FDA approves Pradaxa to prevent stroke in people with atrial fibrillation

The U.S. Food and Drug Administration today approved Pradaxa capsules (dabigatran etexilate) for the prevention of stroke and blood clots in patients with abnormal heart rhythm (atrial fibrillation).
Atrial fibrillation, which affects more than 2 million Americans, involves very fast and uncoordinated contractions of the heart’s two upper heart chambers (atria) and is one of the most common types of abnormal heart rhythm.
Mechanism of action:

Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.

The safety and efficacy of Pradaxa were studied in a clinical trial comparing Pradaxa with the anticoagulant warfarin. In the trial, patients taking Pradaxa had fewer strokes than those who took warfarin.

At recommended therapeutic doses, dabigatran etexilate prolongs the aPTT, ECT, and TT. With an oral dose of 150 mg twice daily the median peak aPTT is approximately 2x control. Twelve hours after the last dose the median aPTT is 1.5x control, with less than 10% of patients exceeding 2x control.

It was highlighted that unlike warfarin, which requires patients to undergo periodic monitoring with blood tests, such monitoring is not necessary for Pradaxa.
As with other approved anti-clotting drugs, bleeding, including life-threatening and fatal bleeding, was among the most common adverse reactions reported by patients treated with Pradaxa. Gastrointestinal symptoms, including an uncomfortable feeling in the stomach (dyspepsia), stomach pain, nausea, heartburn, and bloating also were reported.
Pradaxa was approved with a Medication Guide that informs patients of the risk of serious bleeding. The guide will be distributed each time a patient fills a prescription for the medication.
Pradaxa, manufactured by Boehringer Ingelheim Pharmaceuticals Inc. of Ridgefield, Conn., will be available in 75 milligram and 150 milligram capsules.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230241.htm
http://www.pradaxa.com/pdf/PI_PRADAXA.pdf

Pediatric Basic and Advanced Life Support: 2010 recommendations

The most important changes or points of emphasis in the recommendations for pediatric resuscitation since the publication of the 2005 ILCOR International Consensus on CPR and ECC Science With Treatment Recommendations are summarized in the following list.

• Additional evidence shows that healthcare providers do not reliably determine the presence or absence of a pulse in infants or children.

• New evidence documents the important role of ventilations in CPR for infants and children. However, rescuers who are unable or unwilling to provide ventilations should be encouraged to perform compression-only CPR.
• To achieve effective chest compressions, rescuers should compress at least one third the anterior-posterior dimension of the chest. This corresponds to approximately 1.5 inches (4 cm) in most infants and 2 inches (5 cm) in most children.
• When shocks are indicated for ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) in infants and children, an initial energy dose of 2 to 4 J/kg is reasonable; doses higher than 4 J/kg, especially if delivered with a biphasic defibrillator, may be safe and effective.
• More data support the safety and effectiveness of cuffed tracheal tubes in infants and young children, and the formula for selecting the appropriately sized cuffed tube was updated.
• The safety and value of using cricoid pressure during emergency intubation are not clear. Therefore, the application of cricoid pressure should be modified or discontinued if it impedes ventilation or the speed or ease of intubation.
• Monitoring capnography/capnometry is recommended to confirm proper endotracheal tube position.
• Monitoring capnography/capnometry may be helpful during CPR to help assess and optimize quality of chest compressions.
• On the basis of increasing evidence of potential harm from exposure to high-concentration oxygen after cardiac arrest, once spontaneous circulation is restored, inspired oxygen concentration should be titrated to limit the risk of hyperoxemia.
• Use of a rapid response system in a pediatric inpatient setting may be beneficial to reduce rates of cardiac and respiratory arrest and in-hospital mortality.
• Use of a bundled approach to management of pediatric septic shock is recommended.
• The young victim of a sudden, unexpected cardiac arrest should have an unrestricted, complete autopsy, if possible, with special attention to the possibility of an underlying condition that predisposes to a fatal arrhythmia. Appropriate preservation and genetic analysis of tissue should be considered; detailed testing may reveal an inherited "channelopathy" that may also be present in surviving family members.

 
^{http://circ.ahajournals.org/cgi/content/full/122/16_suppl_2/S466}

2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations

2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations  published in the latest issue of Circulation journal.(1)

The following is a summary of the most important evidence-based recommendations for the performance of basic life support in adults:

• Rescuers should begin CPR if the victim is unresponsive and not breathing (ignoring occasional gasps). Gasping should not prevent initiation of CPR because gasping is not normal breathing, and gasping is a sign of cardiac arrest.
• Following initial assessment, rescuers may begin CPR with chest compressions rather than opening the airway and delivering rescue breathing.
• All rescuers, trained or not, should provide chest compressions to victims of cardiac arrest.
• A strong emphasis on delivering high-quality chest compressions remains essential: rescuers should push hard to a depth of at least 2 inches (or 5 cm) at a rate of at least 100 compressions per minute, allow full chest recoil, and minimize interruptions in chest compressions.
• Rescuers trained to provide ventilations use a compression-ventilation ratio of 30:2.
• For untrained rescuers, EMS dispatchers should provide telephone instruction in chest compression–only CPR.

(1) http://circ.ahajournals.org/content/vol122/16_suppl_2/?etoc

Possible increased risk of thigh bone fracture with bisphosphonates: FDA

On 13^th October, US FDA warned patients and health care providers about the possible risk of atypical thigh bone (femoral) fracture in patients who take bisphosphonates, a class of drugs used to prevent and treat osteoporosis.

 A labeling change has been advocated.

Bisphosphonates inhibit the loss of bone mass in people with osteoporosis. Bisphosphonates have been shown to reduce the rate of osteoporotic fractures -- fractures that can result in pain, hospitalization, and surgery-- in people with osteoporosis.

While it is not clear whether bisphosphonates are the cause, atypical femur fractures, a rare but serious type of thigh bone fracture, have been predominantly reported in patients taking bisphosphonates.

The optimal duration of bisphosphonate use for osteoporosis is unknown, and the FDA is highlighting this uncertainty because these fractures may be related to use of bisphosphonates for longer than five years.

The labeling changes and Medication Guide will affect only those bisphosphonates approved for osteoporosis, including oral bisphosphonates such as Fosamax, Fosamax Plus D, Actonel, Actonel with Calcium, Boniva, Atelvia, and their generic products, as well as injectable bisphosphonates such as Reclast and Boniva.

Labeling changes and the Medication Guide will not apply to bisphosphonates used for Paget’s disease or cancer/hypercalcemia such as Didronel, Zometa, Skelid, and their generic products.

In March 2010, FDA had announced about the ongoing safety review and this is in continuation of that. The FDA has since reviewed all available data on bisphosphonate use, including data summarized in the American Society for Bone Mineral Research Task Force report. The report recommended additional product labeling, better identification and tracking of patients experiencing these breaks, and more research to determine whether and how these drugs cause the serious but uncommon fractures.

The Warnings and Precautions section of all bisphosphonate products for osteoporosis will be revised, and the FDA will require the inclusion of a Medication Guide to better inform patients of the possible increased fracture risk.

 Patients taking bisphosphonates for osteoporosis should not stop using their medication unless told to do so by their health care professional. Those taking bisphosphonates also should report any new thigh or groin pain to their health care provider and be evaluated for a possible femur fracture.

FDA recommends that healthcare professionals should:

• Be aware of the possible risk of atypical subtrochanteric and diaphyseal femur fractures in patients taking bisphosphonates.
• Continue to follow the recommendations in the drug label when prescribing bisphosphonates.
• Discuss the known benefits and potential risks of using bisphosphonates with patients.
• Evaluate any patient who presents with new thigh or groin pain to rule out a femoral fracture.
• Discontinue potent antiresorptive medications (including bisphosphonates) in patients who have evidence of a femoral shaft fracture.
• Consider periodic reevaluation of the need for continued bisphosphonate therapy, particularly in patients who have been treated for over 5 years.

·        The optimal duration of bisphosphonate treatment for osteoporosis is unknown. Bisphosphonate medications approved for the prevention and/or treatment of osteoporosis have clinical trial data supporting fracture reduction efficacy through at least 3 years of treatment and, in some cases, through 5 years. The FDA is continuing its evaluation of data supporting the safety and effectiveness of long term use (greater than 3 to 5 years) of bisphosphonates for the treatment and prevention of osteoporosis and will provide additional guidance at the completion of our review.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm229171.htm

FDA approves Botox to treat chronic migraine

The U.S. Food and Drug Administration today approved Botox injection (onabotulinumtoxinA) to prevent headaches in adult patients with chronic migraine.
Chronic migraine is defined as having a history of migraine and experiencing a headache on most days of the month.
Migraine headaches are described as an intense pulsing or throbbing pain in one area of the head. The headaches are often accompanied by nausea, vomiting, and sensitivity to light and sound. Migraine is three times more common in women than in men.
Migraine usually begins with intermittent headache attacks 14 days or fewer each month (episodic migraine), but some patients go on to develop the more disabling chronic migraine.
Botox is to be given approximately every 12 weeks as multiple injections around the head and neck to try to dull future headache symptoms.
Botox has not been shown to work for the treatment of migraine headaches that occur 14 days or less per month, or for other forms of headache. It is important that patients discuss with their physician whether Botox is appropriate for them.
The most common adverse reactions reported by patients being treated for chronic migraine were neck pain and headache.
OnabotulinumtoxinA, marketed as Botox and Botox Cosmetic, has a boxed warning that says the effects of the botulinum toxin may spread from the area of injection to other areas of the body, causing symptoms similar to those of botulism. Those symptoms include swallowing and breathing difficulties that can be life-threatening.
There has not been a confirmed serious case of spread of toxin effect when Botox has been used at the recommended dose to treat chronic migraine, severe underarm sweating, blepharospasm, or strabismus, or when Botox Cosmetic has been used at the recommended dose to improve frown lines.
Currently approved drugs for pain relief in migraine are-

§  Nonsteroidal anti-inflammatory drugs (NSAIDs). These medications, such as ibuprofen (Advil, Motrin, others) or aspirin, may help relieve mild migraines. Drugs marketed specifically for migraine, such as the combination of acetaminophen, aspirin and caffeine (Excedrin Migraine), also may ease moderate migraines but aren't effective alone for severe migraines.

§  Triptans. They are effective in relieving the pain, nausea and sensitivity to light and sound that are associated with migraines. Medications include sumatriptan (Imitrex), rizatriptan (Maxalt), naratriptan (Amerge), zolmitriptan (Zomig), almotriptan (Axert), frovatriptan (Frova) and eletriptan (Relpax).

§  Ergot. Ergotamine (Migergot, Cafergot), Dihydroergotamine (Migranal).

§  Anti-nausea medications. metoclopramide (oral) or prochlorperazine (oral or suppository).

§  Butalbital combinations. Medications that combine the sedative butalbital with aspirin or acetaminophen (Butapap, Phrenlin Forte) are sometimes used to treat migraine attacks. Some combinations also include caffeine or codeine (Esgic-Plus, Fioricet).

§  Opiates. Medications containing narcotics, particularly codeine

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm229782.htm

Sibutramine

US FDA is recommending against continued prescribing and use of Sibutramine because this drug may pose cardiovascular risks to patients.

FDA has requested that Abbott Laboratories—the manufacturer of Sibutramine— to voluntarily withdraw it from US market. Abbott has agreed to voluntarily stop marketing of Meridia in US.

Sibutramine was FDA-approved in 1997 for weight loss and maintenance of weight loss in patients with BMI ≥30 kg/m² or for patients with a BMI ≥27 kg/m² who have other cardiovascular risk factors.

FDA’s decision is based on the results of Sibutramine Cardiovascular Outcomes (SCOUT) trial, which demonstrated a 16% increase in risk of major adverse CV events (non-fatal heart attack, non-fatal stroke, resuscitation after cardiac arrest and CV death) in patients treated with Sibutramine.

FDA has concluded that the risk for an adverse CV event from Sibutramine in the population studied outweighed any benefit from the modest weight loss observed with the drug.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm228812.htm

COGENT -Clopidogrel and PPIs

Another trial studying the interarction of Clopidogrel and PPIs has been done. Two trials were earlier discussed on this blog in Septmeber.

Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) to assess the efficacy and safety of concomitant administration of clopidogrel and PPIs in patients with coronary artery disease who are receiving clopidogrel plus aspirin has been publihedd in the recent issue of New Eng J of Med.

COGENT was an international, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, phase 3 study of the efficacy and safety of CGT-2168, a fixed-dose combination of clopidogrel (75 mg) and omeprazole (20 mg), as compared with clopidogrel alone. All patients were to receive enteric-coated aspirin at a dose of 75 to 325 mg daily. Blinded study kits and open-label enteric-coated aspirin were supplied by Parexel to the investigators.

The initial planned sample size was 3200 patients, with an accrual period of 1 year and a maximum follow-up period of 2 years. The target sample size was increased to 4200 and then to 5000 to ensure an adequate number of gastrointestinal events. The study was designed to end once 143 gastrointestinal events had occurred; however, the study ended prematurely, when the sponsor suddenly and unexpectedly lost its financial backing; the sponsor is now defunct.

 The event rate, based on Kaplan–Meier analysis, for the primary gastrointestinal end point was reduced from 2.9% with placebo to 1.1% with omeprazole at 180 days after randomization (P<0.001 by the log-rank test)

The rate of the composite end point of overall (overt and occult) clinical gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (P=0.001), as was the rate of the composite end point of overt gastroduodenal bleeding or overt upper gastrointestinal bleeding of unknown origin: from 1.2% in the placebo group (occurring in 15 of 1885 patients) to 0.2% (occurring in 2 of 1876 patients) (P=0.001).

There was also a significant reduction in the number of patients with investigator-defined gastrointestinal events with omeprazole (39 patients) as compared with placebo (68 patients) (P=0.005).

The rate of symptoms of gastroesophageal reflux disease at 180 days was 0.2% in the omeprazole group and 1.2% in the placebo group (P=0.01). There was one case of gastrointestinal obstruction in each of the two groups, with no perforations in either group.

There were 109 adjudicated cardiovascular events (54 in the placebo group and 55 in the omeprazole group), with no significant difference in the rate of the primary cardiovascular end point between the two groups (P=0.98 by the log-rank test)

The event rate at 180 days after randomization was 5.7% in the placebo group and 4.9% in the omeprazole group .

The rate of adjudicated nongastrointestinal bleeding events did not differ significantly between the omeprazole group (0.5%) and the placebo group (0.1%).

There was a significant reduction in the risk of gastrointestinal clinical events, including overt upper gastrointestinal bleeding, in patients receiving dual antiplatelet therapy who were randomly assigned to also receive a PPI.

Furthermore, this prospective, double-blind, randomized trial did not show any significant increases in the risk of cardiovascular events with concomitant use of clopidogrel and omeprazole, a finding that was consistent even in high-risk subgroups and for individual end points.

Conflicting results in this regard are available.

There are limitations to this analysis. First, since the trial was terminated prematurely, its power is limited, owing to a smaller number of events than had been anticipated. Second, because the confidence interval around the hazard ratio for cardiovascular events is wide, the absence of interaction between clopidogrel and omeprazole cannot be viewed as a definitive finding. Given that 94% of the population was white, the expected prevalence of homozygosity for the loss-of-function cytochrome P-450 gene CYP2C19 was 2 to 3%, and in homozygous patients, PPIs may further reduce the level of the active metabolite of clopidogrel to a degree that does indeed blunt the effectiveness of clopidogrel.

The absence of an effect on nongastrointestinal bleeding also supports the absence of an interaction between clopidogrel and omeprazole, since if PPIs diminish the antiplatelet effect of clopidogrel, they should also decrease the rate of nongastrointestinal bleeding.

An additional limitation of the study is that the single-pill formulation we used differs from generic omeprazole with respect to its release kinetics.

The authors concluded that this study provides reassurance that there is no clinically significant cardiovascular interaction between PPIs and clopidogrel PPIs in patients with coronary artery disease who were receiving dual antiplatelet therapy. 

Further research will be necessary to determine the optimal approach to reducing the risk of gastrointestinal adverse events among patients receiving potent antithrombotic therapy, but prophylactic proton-pump inhibition appears to be promising.

http://www.nejm.org/doi/full/10.1056/NEJMoa1007964

Compression Only CPR by Lay Rescuers

A study titled “to investigate the survival of patients with out-of-hospital cardiac arrest using compression-only CPR (COCPR) compared with conventional CPR” has been published in the recent issue of JAMA.
In 2005, an evaluation of out-of-hospital cardiac arrest in Arizona revealed dismal outcomes, so a statewide program aimed at improving survival was established.
These efforts included changes in the approach to the care provided by both bystanders and emergency medical services (EMS) personnel and were based on the increasing evidence in favor of minimizing interruptions in chest compressions during CPR.
This led to alterations in the resuscitative care provided by EMS personnel, termed minimally interrupted cardiac resuscitation (MICR). Simultaneously, a statewide, multifaceted effort to encourage bystanders to use compression-only CPR (COCPR) because this approach is easier to teach, learn, remember, and perform than conventional CPR was established.
 It is a 5-year prospective observational cohort study of survival in patients at least 18 years old with out-of-hospital cardiac arrest between January 1, 2005, and December 31, 2009, in Arizona. The relationship between layperson bystander CPR and survival to hospital discharge was evaluated using multivariable logistic regression.
Main Outcome Measure was Survival to hospital discharge.
Results
A total of 4415 met all inclusion criteria for analysis, including 2900 who received no bystander CPR, 666 who received conventional CPR, and 849 who received COCPR.
Rates of survival to hospital discharge were 5.2% (95% confidence interval [CI], 4.4%-6.0%) for the no bystander CPR group, 7.8% (95% CI, 5.8%-9.8%) for conventional CPR, and 13.3% (95% CI, 11.0%-15.6%) for COCPR.
The adjusted odds ratio (AOR) for survival for conventional CPR vs no CPR was 0.99 (95% CI, 0.69-1.43), for COCPR vs no CPR, 1.59 (95% CI, 1.18-2.13), and for COCPR vs conventional CPR, 1.60 (95% CI, 1.08-2.35).
From 2005 to 2009, lay rescuer CPR increased from 28.2% (95% CI, 24.6%-31.8%) to 39.9% (95% CI, 36.8%-42.9%; P < .001); the proportion of CPR that was COCPR increased from 19.6% (95% CI, 13.6%-25.7%) to 75.9% (95% CI, 71.7%-80.1%; P < .001).
Overall survival increased from 3.7% (95% CI, 2.2%-5.2%) to 9.8% (95% CI, 8.0%-11.6%; P < .001).
Neurologic status for 4310 of 4515 cases of out-of-hospital cardiac arrest (217/315 survivors) of whom 4.2% (95% CI, 3.6%-4.8%) had a good neurologic status (CPC score of 1 or 2).
Proportion of individuals with good neurologic status differed significantly based on the type of CPR provided: no CPR, 86 of 2852, or 3.0% (95% CI, 2.4%-3.6%); conventional CPR, 34 of 651, or 5.2% (95% CI, 3.5%-6.9%); COCPR, 62 of 814, or 7.6% (95% CI, 5.8%-9.4%) (P < .001).

There are multiple reasons COCPR might have advantages over conventional CPR techniques.
1. These include the rapid deterioration of forward blood flow that occurs during even brief disruptions of chest compressions,
2. the long ramp-up time to return to adequate blood flow after resuming chest compressions,
3. the reduction of cardiac venous return with the use of positive pressure ventilation, the complexity of conventional CPR,
4. the significant time required to perform the breaths, the critical importance of cerebral and coronary circulation during arrest, the reduced time required for emergency medical dispatchers to instruct a bystander over the telephone how to perform COCPR, and the reluctance to perform mouth-to-mouth ventilation on strangers.
Conclusion Among patients with out-of-hospital cardiac arrest, layperson compression-only CPR was associated with increased survival compared with conventional CPR and no bystander CPR in this setting with public endorsement of chest compression–only CPR.

http://jama.ama-assn.org/cgi/content/full/304/13/1447

Both Liraglutide and Sitagliptin play significant roles in control of diabetes

In the European Association for the Study of Diabetes (EASD) 2010 Meeting, the results of LEAD (Liraglutide Effect and Action in Diabetes) series of trials were discussed.

Liraglutide, a glucagonlike peptide-1 (GLP-1) agonist and another incretin, the oral agent sitagliptin —a dipeptidyl-peptidase-4 (DPP-4) inhibitor were compared.

The results show that liraglutide is generally well tolerated and reduces glycated hemoglobin levels (HbA_1c) and body weight to a greater extent than sitagliptin when added to metformin treatment.
 The authors specified that the patients on the higher dose of liraglutide reported greater overall patient satisfaction.
Discussant of the session, Dr Jonathan Bodansky (St James University Hospital, Leeds, UK), said both agents were useful additions to the diabetologists' armamentarium, with the decision about therapy coming down to physician and patient choice.
Bodansky agreed the data so far do indicate that liraglutide results in more weight loss than sitagliptin, but "they both go in the right direction," and it is "gratifying" to see weight loss with sitagliptin, he said, which has previously been considered "weight neutral." "This is the first oral drug for glycemia that also has weight loss," he commented.
It was also stressed that the fact that liraglutide induces greater weight loss than sitagliptin has to be balanced against the fact that it is an injectable agent with a high rate of nausea as a side effect.
 It was highlighted that as both liraglutide and sitagliptin showed a fall in glycemia and body weight, so now the patient has a treatment choice. The ideal treatment for type 2 diabetes should improve glycemia and induce progressive weight loss.
This compares with what was on offer from older drug classes, such as sulfonylureas and glitazones, which induce weight gain. Sitagliptin and liraglutide are effective when added to metformin and may become, in time, first-line treatment in the future."
In fact, Bodansky says these newer agents may also allow a cautious reduction in dose of insulin or even withdrawal in some insulin-dependent diabetics. In patients who are overweight with poor diabetes control, a very cautious reduction or withdrawal of insulin while transferring onto newer therapy has been successful in some of our patients.
A 26- week study involving both the drugs was publishedd early this year.(2)
(1) http://www.theheart.org/article/1126861.do
(2) Pratley RE, Nauck M, Bailey T, et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycemic control with metformin: a 26-week, randomized, parallel-group, open-label trial. Lancet 2010; 375:1447-1456.

FDA orders halt to marketing of unapproved single-ingredient oral colchicine

On 30^th September, the U.S. Food and Drug Administration took action against companies that manufacture, distribute, and/or market unapproved single-ingredient oral colchicine.
Colchicine is commonly used for the daily prevention of gout, to treat acute gout flare-ups, and for the treatment of Familial Mediterranean Fever (FMF).
Many single ingredient oral colchicine products have been used by the medical community for decades. These and a variety of other medications have not received the mandatory modern-day FDA-approval required of all prescription drugs.,
This action is part of the FDA's broader initiative against marketed unapproved drugs, announced in a June 2006 Compliance Policy Guide describing the agency’s risk-based enforcement approach for marketed unapproved drug products.
Unapproved versions of colchicine are not generic drugs. Generic drugs are approved by the FDA to assure that the approved generic drug products meet the same standards as the innovator drug. All single-ingredient oral colchicine products, other than Colcrys, that are currently being marketed are unapproved drugs and have never been evaluated by the agency.
The FDA previously took action against unapproved colchicine for injection products on Feb. 6, 2008. This ongoing initiative is designed to bring all unapproved medications, including single-ingredient oral colchicine, up to modern-day safety, efficacy, labeling, and quality standards by ensuring that they comply with FDA approval requirements.
Colcrys is the only FDA-approved single-ingredient oral colchicine product available on the U.S. market.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm227796.htm

www.colcrys.com