Bevacizumab- change in label

On 30^th September, 2011, US FDA informed that changes in bevacizumab (Avastin, Genentech, Inc.) package insert regarding: risk of ovarian failure, osteonecrosis of the jaw, risk of venous thromboembolic event (VTE) and bleeding in patients receiving anticoagulation therapy after first VTE event have been made.

These changes include the following:

• Warning subsection added- increased risk of ovarian failure in premenopausal patients receiving bevacizumab and chemotherapy. It also states a recommendation that females of reproductive potential be informed of the increased risk of ovarian failure prior to starting treatment with bevacizumab,
• Osteonecrosis of the jaw is an adverse reaction of bevacizumab,
• new information regarding the risks of venous thromboembolic events and bleeding in patients receiving anti-coagulation therapy after first VTE event while receiving bevacizumab.

http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm274394.htm

High olive oil consumption has a protective role

A protective role for high olive oil consumption on the risk of stroke in older subjects has been suggested by a study published online on 15^th June, 2011 in Neurology 2011;77:1–1

Sameiri C from From the Research Center INSERM, U897, Department of Nutritional Epidemiology, France determined whether high olive oil consumption, and high plasma oleic acid (as an indirect biological marker of olive oil intake), are associated with lower incidence of stroke in older subjects. They enrolled participants from the Three-City Study with no history of stroke at baseline.

They found that in the main sample, 148 incident strokes occurred. After adjustment for sociodemographic and dietary variables, physical activity, body mass index, and risk factors for stroke, a lower incidence for stroke with higher olive oil use was observed (p for trend = 0.02). Compared to those who never used olive oil, those with intensive use had a 41% lower risk of stroke. It was also seen that higher plasma oleic acid was associated with lower stroke incidence. Compared to those in the first tertile, participants in the third tertile of plasma oleic acid had a 73% reduction of stroke risk.

The authors concluded that in the present population-based study, intensive olive oil use was prospectively associated with a lower stroke risk after controlling for numerous confounding factors, including lifestyle and nutritional factors, main stroke risk factors, and blood lipids.

Statin therapy associated with excess risk of developing diabetes mellitus

Priess D and colleagues from BHF Glasgow Cardiovascular Research Centre, University of Glasgow, United Kingdom conducted a meta-analysis to investigate whether intensive-dose statin therapy is associated with increased risk of new-onset diabetes compared with moderate-dose statin therapy. They included all randomized controlled end-point trials (January 1, 1996, through March 31, 2011) that compared intensive-dose statin therapy with moderate-dose statin therapy and had more than 1000 participants with > 1 year follow-up.

They found that in 5 statin trials with 32 752 participants without diabetes at baseline, 2749 developed diabetes (2.0 additional cases in the intensive-dose group per 1000 patient-years) and 6684 experienced cardiovascular events (6.5 fewer cases in the intensive-dose group per 1000 patient-years) over a weighted mean (SD) follow-up of 4.9 (1.9) years. Odds ratios were 1.12 for new-onset diabetes and 0.84 for cardiovascular events for participants receiving intensive therapy compared with moderate-dose therapy.

The authors concluded that in a pooled analysis of data from 5 statin trials, intensive-dose statin therapy was associated with an increased risk of new-onset diabetes compared with moderate-dose statin therapy.

http://www.ncbi.nlm.nih.gov/pubmed/21693744

PPI use associated with antifracture activity of Alendronate

The use of PPIs to control upper GIT complaints in patients treated with oral bisphosphonates should be discouraged according to a study published on 13^th June, 2011 online in Archives of Internal Medicine.

Bo Abrahamsen, MD, PhD from Institute of Clinical Research, Denmark and colleagues conducted a population-based, national register–based, open cohort observational study of 38 088 new alendronate sodium users with a mean duration of follow-up of 3.5 years.  They related risk of hip fracture to recent pharmacy records of refill of prescriptions for alendronate.

They found that for hip fractures, there was a statistically significant interaction with alendronate for PPI use (P < .05). The treatment response associated with complete refill compliance to alendronate was a 39% risk reduction (P < .001) in patients who were not PPI users, while the risk reduction in concurrent PPI users was not significant (P = .06). It was found that decrease of the risk reduction was dependent on dose and age. In contrast, there was no significant impact of concurrent use of histamine H₂ receptor blockers.

The authors concluded that the concomitant use of PPI and alendronate was associated with a dose-dependent loss of protection against hip fracture with alendronate in elderly patients.

http://archinte.ama-assn.org/cgi/content/abstract/171/11/998?etoc.

Consumption of coffee independent predictor of improved virologic response to therapy in hepatitis C patients

High-level consumption of coffee (more than 3 cups per day) is an independent predictor of improved virologic response to peginterferon plus ribavirin in patients with hepatitis C, according to a study published online on 10^th June, 2011  in the Gastroenterology journal.

Neel D Freedman PhD MPH, from National Cancer Institute, Maryland, USA and colleagues  assessed patients for early virologic response (2 log₁₀ reduction in level of hepatitis C virus RNA at week 12; n = 466), and undetectable hepatitis C virus RNA at weeks 20, 48 , and 72. They enrolled 885 patients from the lead-in phase of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial recorded coffee intake before retreatment with peginterferon α-2a (180 μg/wk) and ribavirin (1000–1200 mg/day).  

Median log₁₀ drop from baseline to week 20 was 2.0 among nondrinkers and 4.0 among patients that drank 3 or more cups/day of coffee (P trend <.0001). After adjustment for age, race/ethnicity, sex, alcohol, cirrhosis, ratio of aspartate aminotransferase to alanine aminotransferase, the IL28B polymorphism rs12979860, dose reduction of peginterferon, and other covariates, odds ratios for drinking 3 or more cups/day vs nondrinking were 2.0 (P trend = .004) for early virologic response, 2.1 (P trend = .005) for week 20 virologic response, 2.4 (P trend = .001) for end of treatment, and 1.8 (P trend = .034) for sustained virologic response.

The authors highlighted that in patients with advanced HCV-related chronic liver disease in the HALT-C trial receiving peginterferon plus ribavirin treatment, 3 or more cups per day coffee drinkers were 3 times more likely to have a virologic response than nondrinkers. In contrast to results for coffee, no effect was observed for tea drinking.

http://www.gastrojournal.org/article/S0016-5085(11)00273-3/fulltext

Finasteride and Dutasteride- Recommendations for label change

FDA has recommended that prior to initiating therapy with 5-alpha reductase inhibitors (ARIs) like finasteride or Dutasteride, the healthcare professionals should  perform appropriate evaluation to rule out other urological conditions, including prostate cancer, that might mimic benign prostatic hyperplasia (BPH).
The Warnings and Precautions section of the labels for the 5-ARI class of drugs has been revised to include new safety information about the increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer).
The decision has been taken in view of the results of two large randomised controlled trials (RCTs) conducted in 2010-the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial.
Finasteride and Dutasteride are available as Proscar, Avodart, and Jalyn.
These are approved to improve symptoms of benign prostatic hyperplasia (BPH).
Proscar and Avodart are also approved to reduce the risk of urinary retention or surgery related to an enlarged prostate.
Propecia is approved to treat male pattern hair loss.
Ironically, 5-ARIs were used for chemoprevention of prostate cancer without the FDA approval.
Also, the guidelines released jointly in 2009 by the American Society of Clinical Oncologists and the American Urological Association recommended that, "Asymptomatic men with a prostate-specific antigen (PSA) ≤3.0 ng/mL who are regularly screened with PSA or are anticipating undergoing annual PSA screening for early detection of prostate cancer may benefit from a discussion of both the benefits of 5-ARIs for 7 years for the prevention of prostate cancer and the potential risks (including the possibility of high-grade prostate cancer)." ⁽¹⁾
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258529.htm
(1) http://caonline.amcancersoc.org/cgi/content/full/61/1/1

Simvastatin (ZOCOR)- New recommendations by FDA

US FDA has recommended that Simvastatin 80 mg should not be started in new patients, including patients already taking lower doses of the drug. 
Simvastatin 80 mg should be used only in patients who have been taking this dose for 12 months or more without evidence of muscle injury (myopathy).
Simvastatin is a lipid lowering drug used by patients who have had a Coronary Artery Disease (CAD) or they are at a high risk of having  CAD.
Simvastatin belongs to the group of HMG-CoA reductase inhibitors (or statins). The known adverse effects of statins are the hepatic damage and myopathy.
FDA has mentionedd that patients taking simvastatin 80 mg daily have an increased risk of myopathy compared to patients taking lower doses of this drug or other drugs in the same class. This risk appears to be higher during the first year of treatment, is often the result of interactions with certain medicines, and is frequently associated with a genetic predisposition toward simvastatin-related myopathy. The most serious form of myopathy, called rhabdomyolysis, can damage the kidneys and lead to kidney failure which can be fatal. FDA is requiring changes to the simvastatin label to add new contraindications (should not be used with certain medications) and dose limitations for using simvastatin with certain medicines.
The new changes to the drug labels for simvastatin-containing medicines are based on FDA's review of the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial and other data described in the Agency's March 2010 Ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury.
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258384.htm

Systolic BP treatment goal of 130 to 135 mm Hg acceptable in Type 2 diabetes

In patients with type 2 diabetes mellitus/impaired fasting glucose/impaired glucose tolerance, a systolic BP treatment goal of 130 to 135 mm Hg is acceptable, according to the results of a meta-analysis published online in June 1, 2011 issue of Circulation.

Sripal Bangalore, MD, MHA, Assistant Professor of Medicine,  from, New York University School of Medicine, USA and colleagues performed a meta-analysis of randomized clinical trials from 1965 to October 2010 of antihypertensive therapy in patients with type 2 diabetes mellitus or impaired fasting glucose/impaired glucose tolerance that enrolled at least 100 patients with achieved systolic BP of 135 mm Hg in the intensive BP control group and 140 mm Hg in the standard BP control group, had a follow-up of at least 1 year, and evaluated macrovascular or microvascular events.

They found that intensive BP control was associated with a 10% reduction in all-cause mortality, a 17% reduction in stroke, and a 20% increase in serious adverse effects, but with similar outcomes for other macrovascular and microvascular (cardiac, renal, and retinal) events compared with standard BP control. More intensive BP control ( 130 mm Hg) was associated with a greater reduction in stroke, but did not reduce other events. Meta–regression analysis showed continued risk reduction for stroke to a systolic BP of <120 mm Hg.

The authors also reported that with more aggressive goals (<130 mm Hg), they observed target organ heterogeneity in that the risk of stroke continued to fall, but there was no benefit regarding the risk of other macrovascular or microvascular (cardiac, renal and retinal) events, and the risk of serious adverse events even increased.

New drugs approved in India in April 2011

Tioconazole Vaginal Gel 65mg per gm	For the local treatment of vulvovaginal candidiasis in adult patients.
Ilaprazole Tablets 5mg/10mg	For the treatment of duodenal ulcer in adults only.
Tapentadol Hydrochloride tablets 50mg/75mg/100mg	For relief of moderate to severe acute pain in adults 18 years of age or older.
S-Bupivacaine Hydrochloride Injection 2.5mg/5mg/7.5mg per ml	For surgical anaesthesia in adults for epidural (including caesarean section), intrathecal, peripheral nerve block.

Gatifloxacin and Tegaserod banned

DCGI banned the manufacture, sale and distribution of Gatifloxacin for human use by oral or injectable route.
http://cdsco.nic.in/PRohibited_gatifloxacin_tegaserod.pdf

DCGI also banned the manufacture, sale and distribution of Tegaserod for human use.
http://cdsco.nic.in/PRohibited_gatifloxacin_tegaserod.pdf

Drugs banned in India

Link to DCGI website which mentions the drugs banned in India.
http://cdsco.nic.in/html/Drugsbanned.html

Azilsartan/chlorthalidone combo bests olmesartan/HCTZ in stage 2 systolic hypertension

Heartwire reported on 24^th May, 2011 that the use of the combination therapy azilsartan medoxomil (Edarbi, Takeda Pharmaceuticals) and chlorthalidone resulted in a more effective reduction in systolic blood pressure (SBP), including ambulatory measures of blood pressure, when compared with combination therapy of olmesartan (Benicar, Daiichi Sankyo) and hydrochlorothiazide (HCTZ) in patients with hypertension, according to the results of a new study.

Presenting the data this week during the late-breaking clinical trials session at the American Society of Hypertension (ASH) 2011 Scientific Meeting, lead investigator Dr William Cushman (Veterans Affairs Medical Center, Memphis, TN) noted that azilsartan, a new angiotensin-receptor blocker (ARB) approved by FDA in February this year, is a highly effective, long-acting agent that is currently in development as a fixed-dose combination with chlorthalidone, a thiazidelike diuretic.

Speaking with the media during a press conference announcing the results, Cushman said chlorthalidone was selected as the second agent with azilsartan and partnered in development because there is growing evidence the drug is more effective than HCTZ. The purpose of the study was to compare the effectiveness of the azilsartan/chlorthalidone combination with the maximum approved dose of olmesartan/HCTZ, that being 40/25 mg.

http://www.theheart.org/article/1230773.do

Celecoxib should not be used in FAP

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has finalised that existing evidence of safety and efficacy does not support the use of celecoxib in the reduction of the number of adenomatous intestinal polyps in familial adenomatous polyposis (FAP).

This review follows Pfizer’s voluntary withdrawal of the marketing authorisation of its celecoxib-containing orphan medicine, Onsenal, which had been authorised for use in FAP patients. The reason for the withdrawal was that Pfizer was unable to provide confirmatory data regarding clinical benefit due to slow enrolment in a clinical trial. These data had been requested by the CHMP at the time of granting of the marketing authorisation for Onsenal.

Celecoxib-containing products are currently authorised in the European Union for the treatment of the symptoms of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. This review was initiated because of concerns that celecoxib may be used off-label in the FAP indication following the withdrawal of Onsenal.

The CHMP concluded that the benefit of celecoxib in FAP patients had not been sufficiently demonstrated and did not outweigh the increased risk of cardiovascular and gastrointestinal side effects, which would result from high dose and long-term treatment used in FAP patients.

http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2011/05/WC500106524.pdf



FDA approves injectable gel to treat fecal incontinence

The U.S. Food and Drug Administration today approved a sterile, injectable gel to treat fecal incontinence in patients for whom other therapies such as diet change, fiber therapy or anti-motility medications failed.
Fecal incontinence is the involuntary loss of bowel control. It can have different causes including nerve damage, weakened anal sphincter associated with aging, or rectum muscle damage.

The Solesta gel is injected into a layer of tissue beneath the anus lining and may help build tissue in that area. By growing the surrounding tissue, the opening of the anus narrows and the patient may be able to better control those muscles.
Solesta is approved for use in patients ages 18 and up.

It should not be used in patients who have active inflammatory bowel disease, immunodeficiency disorders, previous radiation treatment to the pelvic area, significant rectal prolapse, active infections, bleeding, tumors or malformations in the anorectal area, rectal distended veins, an existing implant in the anorectal region, or allergy to hyaluronic acid based products.

Most common side effects are injection area pain and bleeding.
Infection and inflammation of anal tissue are more serious risks, but are less common.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm257112.htm

FDA approves treatment for Clostridium difficile infection

The U.S. Food and Drug Administration recently approved Dificid (fidaxomicin) tablets for the treatment of Clostridium difficile-associated diarrhea (CDAD).
The safety and efficacy of Dificid has been demonstrated in two trials that included 564 patients with CDAD that compared Dificid with vancomycin, a common antibiotic used to treat CDAD. The clinical response was similar in the Dificid group compared with the vancomycin group in both studies. In some patients with CDAD, symptoms can return. In the Dificid trials, a greater number of patients treated with Dificid had a sustained cure three weeks after treatment ended versus those patients treated with vancomycin.
Dificid, a macrolide antibacterial, should be taken two times a day for 10 days with or without food.
To maintain the effectiveness of Dificid, and to reduce the development of drug-resistant bacteria, the drug should be used only to treat infections that are proven or strongly suspected to be caused by C. difficile.
The most common side effects reported with Dificid included nausea, vomiting, headache, abdominal pain, and diarrhea.
People at risk of developing the bacterial infection include the elderly, patients in hospitals or nursing homes, and people taking antibiotics for another infection. The most effective way to prevent CDAD is thorough handwashing with soap and warm water.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm257024.htm

Addition of Boceprevir beneficial in HCV infection

Addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increases the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection according to a study published in New Engl Journal of Medicine 2011 Mar 31;364(13):1195-206

Poodhar F, M.D. from Cedars–Sinai Medical Center, Los Angeles, US evaluated Boceprevir, a potent oral HCV-protease inhibitor, as an additional treatment in phase 1 and phase 2 studies. In  a double-blind study previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.

The investigators found that a total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 40% in group 1; 67% in group 2 (P<0.001), and 68% in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 23% in group 1, in 42%  in group 2 (P=0.04), and in 53% in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively.

The authors concluded that the addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir.

http://www.ncbi.nlm.nih.gov/pubmed/21449783?dopt=Abstract

Rare atypical fractures of the femur: a class effect of bisphosphonates

European Medicines Agency has concluded a class review of bisphosphonates and atypical fractures

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has concluded that rare atypical fractures of the femur are a class effect of bisphosphonates.

The CHMP confirmed that the benefits of bisphosphonates in the treatment and prevention of bone disorders continue to outweigh their risks, but that a warning of the risk of atypical femoral fractures should be added to the prescribing information for all bisphosphonate-containing medicines in the European Union. Such a warning had already been included in the product information for alendronate-containing medicines across Europe, following a review by the CHMP’s Pharmacovigilance Working Party in 2008. It will now be extended to the whole bisphosphonate class.

Prescribers of bisphosphonate-containing medicines should be aware that atypical fractures of the femur may occur rarely. If an atypical fracture is suspected in one leg, then the other leg should also be examined. Doctors who are prescribing these medicines for osteoporosis should regularly review the need for continued treatment, especially after five or more years of use.

Patients who are taking bisphosphonate-containing medicines need to be aware of the risk of this unusual fracture of the femur. They should contact their doctor if they have any pain, weakness or discomfort in the thigh, hip or groin, as this may be an indication of a possible fracture.

http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2011/04/WC500105281.pdf

Comparison of Dalteparin to unfractionated heparin in decreasing incidence of proximal DVT

The investigators of PROTECT trial tested the superiority of dalteparin over unfractionated heparin in a multicentric trial by randomly assigning 3764 patients to receive either subcutaneous dalteparin (at a dose of 5000 IU once daily) plus placebo once daily (for parallel-group twice-daily injections) or unfractionated heparin (at a dose of 5000 IU twice daily) while they were in the intensive care unit.

The primary outcome, proximal leg deep-vein thrombosis, was diagnosed on compression ultrasonography performed within 2 days after admission, twice weekly, and as clinically indicated.

There was no significant between-group difference in the rate of proximal leg deep-vein thrombosis, which occurred in 5.1% receiving dalteparin versus 5.8%   receiving unfractionated heparin.

The proportion of patients with pulmonary emboli was significantly lower with dalteparin (24 patients, 1.3%) than with unfractionated heparin (43 patients, 2.3%).

There was no significant between-group difference in the rates of major bleeding or death in the hospital. In prespecified per-protocol analyses, the results were similar to those of the main analyses, but fewer patients receiving dalteparin had heparin-induced thrombocytopenia.

The authors concluded that among critically ill patients, dalteparin was not superior to unfractionated heparin in decreasing the incidence of proximal deep-vein thrombosis.

http://www.nejm.org/doi/full/10.1056/NEJMoa1014475?query=oncology-hematology

FDA approves Zytiga for late-stage prostate cancer

U.S. Food and Drug Administration has approved Zytiga (abiraterone acetate) in combination with prednisone (a steroid) to treat patients with late-stage (metastatic) castration-resistant prostate cancer who have received prior docetaxel (chemotherapy).

Abiraterone acetate (CB7630) is an orally administered inhibitor of the steroidal enzyme CYP17 (17α-hydroxylase/C17,20 lyase), a cytochrome p450 complex that is involved in testosterone production and estrogen production Zytiga has been approved ahead of the product’s June 20, 2011 regulatory goal date.

Zytiga’s safety and effectiveness were established in a clinical study of 1,195 patients with late-stage castration-resistant prostate cancer who had received prior treatment with docetaxel chemotherapy. Patients received either Zytiga once daily in combination with prednisone two times a day or a placebo twice daily in combination with prednisone.

The study was designed to measure overall survival, the length of time from when the treatment started until a patient's death. Patients who received the Zytiga and prednisone combination had a median overall survival of 14.8 months compared to 10.9 months for patients receiving the placebo and prednisone combination.

The most commonly reported side effects in patients receiving Zytiga included joint swelling or discomfort, low levels of potassium in the blood, fluid retention (usually of the legs and feet), muscle discomfort, hot flashes, diarrhea, urinary tract infection, cough, high blood pressure, heartbeat disorders, urinary frequency, increased nighttime urination, upset stomach or indigestion and upper respiratory tract infection.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm253055.htm

FDA approves Linagliptin for Type 2 Diabetes

The U.S. Food and Drug Administration today approved Tradjenta (linagliptin) tablets, used with diet and exercise, to improve blood glucose control in adults with Type 2 diabetes.

Linagliptin is a dipeptidyl peptidase-4 or DPP-4 enzyme inhibitor. Thus it prevents the degradation of the incretins and ultimately increase the level of insulin after a meal.

Tradjenta was demonstrated to be safe and effective in eight double-blind, placebo-controlled clinical studies involving about 3,800 patients with Type 2 diabetes. The studies showed improvement in blood glucose control compared with placebo.

Tradjenta has been studied as a stand-alone therapy and in combination with other Type 2 diabetes therapies including metformin, glimepiride, and pioglitazone. Tradjenta has not been studied in combination with insulin, and should not be used to treat people with Type 1 diabetes or in those who have increased ketones in their blood or urine (diabetic ketoacidosis).

The most common side effects of Tradjenta are upper respiratory infection, stuffy or runny nose, sore throat, muscle pain, and headache.

Other DPP-4 inhibitors in the market are Sitagliptin and Vildagliptin.

Exenatide is the incretin mimetic available as a drug.

The DPP-4 inhibitors and incretin mimetics are approved for use alongwith diet control and exercise.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm253501.htm

Olmesartan:Safety update report by FDA

After reviewing the results of the ROADMAP and ORIENT trials (1), US FDA has determined that the benefits of Benicar (Olmesartan) continue to outweigh its potential risks when used for the treatment of patients with high blood pressure according to the drug label.(2)

Benicar (Olmesartan) is not recommended as a treatment to delay or prevent protein in the urine (microalbuminuria) in diabetic patients.

In November, 2011, US FDA (3) had mentioned that it 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.

ROADMAP and ORIENT are both long-term clinical trials. In both trials, patients with type 2 diabetes were given either Benicar or placebo to determine if treatment with Benicar would slow the progression of kidney disease. An unexpected finding observed in both trials was a greater number of deaths from a cardiovascular cause (heart attack, sudden death, or stroke) in the Benicar-treated patients compared to placebo.
 Benicar (olmesartan) is in the class of drugs called angiotensin II receptor blockers (ARBs). 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 heart attack 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.

(1)  Haller H, Ito S, Izzo JL, et al. Olmesartan for the delay or prevention of microalbuminuria in Type 2 Diabetes. N Engl J Med 2011;364:907-17

(2)  http://www.theheart.org/article/1211653.do

(3) http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm215222.htm

Screen time has a potential adverse influence on retinal microvascular structure.

The magnitude of arteriolar narrowing associated with each hour daily of TV viewing is similar to that associated with a 10-mm Hg increase in systolic blood pressure in children.

A study mentioning the influence of physical activity and screen time on the retinal microvasculature in young children will be published in May issue of Arterioscler Thromb Vasc Biol. 2011

Gopinath B and colleagues of University of Sydney, Australia have investigated the associations among physical activity (outdoor and indoor sporting activities), sedentary behaviors (including screen time, television [TV] viewing, and computer and videogame usage), and retinal microvascular caliber in schoolchildren.

Six-year-old students (1765/2238) from a random cluster sample of 34 Sydney schools were examined. Parents completed questionnaires about physical and sedentary activities. Retinal images were taken, and retinal vessel caliber was quantified.

After adjusting for age, sex, ethnicity, eye color, axial length, body mass index, birth weight, and mean arterial blood pressure, children who spent more time in outdoor sporting activities (in the highest tertile of activity) had 2.2 μm (95% CI 0.65 to 3.71) wider mean retinal arteriolar caliber than those in the lowest tertile (P(trend)=0.004). Increasing quartiles of time spent watching TV were associated with narrower mean retinal arteriolar caliber ≈2.3 μm (95% CI 0.73 to 3.92), P(trend)=0.003.

The authors concluded that the data suggests that physical activity could have a beneficial influence, whereas screen time has a potential adverse influence on retinal microvascular structure.

http://www.ncbi.nlm.nih.gov/pubmed/21508347

Calcium supplements and cardiovascular events

Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, according  to a study published in April issue of BMJ (1). 

Bolland BJ and colleagues have reanalysed of WHI CaD Study limited access dataset with incorporation of meta-analysis eight other studies have. WHI CaD Study, a seven year, randomized, placebo controlled trial of calcium and vitamin D (1g calcium and 400 IU vitamin D daily) in 36 282 community dwelling postmenopausal women.

Main outcome measure: Incidence of four cardiovascular events and their combinations (myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke) assessed with patient-level data and trial-level data.

The results of WHI CaD Study show that there is an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events. In the 16 718 women (46%) who were not taking personal calcium supplements at randomization the hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22 (P=0.05 for clinical myocardial infarction or stroke, P=0.04 for clinical myocardial infarction or revascularisation), whereas in the women taking personal calcium supplements cardiovascular risk did not alter with allocation to calcium and vitamin D.

In meta-analyses of three placebo controlled trials, calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.21 (P=0.04), stroke (P=0.05), and the composite of myocardial infarction or stroke (P=0.02).

Calcium or calcium and vitamin D increased the risk of myocardial infarction (P=0.004) and the composite of myocardial infarction or stroke (P=0.009).

The authors concluded that Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction. This finding was obscured in the WHI CaD Study by the widespread use of personal calcium supplements.

(1) http://www.bmj.com/content/342/bmj.d2040 

Dietary Guidelines 2010

The US Department of Agriculture (USDA) has released the Dietary Guidelines for Americans, 2010 which are intended for Americans ages 2 years and older, including those at increased risk of chronic disease.

 The main concepts of the guidelines are to maintain calorie balance over time to achieve and sustain a healthy weight and to focus on consuming nutrient-dense foods and beverages.

The key recommendations are:

1.     Balancing calories and manage weight

•                 Prevent and/or reduce overweight and obesity through improved eating and physical activity behaviors.

•                 Control total calorie intake to manage body weight. For people who are overweight or obese, this will mean consuming fewer calories from foods and beverages.

•                 Increase physical activity and reduce time spent in sedentary behaviors.

•                 Maintain appropriate calorie balance during each stage of life—childhood, adolescence, adulthood, pregnancy and breastfeeding, and older age.

2.     Foods and food components to reduce

•                 Reduce daily sodium intake to less than 2,300 milligrams (mg) and further reduce intake to 1,500 mg among persons who are 51 and older and those of any age who are African American or have hypertension, diabetes, or chronic kidney disease. The 1,500 mg recommendation applies to about half of the U.S. population, including children, and the majority of adults.

•                 Consume less than 10 percent of calories from saturated fatty acids by replacing them with monounsaturated and polyunsaturated fatty acids.

•                 Consume less than 300 mg per day of dietary cholesterol.

•                 Keep trans fatty acid consumption as low as possible by limiting foods that contain synthetic sources of trans fats, such as partially hydrogenated oils, and by limiting other solid fats.

•                 Reduce the intake of calories from solid fats and added sugars.

•                 Limit the consumption of foods that contain refined grains, especially refined grain foods that contain solid fats, added sugars, and sodium.

If alcohol is consumed, it should be consumed in moderation—up to one drink per day for women and two drinks per day for men—and only by adults of legal drinking age.
For detalied guidelines refer to http://www.cnpp.usda.gov/Publications/DietaryGuidelines/2010/PolicyDoc/ExecSumm.pdf
http://www.cnpp.usda.gov/DGAs2010-PolicyDocument.htm

HPS trial post hoc analysis

The results of Heart Protection Study  post-hoc analysis have been publishedd in the latest issue of Lancet.(1) The HPS tested the hypothesis that the effects of statin therapy differ according to baseline concentrations of CRP and LDL cholesterol.

Patients were categorised into six baseline CRP groups (<1·25, 1·25—1·99, 2·00—2·99, 3·00—4·99, 5·00—7·99, and ≥8·00 mg/L), each including about 3000 patients.

Results showing the effect of Simvastatin on LDL_C levels have been published earlier. Results of this post-hoc analysis:

·        Allocation to simvastatin produced a significant 24% (95% CI 19—28) proportional reduction in the incidence of first major vascular event after randomisation.

·        There was no significant trend in the proportional risk reduction with increasing baseline CRP, with significant reductions in each of the baseline CRP groups, including in participants with CRP concentration less than 1·25 mg/L (29% risk reduction, 99% CI 12—43; p<0·0001).

·        Indeed, even in those with baseline CRP concentration less than 1 mg/L, there was a significant 27% (99% CI 5—44) reduction in risk (166 [13·7%] allocated to simvastatin vs 218 [18·3%] allocated to placebo; p=0·0022).

·        Allocation to simvastatin reduced the incidence of first major coronary event by 27% (95% CI 21—33), of first stroke by 25% (15—34), and of first revascularisation by 24% (17—30), with no significant trend in the proportional risk reduction with increasing baseline CRP concentration for any of these outcomes.

·        There was also no significant trend in the proportional reduction in vascular death with increasing baseline CRP.

·        The proportional risk reduction in participants with low LDL cholesterol and low CRP (27%, 99% CI 11—40; p<0·0001) was statistically similar to that in participants with high LDL cholesterol and high CRP (23%, 10—35; p<0·0001). The authors have mentioned that even when the threshold used to define low LDL cholesterol was reduced to 2·8 mmol/L (which was the median baseline concentration in the JUPITER trial), the proportional reduction in major vascular events in participants with low LDL cholesterol and low CRP (92 [13·6%] vs 128 [18·2%]; risk reduction 0·73, 99% CI 0·52—1·04; p=0·0213) was still similar to the reduction recorded overall.

According to the authors the results of this post-hoc analysis does not lend support to the hypothesis that baseline CRP concentration modifies the vascular benefits of statin therapy materially.

The discussion on the hypothesis has been done on http://www.theheart.org/article/1177999.do

(1) http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62174-5/fulltext?_eventId=login#bib2

Antihypertensive effect of Hydrochlorthiazide

A meta-analysis of use of hydrochlorthiazide (HCTZ) in management of hypertension has been published in the January issue of J Am Coll Cardiol (1) .

The trials with the following criteria were included in the meta-analysis: 1) randomized trials involving patients with hypertension that assessed the antihypertensive efficacy by 24-h Ambulatory Blood Pressure (ABP) monitoring comparing HCTZ with other antihypertensive drug classes; 2) use of HCTZ as a monotherapy in the trial; and 3) trial duration of at least 4 weeks.

The main outcome of the present analysis was BP (systolic/diastolic) reduction from baseline to follow-up.

Results: The antihypertensive efficacy of HCTZ in the dose of 12.5 to 25 mg was assessed from 14 randomized controlled trials.

·       The mean baseline BP in these studies was 148 ± 7.5/92 ± 5.6 mm Hg.

·       After treatment with HCTZ for a mean duration of 17 weeks, systolic ABP decreased by 6.5 mm Hg  and diastolic ABP by 4.5 mm Hg.

·       Other antihypertensive agents such as ACE inhibitors, ARBs, beta-blockers, and calcium antagonists were significantly more efficacious than HCTZ in the dose of 12.5 to 25 mg.

·       In head-to-head comparisons with other antihypertensive drug classes, HCTZ in the usual dose of 12.5 to 25 mg lowered systolic ABP less well than ACE inhibitors by 4.5 mm Hg (p = 0.001), ARBs by 5.1 mm Hg, beta-blockers by 6.2 mm Hg (p < 0.00001), and calcium antagonists by 4.5 mm Hg (p = 0.02).

·        HCTZ lowered diastolic ABP less well than ACE inhibitors by 4.0 mm Hg (p < 0.0001), ARBs by 2.9 mm Hg (p = 0.002), beta-blockers by 6.7 mm Hg (p < 0.00001), and calcium antagonists by 4.2 mm Hg (p = 0.0001)

·   The antihypertensive effect of HCTZ was similar to other antihypertensives in controlling the office BP, whereas it was inferior to other antihypertensives in controlling ABP.

·    The authors have mentioned that assessing the antihypertensive efficacy of HCTZ by office BP measurements only is deceptive and is prone to provide to physicians and patients a false sense of security.

·       At a daily dose of 50 mg and above, HCTZ's antihypertensive efficacy seems to be similar to most other drug classes. However, all biochemical adverse effects such as hypokalemia, hyponatremia, hyperuricemia, insulin resistance, and visceral fat accumulation are dose dependent and become clinically more significant with daily doses exceeding 25 mg (2).  

·       In its commonly used dose of 12.5 to 25 mg once a day, there has been no evidence that HCTZ reduces myocardial infarction, stroke, or death.

·       Numerous, mostly factorial design studies have shown that when combined with these drug classes, HCTZ, even at low doses, elicits a distinct incremental fall in BP. That indicates that HCTZ is more useful as an "enhancer" or "sensitizer" for the antihypertensive effect of renin-angiotensin system blockers than as a monotherapeutic agent. The ACCOMLISH trial shows HCTZ to be inferior to amlodipine.(3)

·       The authors concluded that HCTZ in its commonly used dose of 12.5 to 25 mg daily lowers BP significantly less well than do all other drug classes as measured in head-to-head studies by ABP monitoring.

The meta-analysis has also been discussed on: http://www.theheart.org/article/1176571.do#bib_2

References:

1.     http://content.onlinejacc.org/cgi/content/long/57/5/590

2.     Messerli FH, Bangalore S, Julius S. Risk/benefit assessment of beta-blockers and diuretics precludes their use for first-line therapy in hypertension Circulation 2008;117:2706-2715discussion 2715

3.     Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients N Engl J Med 2008;359:2417-2428.