymphomas, the reporting rate with Etanercept was 11 per 100,000 patient years, 5 times the background rate for lymphomas in children.
The team has concluded that the risk of malignancy should be considered prior to initiating TNF blockers in children, particularly as some of the reported cases involved types of cancers not commonly seen in children and that are usually associated with immunosuppression. Further, they suggest that the true incidence rate for these events in the pediatric population may be even higher due to substantial under-reporting to FDA's MedWatch program. Another concern is that the latency period of malignancy indicates there may be an extensive interval between the onset of TNF blocker treatment and the diagnosis of malignancy.
According to Diak, the number of reported cases of malignancy in children using TNF blockers is likely to increase as the usage and duration of therapy with TNF blockers increases.
However, the cases were confounded by the potential underlying risk of malignancy in patients with autoimmune disease and the use of concomitant immunosuppressants, preventing a clear causal relationship from being established.
Source: Arthritis & Rheumatism, 2010
Treatment-resistant bipolar disorder: Ketamine reduces symptoms of depression within 40 minutes
A single intravenous dose of the anesthetic agent Ketamine appears to reduce symptoms of depression within 40 minutes among those with bipolar disorder who have not responded to other treatments.
Bipolar disorder is one of the most severe psychiatric disorders and ranks in the top 10 causes of medical disability worldwide. About 4 percent of Americans will develop bipolar disorder in their lifetimes, and depressive symptoms dominate for most of the course of the illness. Several treatments for bipolar depression are currently approved, but some patients do not respond to these therapies despite adequate trials. In addition, existing treatments are associated with a lag of onset; most patients do not respond within the first week of therapy, resulting in considerable illness and increased suicide risk.
One reason for the lack of better therapies is a limited understanding of the neurobiological basis of bipolar disorder. However, recent research suggest dysfunction in the brain's glutamatergic system, which plays a role in information processing and memory formation, may contribute.
Nancy Diazgranados, and colleagues at the National Institute of Mental Health ( NIMH ), Bethesda ( United States ) assessed the effectiveness of one modulator of this system, Ketamine hydrochloride, commonly used as an anesthetic ( Ketanest ), for bipolar depression.
From October 2006 through June 2009, 18 participants with bipolar depression that had failed to respond to Lithium or Valproate received an intravenous infusion of either Ketamine or a placebo on two test days two weeks apart. The order of the infusions was randomly assigned. Participants were assessed using a depression rating scale before each injection and then 40, 80, 120 and 230 minutes and one, two, three, seven, 10 and 14 days afterward.
Within 40 minutes, those who received Ketamine experienced a significant improvement in depressive symptoms compared with those who took placebo, an improvement that was largest at day two and remained significant through day three. At some point during the course of the trial, 71% of participants responded to Ketamine and 6% responded to placebo.
According to Authors, these findings are particularly noteworthy because a substantial proportion of study participants had been prescribed complex polypharmacy regimens in the past with substantial treatment failures. The mean number of past antidepressant trials was 7, and more than 55% of participants failed to respond to electroconvulsive therapy. The toll of this protracted and refractory illness on the subjects was evident, in that two-thirds of participants were on psychiatric disability and nearly all were unemployed.
No serious adverse effects were reported during the study. The results lend support to the hypothesis that the glutamatergic system is implicated in the development of bipolar disorder, and that targeting it may lead to improved therapies.
Future research will need to address whether differences in kinetics associated with intravenous administration, which allows for faster absorption and avoids hepatic metabolism, are important or necessary for rapid antidepressant effects to occur. In addition, future studies should examine strategies for long-term maintenance of ketamine's rapid antidepressant response.
Source: Archives of General Psychiatry, 2010
Psoriasis drugs: a comparison between Etanercept and Ustekinumab
Researchers at The University of Manchester ( UK ) have compared the drugs Etanercept ( Enbrel ) and Ustekinumab ( Stelara ), relatively new biological therapies that have proved effective in the management of moderate to severe psoriasis.
Little research has been done to test the benefit-risk profiles of these new biological agents or compare their relative effectiveness. The Manchester-led international study tested the two drugs on 903 patients with moderate to severe psoriasis over a 12-week period.
The team, headed by Chris Griffiths at Salford Royal Hospital, Greater Manchester, found that there was at least a 75% improvement in the severity of psoriasis symptoms in 56.8% of patients who received twice-weekly 50mg sub-cutaneous injections of Etanercept after 12 weeks.
Ustekinumab was given to patients in two doses, 45mg and 90mg, and involved just two sub-cutaneous injections over the 12-week period. A 75% improvement in symptoms was observed in 67.5% of patients taking the 45mg dose and 73.8% receiving the 90mg dose.
The findings have shown that the efficacy of Ustekinumab at either dosage was superior to that of high-dose Etanercept using the 75% improvement measure over a 12-week period.
Similarly, a higher proportion of patients using Ustekinumab were reported to have no or minimal disease symptoms after 12 weeks than those given etanercept, 70.6% at 90mg Ustekinumab compared to 49.0% receiving Etanercept.
About one in 50 people are afflicted by psoriasis. The condition is currently incurable and causes significant impairment in the sufferer's quality of life. In severe cases more than 20% of the skin's surface area can be affected. Therapeutic agents used for the management of the condition commonly target the underlying inflammation.
Immunosupressive agents, such as Methotrexate and Cyclosporin, have proved effective in treating psoriasis but new biological agents that block selective stages of the body's inflammatory process now provide alternative therapies. Etanercept and Ustekinumab are two such agents.
The safety of Ustekinumab and Etanercept, including the rates and types of adverse events and laboratory abnormalities, appeared to be generally similar with short-term treatment.
There were, however, more injection-site reactions with Etanercept but this may be accounted for by the fact patients received more injections of this drug than Ustekinumab.
The results of this study could have implications for determining the optimal approach to the treatment of psoriasis and, in particular, the need for therapeutic strategies targeting the body's immune system to provide the greatest benefit and safety.
The research is published in the New England Journal of Medicine ( NEJM ).
Source: University of Manchester, 2010
Advances in renal cell carcinoma management
Renal cell carcinoma ( RCC ) accounts for about 3% of all solid tumours in adults, and worldwide, more than 200.000 new cases and 100.000 deaths result each year from this malignancy.
In contrast to most other malignant tumours in the urogenital system, there was a period of stagnation in the development of new treatment modalities for many decades. Surgery in an early stage always was and still is the only measure to cure kidney carcinoma, and surgery plays an important role in the treatment of metastases as long as they can be removed completely.
Angiogenesis plays a major role in the growth of malignant tumours, and several substances could be developed to block key proteins involved in angiogenesis and tumour proliferation.
The main strategies target either directly the vascular endothelial growth factor ( VEGF ), its related receptor or the mammalian target of Rapamycin ( mTOR ) signal transduction pathway.
VEGF is the most prominent regulator of angiogenesis. Bevacizumab ( Avastin ) is a monoclonal antibody against VEGF that binds and neutralises all biologic active isoformes of VEGF. Bevacizumab is one of the drugs used as first-line therapy, and there is consensus that the combination of Bevacizumab and Interferon-alpha is most efficient.
Sunitinib ( Sutent ) is a highly potent selective inhibitor of multiple tyrosine kinases of the VEGF and PDGF ( platelet derived growth factor ) receptors. In addition to inhibition of angiogenesis it has direct antiproliferative effects. Sunitinib is recommended as first-line therapy for intermediate- or low-risk patients. Many studies have shown its efficacy.
Sorafenib ( Nexavar ) is a tyrosine kinase inhibitor which inhibits not only the VEGF/PDGF receptors, but also the enzyme RAF ( rapidly growing fibrosarcoma ) kinase, a critical component of the RAF signaling pathway that controls cell division and proliferation. Sorafenib is advised as second-line therapy. Treatment of cytokine-refractory mRCC patients with Sorafenib has been reported to double the progression free survival compared with placebo.
Initially, mTOR inhibitors were used as an immunosuppressant to prevent rejection of organ transplants. Temsirolimus ( Torisel ) is a specific inhibitor of mTOR and interferes with the synthesis of proteins that regulate proliferation, growth, and survival of tumour cells. Treatment with Temsirolimus leads to cell cycle arrest in the G1 phase, and also inhibits tumour angiogenesis by reducing synthesis of VEGF.
Temsirolimus is indicated as first-line therapy in high risk patients. It is administered intravenously. Everolimus ( Afinitor ), which is given orally, has shown in a phase III study to be effective in patients relapsing after initial therapy with tyrosine kinase inhibitors.
None of these drugs cure the patients, but they are able to stabilise metastatic renal cell carcinoma for a certain period of time. Many questions remain open, however. Obviously, there is no cross-resistance in between these drugs, and they can be administered sequentially.
Source: European Association of Urology, 2010
Dasatinib and Nilotinib: phase III clinical trials show improved responses over Imatinib
Two drugs approved for treatment of drug-resistant chronic myeloid leukemia ( CML ) provide patients with quicker, better responses as a first therapy than the existing front-line medication.
These two studies are published in the New England Journal of Medicine.
Separate international phase III clinical trials compared high-quality remissions after one year of treatment between the standard-of-care drug Imatinib, also known as Gleevec ( Glivec in Europe ), and the second-line drugs Nilotinib ( Tasigna ) and Dasatinib ( Sprycel ). In both trials, previously untreated CML patients who took the newer drugs reached complete cytogenetic response and major molecular response faster than those taking Imatinib. They were also less likely to have their disease progress to advanced stages.
According to Hagop Kantarjian, at The University of Texas MD Anderson Cancer, the second-generation CML drugs are more effective than Imatinib and less toxic overall.
Imatinib, a targeted therapy that blocks the activity of a fusion protein called BCR-ABL that is created by the aberrant Philadelphia chromosome, was a breakthrough drug for CML, nearly doubling the median five-year survival rate for the disease from 50 to 90 percent.
However, 30-40 percent of Imatinib patients don't reach a complete cytogenetic or major molecular response, and over time their disease becomes resistant to the drug.
Dasatinib versus Imatinib
In the DASISION ( Dasatinib versus Imatinib Study In Treatment-naïve CML Patients ) trial, 519 previously untreated CML patients were randomized to either 100 mg of Dasatinib once a day or 400 mg of Imatinib once a day.
In the Dasatinib arm, 77% of patients achieved a confirmed complete cytogenetic response ( CcyR ), 46% reached major molecular response ( MMR ) and 1.9% had their chronic myeloid leukemia progress.
Of those receiving Imatinib, 66% reached complete cytogenetic response, 28% major molecular response, and 3.5% had their disease progress.
Responses were faster with Dasatinib, with 54% at CCyR at 3 months and 73% at six months compared with 31% and 59% for Imatinib.
Side effects for Dasatinib and Imatinib were mostly low-grade. Hematologic side effects were slightly more common on dasatinib, while other low-grade side effects such as nausea, vomiting, muscle pain and inflammation were higher on Imatinib.
Nilotinib versus Imatinib
In the ENEST ( Evaluating Nilotinib Efficacy and Safety in Clinical Trials - Newly Diagnosed Patients ) trial, 836 new CML patients were randomized to either 300 mg or 400 mg of Nilotinib twice daily, or to 400 mg of Imatinib once a day.
Results in both Nilotinib arms of the trial were nearly identical. In the 300 mg twice daily group, 80% of patients reached complete cytogenetic response, 44% achieved major molecular response and less than 1% had disease progression. For the higher dose nilotinib, the numbers were 78%, 43% and also less than 1%.
In the Imatinib arm, 65% achieved complete cytogenetic response, 22% reached major molecular response, and 4% had their disease progress.
Patients on Nilotinib achieved major molecular response earlier than those on imatinib, with median times to MMR of 5.7 and 5.8 months, compared with 8.3 months for Imatinib.
Nilotinib and Imatinib had favorable safety profiles, with serious side effects uncommon for either drug. Hematologic side effects ( decreased levels of red blood cells, white blood cells or platelets ) were slightly more common among those on Imatinib. Nausea, diarrhea, vomiting, muscle spasms and edema were higher on Imatinib, but rash, headache, hair loss and itching were higher on Nilotinib.
Source: University of Texas MD Anderson Cancer Center, 2010
SPIRIT IV: Xience V has shown enhanced safety and efficacy in the treatment of de novo native coronary artery lesions compared to Taxus
Data from SPIRIT IV clinical trial, a large-scale multi-center study of nearly 4,000 patients in the United States, showed that Everolimus-eluting stents ( Xience V ) demonstrated enhanced safety and efficacy in the treatment of de novo native coronary artery lesions when compared to Paclitaxel-eluting stents ( Taxus ). The trial, which was powered for superiority for clinical endpoints without angiographic follow up, also examined the differences in performance of the two stents in patients with diabetes.
The data are published in the New England Journal of Medicine ( NEJM ).
The primary endpoint of the trial was target-lesion failure ( TLF ) at one year, a composite measure of cardiac death, target-vessel heart attack or ischemia-driven target-lesion revascularization ( TLR ). Major secondary endpoints of the trial were ischemia-driven TLR at one year, and the composite rate of cardiac death or target-vessel heart attack at one year.
For Everolimus-eluting stents, TLF at one year was 4.2%, and for Paclitaxel-eluting stents, TLF was 6.8%, a significant 38% reduction.
At one-year, ischemia-driven TLR was 2.5% for Everolimus-eluting stents and 4.6% for Paclitaxel-eluting stents, a significant 45% reduction.
The composite rates of cardiac death or target-vessel myocardial infarction through one year were not statistically different with the 2 stents ( 2.2% for Everolimus-eluting stents and 3.2% for Paclitaxel-eluting stents ). The one-year rates of myocardial infarction and stent thrombosis, however, were also lower with Everolimus-eluting stents than with Paclitaxel-eluting stents ( 1.9% vs 3.1% for myocardial infarction and 0.17% vs 0.85% stent thrombosis ).
The results were consistent regardless of lesion length, vessel size and the number of lesions treated. However, in the diabetic-patient subgroup, the study found a comparable rate of TLF with both stents, whereas in patients without diabetes, Everolimus-eluting stents reduced TLF by 53% compared to Paclitaxel-eluting stents.
Source: Cardiovascular Research Foundation, 2010
Xience V - coronary artery lesions
Taxus - coronary artery lesions
Xience V ? Taxus
Metastatic renal-cell carcinoma: switch to metronomic chemotherapy could offer new treatment option
A new multi-targeted chemo-switch drug regimen shows promising anti-tumour activity with manageable side effects in patients with metastatic renal-cell carcinoma ( RCC ), a disease with few treatment options. Combining maximum tolerated dose ( MTD ) chemotherapy ( Gemcitabine; Gemzar ) with metronomic chemotherapy ( frequent low-dose chemotherapy with Capecitabine; Xeloda ) plus Sorafenib ( Nexavar ), results in greater progression-free survival ( PFS ) and tumour response than previously reported with Sorafenib alone or with chemotherapy, and might provide a new first-line treatment option for patients with advanced kidney cancer.
Renal-cell carcinoma is the most common form of kidney cancer, causing over 102,000 deaths worldwide each year. But treatment options are limited and survival is poor, with responses to chemotherapy, hormonal and biological therapy, and standard treatment with targeted drugs remaining modest.
However, recent preclinical studies have suggested that combining treatment options could improve response to treatment and survival. Combined treatment entails initial treatment at the MTD of one chemotherapy drug, followed by maintenance with a metronomic dose of a second chemotherapy drug ( giving patients lower doses more frequently to prevent the cancer from growing by inhibiting the development of new blood vessels ) plus a targeted inhibitor of vascular endothelial growth factor ( VEGF ) and platelet-derived growth factor receptor ( PDGFR ) to increase anti-tumour activity.
To investigate whether this multi-targeted chemo-switch strategy might improve outcomes in patients with metastatic renal-cell carcinoma, Joaquim Bellmunt from University Hospital del Mar, Barcelona, Spain, and colleagues from the Spanish Oncology Genitourinary Group ( SOGUG ) did a phase 2 study involving 44 patients from eight centres across Spain; 40% received six cycles of treatment consisting of MTD Gemcitabine ( days 1 and 8) with metronomic capecitabine twice a day, and VEGFR and PDGFR inhibitor Sorafenib twice a day ( days 1-21 ), followed by Sorafenib monotherapy.
Findings showed that median PFS was 11.1 months, compared with previous results with Gemcitabine and Capecitabine of 5-8 months, and less than 7 months with Sorafenib alone. Additionally, a partial response was reported in 50% of patients, compared with 16% of patients in previous studies with Gemcitabine and Capecitabine, and less than 5% of patients with Sorafenib alone. Stable disease was achieved in 17 ( 42.5% ) patients.
All patients reported at least one adverse event during the study, with over half reporting a grade 3 event. However, these events were manageable in most patients, with fatigue and asthenia, hand-foot skin reactions, and neutropenia the only grade 3 adverse events reported in more than 10% of patients.
In conclusion, the combination of Sorafenib with MTD Gemcitabine and metronomic Capecitabine resulted in a clinical benefit rate of over 90%, with an acceptable level of toxicity.
Source: Lancet Oncology, 2010
renal-cell carcinoma - metronomic chemotherapy
Chronic myeloid leukaemia: a vaccine made with leukemia cells may reduce or eliminate the last remaining cancer cells
Preliminary studies by Researchers at Johns Hopkins Kimmel Cancer Center, have shown that a vaccine made with leukemia cells may be able to reduce or eliminate the last remaining cancer cells in some chronic myeloid leukemia ( CML ) patients taking the drug Imatinib mesylate ( Gleevec, Glivec ).
Imatinib, one of the first targeted cancer therapies with wide success in chronic myeloid leukemia patients, destroys most leukemic cells in the body, but in most patients, some cancerous cells remain and are measurable with sensitive molecular tests. These remaining cells are a source of relapse, especially if Imatinib therapy is stopped.
In a pilot study published in Clinical Cancer Research, the Johns Hopkins investigators used a vaccine made from CML cells irradiated to halt their cancerous potential and genetically altered to produce an immune system stimulator called GM-CSF. The treated cells also carry molecules, called antigens, specific to CML cells, which prime the immune system to recognize and kill circulating CML cells.
The study vaccine was given to 19 CML patients with measurable cancer cells, despite taking Imatinib for at least one year. A series of 10 skin injections were given every three weeks for a total of four times. After a median of 72 months of follow-up, the number of remaining cancer cells declined in 13 patients, 12 of whom reached their lowest levels of residual cancer cells. In seven patients, chronic myeloid leukemia became completely undetectable. Because the study was conducted in a limited number of patients and not compared with other therapies, the researchers warn they cannot be sure that the responses were a result of the vaccine.
The Researchers will be testing blood samples taken from the study patients to identify the precise antigens that the immune system is recognizing. With this information, they will tailor their vaccine for additional studies that monitor immune response more precisely.
Patients receiving the trial vaccine experienced relatively few side effects that included injection site pain and swelling, occasional muscle aches and mild fevers.
According to the investigators, most patients with chronic myeloid leukemia will need to remain on Imatinib therapy for the rest of their lives. More than 90 percent of them will achieve remission, but about 10 to 15 percent of patients cannot tolerate the drug long term. Often patients have low blood cell counts, fluid retention, significant nausea and other gastrointestinal problems. Secondary therapies, including Dasatinib ( Sprycel ) and Nilotinib ( Tasigna ), also have many side effects.
Another common side effect of Imatinib is fatigue.
Imatinib also cannot be taken during pregnancy, and since one-third of CML patients are in their 20s and 30s, many patients hoping to start families would like to discontinue taking it.
Source: Johns Hopkins Medical Institutions, 2010
Advanced kidney cancer: Sorafenib shrinks tumor prior to surgery
Physicians who conducted a pilot study at University of North Carolina ( UNC ) Lineberger Comprehensive Cancer Center found that therapy before surgery with the drug Sorafenib ( Nexavar ) can reduce the size of large kidney tumors and could be safely undertaken administered without adding significantly to the risks of surgery.
The findngs are published in the Journal of Clinical Oncology.
At present, removal of the primary tumor ( often with the kidney as well ) is the standard treatment for patients with kidney cancer, whether the disease is localized to the kidney or has spread to distant sites. This broad spectrum includes patients with very large tumors that may not be ideal for surgical removal as well as patients who may benefit from early systemic interventions, but who would also benefit from removing the kidney later.
The study addressed the question of whether systemic therapy, and in particular, therapy that targets the process by which tumors seek and find new blood vessels to fuel their growth, can benefit patients before they undergo surgery to remove tumors.
The study was conducted to evaluate the safety and feasibility of preoperative treatment using Sorafenib in 30 patients with stage two or higher kidney cancer including metastatic disease. Patients received their treatment at UNC Lineberger Comprehensive Cancer Center and at Rex Cancer Center in Raleigh. They took two daily oral doses of the drug for between four to eight weeks prior to surgery.
Sorafenib is a targeted drug used to treat advanced kidney cancer and a type of liver cancer; it prevents the growth of new blood vessels that fuel tumor growth. Sorafenib is one among the class of new targeted agents approved by the FDA in 2005 for evidence of benefit for patients with metastatic kidney carcinoma.
Two previous studies had been conducted using similar targeted therapy drugs, Sunitinib ( Sutent ) and Bevacizumab ( Avastin ), but UNC study is the largest to evaluate the use of Sorafenib alone, and the first to explore the possibility that pre-operative treatment might benefit patients who do not have metastatic disease.
The study has demonstrated that Sorafenib is well-tolerated for pre-surgery use, with no increase in the rates of complications or difficulties recovering from surgical removal of the kidney.
Another important aspect of this study is the successful integration of systemic therapy with what is traditionally a surgical stage of the disease.
In conclusion, it has been seen a significant reduction in the size of tumors using Sorafenib, reducing the extent of surgery and making patient recovery less challenging. A larger study needs to be conducted to determine if preoperative systemic therapy improves outcomes in patients undergoing surgery for kidney tumor.
Source: University of North Carolina School of Medicine, 2010
advanced kidney cancer - Sorafenib
tumor - surgery
kidney cancer ? Sorafenib
Sorafenib ? surgery
University of Texas M. D. Anderson Cancer Center
BATTLE links potential biomarkers to drugs for lung cancer
Biopsy-based study tilts field toward personalized treatment, more efficient clinical trials
VIDEO: Edward Kim, M.D., associate professor in M. D. Anderson's Department of Thoracic/Head and Neck Medical Oncology and principal investigator on the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination...
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WASHINGTON, D.C. - The first lung cancer clinical trial to guide targeted therapies to patients based on molecular signatures in tumor biopsies is a step toward personalized care and more effective, efficient clinical trials for new drugs, study leaders reported today during the American Association for Cancer Research 101st Annual Meeting 2010.
Researchers at The University of Texas M. D. Anderson Cancer Center presented the results of the study that used an innovative statistical model to match four drugs to specific molecular signatures, or biomarkers, in the tumors of 255 stage IV non-small cell lung cancer patients who had received between one and nine previous treatments.
"New drugs that target molecular pathways help a small percentage of lung cancer patients, but right now there's no way to determine who those patients are before treatment," said Edward Kim, M.D., associate professor in M. D. Anderson's Department of Thoracic/Head and Neck Medical Oncology and principal investigator on the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) clinical trials.
"BATTLE evaluated tumor biomarkers in hopes that we can treat lung cancer, which kills more people than any other type of cancer, like we treat breast or colon cancer, using validated biomarkers to guide treatment and improve survival," Kim said. The National Cancer Institute estimates that 219,440 new cases of lung cancer were diagnosed in 2009 and 159,390 people died from the disease.
Kim said BATTLE also points the way to more precise clinical trials that will require smaller numbers of patients to test a targeted therapy rather than large trials open to all-comers. "Lung cancer research has been plagued by large, Phase III clinical trials that showed minor effects or even failed to enroll enough patients to finish," Kim said.
IMAGE: Edward Kim, M.D., associate professor in M. D. Anderson's Department of Thoracic/Head and Neck Medical Oncology and principal investigator on the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination...
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"Two lung cancer tumors might appear identical under a microscope and have the same staging, but they behave differently," said Waun Ki Hong, M.D., head of M.D. Anderson's Division of Cancer Medicine and principal investigator on the BATTLE grant from the U.S. Department of Defense. "The name of the game now is to treat based on the molecular defects in the tumor."
BATTLE identifies potential biomarkers
The Phase II clinical trial found evidence that each of the four drugs targets specific molecular signatures better than the other three. The drugs used in the trial were erlotinib (Tarceva®), sorafenib (Nexavar®), vandetanib (Zactima®) and erlotinib with bexarotene (Targretin®). Each drug is designed to target specific molecular pathways; currently, none has a validated biomarker to guide its use.
BATTLE's end point was disease control at eight weeks, which recent research has found is a good indicator of overall survival. The study found, for example, that 61 percent of patients with a KRAS mutation in their tumors who took sorafenib had disease control at eight weeks, compared with 32 percent for the other three drugs. Erlotinib did best against EGFR mutations, vandetanib for high VEGFR-2 expression and the erlotinib-bexarotene fared best with Cyclin D1 defects or amplified numbers of the EGFR gene. These exploratory analyses raise interesting areas of future research.
Overall, 46 percent of patients on the trial had disease control at 8 weeks, compared with a historical experience of around 30 percent for late-stage lung cancer patients. Median overall survival was nine months, and 38 percent of patients survived to one year. Toxicities from the four drugs were minimal, with only 6.5 percent experiencing a significant side effect.
Kim cautioned that Phase II trial findings of biomarker effectiveness need to be validated in Phase III trials, which are typically sponsored by pharmaceutical companies or performed in cooperative groups.
A model for efficient clinical trials
By successfully collecting new tumor biopsies on each patient and employing a Bayesian adaptive randomization statistical model, BATTLE provides an example for improving clinical trials.
"BATTLE is an important step toward personalized medicine and marks a paradigm shift for clinical trials by demonstrating the feasibility of a biopsy-based, hypothesis-driven biomarker trial," said Roy Herbst, M.D., Ph.D., professor in the Department of Thoracic/Head and Neck Medical Oncology and co-principal investigator on the BATTLE clinical trials.
Patients agreed to have a new biopsy for the trial, Kim said, which was crucial to the study design because it provided fresh information on the tumor's molecular status that may have been altered by treatment since the patient's previous biopsy.
"BATTLE employed an adaptive randomization approach that allowed the statistical model to learn as the clinical trial progressed," said J. Jack Lee, Ph.D., professor in M. D. Anderson's Department of Biostatistics.
The first 97 patients were equally randomized to BATTLE's four arms. As the study progressed, information from patients' biopsies and outcomes was employed by the model to guide assignment of drugs to new patients, who became more likely to receive a drug that had worked for earlier patients with the same tumor biomarkers.
The model leads to greater use of successful drugs and minimization or dropping of those less successful. While vandetanib helped those with VEGFR overexpression, it was dropped for patients with the KRAS mutation, Lee said.
By identifying biomarkers, and thus a potential patient population for a drug at Phase II, a follow-up Phase III will require smaller sample sizes and proceed more quickly than an all-comers trial with thousands of patients, Lee said.
Kim said future BATTLE trials will test combinations of therapies as well as single agents and will concentrate on the entire range of staging for lung cancer patients, including frontline therapy. Ultimately, the researchers plan to try the BATTLE approach in personalizing prevention clinical trials.
The BATTLE program is part of a federally funded program that began in 2000 and was established in honor of R. Duffy Wall, a lung cancer patient at M. D. Anderson who unfortunately lost his life to the disease. The program is funded through the United States Army's medical research program and was supported by Senator Kay Bailey Hutchison, Representative John Culberson, and many other current and former members of Congress.
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Type 1 Gaucher disease: Vpriv approved in Europe
European Commission has granted marketing authorisation for Vpriv ( Velaglucerase alfa ), a human cell line derived enzyme replacement therapy ( ERT ) for the long-term treatment of type 1 Gaucher disease. Vpriv has been authorized as an orphan medicine through the Centralised Procedure, making it available in 30 countries across Europe.
This approval was based on data from Velaglucerase alfa clinical development programme which represents the largest and most comprehensive clinical data set supporting registration for an ERT for type 1 Gaucher disease. In total, over 100 Gaucher patients at 24 sites in 10 countries around the world participated in the clinical studies, all of which met their primary endpoints.
Across Europe, hundreds of type 1 Gaucher patients have been receiving Velaglucerase alfa through early access programmes, developed in partnership with national authorities, Gaucher expert physicians and patient associations. Globally there are over 850 patients on Velaglucerase alfa and demand continues to be strong. As a result, Shire has implemented a program to carefully monitor demand and manage requests from physicians and patients in order to ensure long-term, uninterrupted treatment with Vpriv.
Velaglucerase alfa is made using Shire's gene-activation technology, in a human cell line. Velaglucerase alfa has the exact human amino acid sequence as the endogenous glucocerebrosidase enzyme and also has a human glycosylation pattern. The safety and efficacy of Velaglucerase alfa was assessed in adults and children aged 4 years and older via a phase three program, which included Gaucher patients who switched to Velaglucerase alfa after being treated with Imiglucerase ( Cerezyme ), as well as naive patients, including an active comparison with Imiglucerase.
Vpriv was approved in the United States by the Food and Drug Administration ( FDA ) on February 26, 2010.
The most serious adverse reactions in patients treated with Velaglucerase alfa were hypersensitivity reactions.
Infusion-related reactions were the most commonly observed adverse reactions in patients treated with Vpriv in clinical studies. The most commonly observed symptoms of infusion-related reactions were: headache, dizziness, hypotension, hypertension, nausea, fatigue/asthenia, and pyrexia. Generally the infusion-related reactions were mild and, in treatment-naive patients, onset occurred mostly during the first 6 months of treatment and tended to occur less frequently with time. Other commonly observed adverse reactions in less than 10% of patients were: abdominal pain, back pain, joint pain, upper respiratory tract infection, and activated partial thromboplastin time prolonged. Adverse reactions more commonly seen in paediatric patients ( greater than 10% difference ) included upper respiratory tract infection, rash, activated partial thromboplastin time prolonged, and pyrexia. In clinical trials one patient developed neutralizing antibodies.
Gaucher disease is an autosomal recessive disorder caused by mutations in the GBA gene which results in a deficiency of the lysosomal enzyme beta-glucocerebrosidase. This enzymatic deficiency causes an accumulation of glucocerebroside, primarily in macrophages. In this lysosomal storage disorder ( LSD ), clinical features are reflective of the distribution of Gaucher cells in the liver, spleen, bone marrow, and other organs. The accumulation of glucocerebrosidase in the liver and spleen leads to organomegaly. Presence of Gaucher cells in the bone marrow and spleen lead to clinically significant anemia and thrombocytopenia.
Gaucher disease is the most prevalent of the lysosomal storage disorders diseases. Gaucher disease has classically been categorized into 3 clinical types. Type 1 Gaucher disease is characterized by variability in signs, symptoms, severity, and progression. Type 1 is the most common and is distinguished from type 2 and type 3 by the lack of early neurological symptoms.
Source: Shire, 2010
Gaucher disease ? Vpriv
AVERROES trial: Apixaban reduces risk of stroke and systemic embolism in atrial fibrillation
The phase 3 AVERROES ( Apixaban Versus Acetylsalicylic acid to Prevent Strokes ) trial, designed to show the superiority of Apixaban over Acetylsalicylic acid ( Aspirin ) for the prevention of stroke or systemic embolism in high-risk atrial fibrillation patients unsuitable for treatment with a vitamin K antagonist [ Warfarin ( Coumadin ) ], was terminated early following a recommendation from the Data Monitoring Committee.
A predefined interim analysis had shown clear evidence of a clinically important reduction in stroke and systematic embolism and an acceptable safety profile for Apixaban compared to Acetylsalicylic acid.
AVERROES was a double-blind randomised trial which recruited 5600 patients with atrial fibrillation ( mean age 70 years ) demonstrated or expected to be unsuitable for treatment with Warfarin ( because of difficulty in controlling treatment effect, increased risk of haemorrhage, patient refusal to take Warfarin or intermediate stroke risk ). So far, Acetylsalicylic acid was the only effective treatment for stroke prevention in patients unsuitable for Warfarin.
Apixaban, a factor Xa inhibitor, has already been investigated for the prevention of deep vein thrombosis, following orthopaedic surgery, and after acute coronary syndrome, but not so far in patients with atrial fibrillation. The AVERROES trial compared the effects of Apixaban and Acetylsalicylic acid in these patients. Another trial, ARISTOTLE ( not yet completed ) is studying Apixaban against Warfarin in patients suitable for Warfarin.
The AVERROES study was performed at 520 sites worldwide and recruitment was completed in December 2009. The primary endpoint was a composite of stroke or systemic embolism, while the primary safety endpoint was major haemorrhage. Secondary and tertiary endpoints were a composite of stroke, systemic embolism, myocardial infarction or vascular death, and total death.
At the interim analysis results showed that the annual rate of stroke or systemic embolism ( the primary outcome ) was 3.9% per year on Acetylsalicylic acid and 1.7% per year on Apixaban ( HR=0.45, p<0.001 ). The rate of major haemorrhage was 1.4% per year on Acetylsalicylic acid and 1.6% per year on Apixaban ( HR=1.18, p=0.33 ). The rate of haemorrhagic stroke was 0.2% per year in both treatment groups and there was no evidence of hepatic toxicity or other major adverse events.
In conclusion, the results of AVERROES trial have shown a reduction in stroke and systemic embolism in patients treated with Apixaban and the increased risk of haemorrhage is small.
Source: European Society of Cardiology Meeting, 2010
Apixaban - stroke and
Apixaban - systemic embolism
Apixaban - atrial fibrillation
ANTIPAF trial: sartans do not reduce the number of AF episodes in patients with paroxysmal atrial fibrillation and without structural heart disease
Atrial fibrillation ( AF ) is a progressive chronic disease in which episodes become more frequent and long-lasting over time. Conventional anti-arrhythmic therapy aims at halting progression and reducing symptoms, but the use of most anti-arrhythmic drugs is compromised by severe side effects, such as pro-arrhythmia or extra-cardiac organ toxicity.
A number of meta-analyses have shown that angiotensin II antagonists ( or ARBs, sartans ) may have the potential to reduce recurrence of atrial fibrillation , with an almost placebo-like tolerability. However, the available evidence from meta-analyses is heterogeneous with respect to the patient populations under investigation, the specific study designs, and the methods used to detect recurrent atrial fibrillation.
The ANTIPAF ( ANgiotensin II anTagonists In Paroxysmal Atrial Fibrillation ) trial was the first trial to prospectively evaluate the principal hypothesis that the angiotensin II receptor antagonist Olmesartan ( Benicar, Olmetec ) suppresses episodes of paroxysmal atrial fibrillation.
The primary endpoint of the trial was the percentage of days with documented episodes of paroxysmal atrial fibrillation throughout 12 months of follow-up. Secondary endpoints included the time to first occurrence of a documented relapse of atrial fibrillation, quality of life, time to first atrial fibrillation recurrence, time to persistent atrial fibrillation, and the number of hospitalisations.
Patients were stratified according to presence of beta-blocker therapy and randomised to placebo or Olmesartan ( 40 mg/day ). Concomitant therapy with sartans, ACE inhibitors, and antiarrhythmic drugs was prohibited. Patients were followed using daily trans-telephonic ECG recordings ( at least one 1-minute ECG/day ) independent of symptoms, and were encouraged to submit further tele-ECGs in any case of atrial fibrillation-related symptoms.
Follow-up visits were scheduled after 3, 6, 9 and 12 months, which included long-term ECGs, transthoracic echocardiography, laboratory markers, and assessment of quality of life.
425 patients ( at least 18 years old ) with documented episodes of paroxysmal atrial fibrillation were included from 37 Centres in Germany. A total of 87,818 tele-ECGs were analysed during follow-up ( 44,888 ECGs in the placebo group and 42,930 ECGs in the Olmesartan group ). Thus, a mean of 207 tele-ECGs were recorded per patient with an average of 1.12 tele-ECGs per patient and day of follow-up.
The study demonstrated no significant difference in the burden of atrial fibrillation ( primary endpoint ) between both treatment groups. Further secondary outcome parameters such as quality of life, time to first atrial fibrillation recurrence, time to persistent atrial fibrillation, and the number of hospitalisations were also similar between groups. However, the time to prescription of recovery medication [ Amiodarone ( Cordarone ) ] was longer in patients treated with Olmesartan than in those receiving placebo.
In conclusions: in patients with atrial fibrillation and concomitant structural heart disease such as hypertensive heart disease or systolic heart failure, sartans are effective adjunct therapies while being highly tolerable. ANTIPAF provides pivotal evidence, however, that sartans do not reduce the number of atrial fibrillation episodes in patients with paroxysmal atrial fibrillation and without structural heart disease.
Source: European Society of Cardiology Meeting, 2010
sartans - paroxysmal atrial fibrillation
paroxysmal atrial fibrillation - structural heart disease
EINSTEIN DVT trial: Rivaroxaban is an effective and safe treatment for acute symptomatic deep vein thrombosis
Results of the Phase III EINSTEIN-DVT study have shown that the oral anticoagulant Rivaroxaban ( Xarelto ) achieved the primary efficacy and safety outcomes in the treatment of patients with acute, symptomatic deep vein thrombosis ( DVT ).
Rivaroxaban has demonstrated non-inferior efficacy in the treatment of deep vein thrombosis compared with initial Enoxaparin ( Clexane, Lovenox ) treatment followed by a vitamin K antagonist, the current standard therapy for the treatment of deep vein thrombosis.
Recurrent symptomatic venous thromboembolism ( ie, the composite of recurrent deep vein thrombosis, non-fatal or fatal pulmonary embolism ) occurred in 2.1% of the Rivaroxaban recipients and 3.0% of the subjects receiving standard therapy ( p<0.0001 for non-inferiority ).
The EINSTEIN-DVT trial has also demonstrated similar rates of major and clinically relevant non-major bleeding, the principal safety outcome, for Rivaroxaban compared with the current standard therapy ( 8.1% vs. 8.1%, respectively ).
No liver signal attributable to Rivaroxaban was observed in the study.
The EINSTEIN-DVT trial was designed to investigate a new single-drug approach with Rivaroxaban in comparison to standard therapy in a randomised, open-label, non-inferiority study. The trial involved more than 3,400 patients with acute symptomatic deep vein thrombosis, but without any symptoms of pulmonary embolism, across 253 sites in 32 countries worldwide.
Patients received either oral Rivaroxaban ( 15 mg twice-daily for the first three weeks, followed by 20 mg once daily ) or body weight-adjusted subcutaneous Enoxaparin followed by Warfarin ( Coumadin ) or Acenocoumarol ( Sintrom ) ( dose adjusted to maintain a therapeutic normalised ratio ) for 3, 6 or 12 months, based on the attending physician?s assessment at baseline.
The primary efficacy outcome was the cumulative incidence of symptomatic recurrent venous thromboembolism ( non-fatal or fatal ). The principal safety outcome was the composite of major and clinically relevant non-major bleeding.
Source: European Society of Cardiology Meeting, 2010
deep vein thrombosis - Rivaroxaban
August 31, 2010
Treatment of Deep Vein Thrombosis:
Bayer?s Rivaroxaban Successfully Meets Primary Efficacy Outcome and Demonstrates Similar Safety to Standard Therapy in Phase III EINSTEIN-DVT Non-Inferiority Study
Results from EINSTEIN-DVT Study Presented at European Society of Cardiology Congress 2010
Berlin, Germany, August 31, 2010 ? The Phase III EINSTEIN-DVT clinical trial of the oral anticoagulant rivaroxaban demonstrated non-inferiority compared to the standard of care for the prevention of recurrent venous thromboembolism (VTE) in patients with acute symptomatic deep vein thrombosis (DVT), with a comparable safety profile. The data were presented today during a Hot Line session at the European Society of Cardiology (ESC) Congress.
?Results from EINSTEIN-DVT could transform the way physicians treat deep vein thrombosis,? said lead investigator Harry R. Büller, M.D., Academic Medical Center in Amsterdam, Netherlands, who presented the results. "While the current standard of care is effective when well-controlled, it is often associated with significant drawbacks for patients and physicians. A novel single-drug approach such as oral rivaroxaban could potentially provide an effective and well-tolerated, simple, fixed-dose regimen for the treatment of deep vein thrombosis as a replacement for current standard therapy.?
In the study, oral rivaroxaban demonstrated non-inferiority for the primary efficacy outcome, defined as the cumulative incidence of symptomatic recurrent DVT and non-fatal or fatal PE, in patients with acute symptomatic DVT compared with the current standard of care of enoxaparin followed by a vitamin K antagonist (VKA) [2.1% vs. 3.0%, respectively (p <0.0001 for non-inferiority)]. Rivaroxaban also demonstrated similar results compared to the standard of care for the principal safety outcome measuring a composite of major and non-major clinically relevant bleeding events [8.1% in both treatment groups, (p=0.77)]. Monthly liver function tests did not reveal a signal for impaired liver safety. Rivaroxaban was well tolerated in the study, and discontinuation rates related to adverse events were low and similar in both treatment groups.
Net clinical benefit, a pre-specified secondary outcome defined as the composite of the primary efficacy outcome plus major bleeding, demonstrated an improvement for rivaroxaban compared to standard therapy (2.9% vs. 4.2%, respectively; HR of 0.67, CI: 0.47 ? 0.95). Other presented secondary outcomes, including all-cause mortality (2.2% vs. 2.9%, respectively; HR of 0.67, CI: 0.44 ? 1.02) and cardiovascular events (0.7% vs. 0.8%, respectively; HR of 0.79, CI: 0.36 ? 1.71) were not statistically significantly different.
EINSTEIN-DVT is the sixth Phase III trial in the ongoing rivaroxaban global development program that demonstrated either non-inferiority (EINSTEIN-DVT) or superiority (RECORD1-4 and EINSTEIN-EXTENSION).
Bayer?s first regulatory filings in the VTE treatment setting are planned for the second half of 2010.
About the EINSTEIN Clinical Trial Program
EINSTEIN is a global clinical development program composed of three clinical studies in nearly 9,000 patients: EINSTEIN-DVT, EINSTEIN-PE and EINSTEIN-Extension. Two of these studies enrolled patients with acute, symptomatic deep vein thrombosis (EINSTEIN-DVT) or pulmonary embolism (EINSTEIN-PE). In these two trials, patients received oral rivaroxaban 15 mg twice-daily for the first three weeks, followed by oral rivaroxaban 20 mg once-daily, compared with initial enoxaparin treatment followed by a vitamin K antagonist.
The multinational Phase III EINSTEIN-DVT study investigated a new single-drug approach with rivaroxaban compared with standard therapy in a randomized, open-label non-inferiority study involving more than 3,400 patients with acute symptomatic DVT, but without any symptoms of PE. Standard therapy for DVT currently includes two compounds: low molecular weight heparin administered by subcutaneous injection, followed by a vitamin K antagonist, which requires regular monitoring of the prothrombin time, reported as the International Normalized Ratio (INR), to optimize efficacy and safety.
Patients received either oral rivaroxaban or body weight-adjusted enoxaparin followed by warfarin or acenocoumarol, dose adjusted to maintain a therapeutic INR (target 2.5, range 2.0-3.0), for 3, 6 or 12 months, based on the physician?s assessment at baseline.
The primary efficacy outcome of EINSTEIN-DVT is the cumulative incidence of symptomatic recurrent DVT and non-fatal or fatal PE. The principal safety outcome is the composite of major and clinically relevant non-major bleeding.
The third study, EINSTEIN-Extension, evaluated the efficacy and safety of rivaroxaban compared to placebo in the secondary prevention of recurrent symptomatic venous blood clots by extending preventative treatment by 6 or 12 months beyond a previously completed regimen of 6 or 12 months of therapy, and enrolled approximately 1,200 patients with symptomatic DVT or PE. The results of the Phase III EINSTEIN-Extension study were presented in December 2009 at the 51st Annual Meeting of the American Society of Hematology (ASH) in New Orleans (USA). The data demonstrated that in patients who had been treated for a previous acute deep vein thrombosis (DVT) or pulmonary embolism (PE), oral rivaroxaban 20 mg once-daily significantly reduced the risk of recurrent symptomatic venous thromboembolism (VTE) by 82 % compared to placebo. The rate of major bleeding was low.
About Deep Vein Thrombosis (DVT)
DVT is the formation of a blood clot in a deep vein that partially or totally blocks the flow of blood. It is estimated that more than 680,000 DVT events occur in the EU each year. The majority of patients suffering from a venous blood clot will experience a DVT alone. However, DVT can progress to become a potentially fatal PE if the blood clot breaks apart and travels to the lungs, ultimately blocking a blood vessel there. Even in the absence of a PE, DVT alone can have burdensome and costly consequences such as post-thrombotic syndrome and an increased risk of recurring blood clots, therefore achieving treatment goals is essential.
Standard therapy for DVT currently includes two compounds: low molecular weight heparin administered by subcutaneous injection, followed by a vitamin K antagonist. The multinational EINSTEIN-DVT study compared the efficacy and safety of a novel single-drug approach with rivaroxaban to current dual standard therapy in a study involving more than 3,400 patients with acute symptomatic DVT in the deep veins of the knee or thigh, but without any symptoms of PE.
Rivaroxaban is a novel oral anticoagulant that was invented in Bayer Schering Pharma?s Wuppertal laboratories in Germany, and is being jointly developed by Bayer HealthCare and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. It has a rapid onset of action with a predictable dose response and high bioavailability, no requirement for coagulation monitoring, as well as a limited potential for food and drug interactions. Rivaroxaban is marketed under the brand name Xarelto® for VTE prevention in adult patients following elective hip or knee replacement surgery, and it is the only new oral anticoagulant that has consistently demonstrated superior efficacy over enoxaparin for this indication. Xarelto® is approved in more than 100 countries worldwide and has been successfully launched in more than 75 countries by Bayer Schering Pharma achieving the market leader position among the new oral anticoagulants.
The extensive clinical trial program supporting rivaroxaban makes it the most studied oral, direct Factor Xa inhibitor in the world today. More than 65,000 patients are participating in the rivaroxaban clinical development program, which will evaluate the product in the prevention and treatment of a broad range of acute and chronic blood-clotting disorders, including stroke prevention in patients with atrial fibrillation, secondary prevention of acute coronary syndrome, and VTE prevention in hospitalized, medically ill patients.
If approved by the FDA, Ortho-McNeil, a division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. (a Johnson & Johnson Company), will commercialize rivaroxaban in the U.S. The U.S. Bayer HealthCare sales force will support the Ortho-McNeil sales force by detailing rivaroxaban in designated hospital accounts. Bayer HealthCare is exclusively responsible for the marketing of rivaroxaban in countries outside the U.S.
To learn more about thrombosis, please visit www.thrombosisadviser.com.
Acute coronary syndrome: safety of two intravenous Heparin doses as adjunct to PCI in patients treated with Fondaparinux
Results from the FUTURA/OASIS 8 study provide initial evidence that a low dose of unfractionated Heparin does not reduce the incidence of bleeding or vascular complications in PCI ( percutaneous coronary intervention ) patients treated with the anticoagulant Fondaparinux ( Arixtra ). Findings showed that the rates of peri-PCI major bleeding were 1.4% in those given low dose Heparin and 1.2% the standard dose.
An earlier trial, OASIS 5 had shown that anticoagulation with Fondaparinux was more effective in reducing mortality and serious bleeding rates in post-MI patients than with Enoxaparin ( Lovenox ). However, rates of catheter thrombosis during angioplasty with Fondaparinux were found to be higher than with Enoxaparin, which prompted the adjunctive use of unfractionated Heparin to prevent clotting in patients treated with Fondaparinux. However there was uncertainty about the optimal dose.
FUTURA/OASIS 8, designed to resolve that uncertainty, was a phase 3, multicentre, randomised trial in 2026 patients undergoing PCI within 72 hours of hospital admission for unstable angina or myocardial infarction. As soon as possible after arrival, they received Fondaparinux 2.5 mg daily, and those requiring PCI were randomised to low fixed dose Heparin ( 50 U/kg ) or standard dose Heparin ( 85 U/kg or 60 U/kg with glycoprotein IIb/IIIa inhibitors ).
The primary outcome was a composite of peri-PCI major bleeding, minor bleeding or major vascular complications, and results showed there was no difference between the two dose regimes in this endpoint. However, while the low dose regimen did not lower the risk of major bleeding, it did lower minor bleeding rates by 60%. And there was also a trend towards higher risk of death, myocardial infarction or target vessel revascularisation ( secondary endpoint ) with the lower dose. The rates of catheter thrombosis were very low in both groups ( 0.5% and 0.1% in the low and standard dose respectively ).
It was also noted that the rates of major bleeding in FUTURA-OASIS 8 ( 1.4% low dose and 1.2% standard dose ) were not significantly different from that observed in the Fondaparinux arm of the OASIS 5 trial ( 1.5% ) but lower than in the Enoxaparin arm ( 3.6% ).
In conclusion, the standard dose of unfractionated Heparin may be the optimal treatment strategy in PCI patients on Fondaparinux, while maintaining the major advantage of Fondaparinux which is a low rate of major bleeding.
Source: European Society of Cardiology Meeting, 2010