Thursday, September 30, 2010

Use of alteplase upto 4.5 h of onset of AIS symptoms: an update

Stroke is the leading cause of disability in the elderly, and i.v. alteplase (recombinant tissue plasminogen activator) is the only Food and Drug Administration (FDA)-approved thrombolytic agent for the treatment of AIS. FDA still recommends the use of Alteplase in patients of AIS within 3 h of the onset of symptoms. But, the professional stroke organizations extended the recommended time between symptom onset and administration of alteplase from 3 to 4.5 hours on the basis of reports published in September 2008 from two large international studies which had demonstrated that therapy with i.v. alteplase remains safe and effective when given 3–4.5 hours after AIS onset.
One of the trials (1) the compared efficacy and safety of alteplase (0.9 mg of alteplase per kilogram), administered intravenously (with an upper limit of 90 mg) administered between 3 and 4.5 hours after the onset of a stroke with placebo.
In the second study (2) the comparison was between the patients treated between 3 h and 4•5 h versus those treated within 3 h. Alteplase remained safe when given at 3—4•5 h after ischaemic stroke, offering an opportunity for patients who cannot be treated within the standard 3-h timeframe.
Now, the September issue of Lancet Neurology3 has reported an updated analysis of the implementation of the wider time window, its effect on the admission-to-treatment time, and safety and functional outcome in patients recorded in SITS-ISTR.
The patients treated according to the criteria of the European Summary of Product Characteristics, except for the time window, were included. Patients were grouped according to whether they were registered into SITS-ISTR before or after October, 2008. The admission-to-treatment time and rates of symptomatic intracerebral haemorrhage, mortality, and functional independence at 3 months were measured.
Results:
The proportion of patients treated within 3-4.5 h by the end of 2009 was three times higher than in the first three quarters of 2008 (282 of 1293 [22%] vs 67 of 1023 [7%]).
The median admission-to-treatment time was 65 min both for patients registered before and after October, 2008 (p=0.94). 352 (2%) of 21 204 patients treated within 3 h and 52 (2%) of 2317 treated within 3-4.5 h of stroke had symptomatic intracerebral haemorrhage at 3 months (adjusted odds ratio [OR] 1.44, 95% CI 1.05-1.97; p=0.02).
2287 (12%) of 18 583 patients who were treated within 3 h and 218 (12%) of 1817 who were treated within 3-4.5 h had died by the 3-month follow-up (adjusted OR 1.26, 95% CI 1.07-1.49; p=0.005); 10 531 (57%) of 18 317 patients treated within 3 h of stroke and 1075 (60%) of 1784 who were treated within 3-4.5 h were functionally independent at 3 months.
The authors concluded that since October, 2008, thrombolysis within 3-4.5 h after stroke has been implemented rapidly, with a simultaneous increase in the number of patients treated within 3 h; admission-to-treatment time has not increased.
Safety and functional outcomes are less favourable after 3 h, but the wider time window now offers an opportunity for treatment of those patients who cannot be treated earlier.
Thrombolysis should be initiated within 4.5 h after onset of ischaemic stroke, although every effort should be made to treat patients as early as possible after symptom onset.
The evidence supports a wider treatment window and professional organizations recommend it. Nevertheless, time is brain, and eligible patients should be treated as soon as possible.Earlier is better.
1.http://www.nejm.org/doi/pdf/10.1056/NEJMoa0804656
2.http://www.thelancet.com/journals/lancet/article/PIIS0140673608613392/abstract
3. Ahmed N et al. Implementation and outcome of thrombolysis with alteplase 3–4.5 h after an acute stroke: An updated analysis from SITS-ISTR. Lancet Neurol 2010 Sep; 9:866.

Wednesday, September 22, 2010

Clopidogrel and PPIs

Two studies involving the use of Clopidogrel and PPIs have been published in the September issues of two medical journals. One of them reports that PPI therapy did not modify the effect of clopidogrel on cardiovascular outcomes and that PPI use was associated with increased cardiovascular risk independent of concomitant use of clopidogrel.
And the other states that a metabolic drug-drug interaction exists between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.

A Study has been published in the September issue of Annals of Internal Medicine which involved all patients discharged after first-time myocardial infarction from 2000 to 2006 in all the hospitals in Denmark. A total of 71 987 patients were admitted with myocardial infarction from 2000 to 2006. Of these,  1889 patients with previous myocardial infarction were excluded, 13 324 patients who died during hospitalization or within 30 days of discharge, and 368 patients with partially missing data. Of the 56 406 patients included in the study, 24 704 (43.8%) claimed a prescription for clopidogrel within 30 days of discharge. Of these, 6753 patients (27.3%) claimed at least 1 prescription for PPIs within 1 year of discharge. The use of PPIs was equal in the 2 cohorts and independent of clopidogrel use
The study is nationwide on unselected population that represents the average patient who has had a myocardial infarction.
 It has been demonstrated that PPI therapy did not modify the effect of clopidogrel on cardiovascular outcomes and that PPI use was associated with increased cardiovascular risk independent of concomitant use of clopidogrel.
A reduction in risk for gastrointestinal bleeding related to PPI therapy for patients who received clopidogrel, although it did not reach statistical significance was also demonstrated.
The data set provided no evidence of differences in risk between the subtypes of PPIs, with or without clopidogrel. Sensitivity analyses also provided no evidence of differences in risk related to heart failure, diabetes, age, hospitals, or PPI dosages. However, a statistically significant interaction between PCI and PPIs in the group that received clopidogrel was found.
Limitations: No self-reported patient data regarding adherence.
The authors suspect that the increased cardiovascular risk in all patients who received a PPI can be explained by differences in baseline comorbid conditions that were unmeasured or measured imperfectly.
Strengths: large size of our cohort based on a nationwide, unselected population that represents average patients in a contemporary clinical setting who have had a myocardial infarction.
The patients who received clopidogrel and PPIs at discharge after a first-time myocardial infarction had similar risks for cardiovascular death, myocardial infarction, or stroke as did those of patients who received PPIs alone.
 In conclusion, PPIs seem to be associated with an increased risk for adverse cardiovascular outcomes regardless of clopidogrel use, but concomitant PPI and clopidogrel use was not associated with any additional increase in risk over that observed for patients who received a PPI alone.
The authors believe that the increased cardiovascular risk associated with PPI use independent of clopidogrel is caused by unmeasured confounders. These results seem to refute concerns about increased risk for ischemic events during concomitant PPI and clopidogrel therapy.

Another study has been published in the Journal of Clinical Pharmacology and Therapeutics titled Differential Effects of Omeprazole and Pantoprazole on the Pharmacodynamics and Pharmacokinetics of Clopidogrel in Healthy Subjects: Randomized, Placebo-Controlled, Crossover Comparison Studies. In this four randomized, placebo-controlled, crossover studies were conducted among 282 healthy subjects.
The groups were:
Clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and omeprazole (80 mg) administered simultaneously (study 1);
Clopidogrel (300-mg loading dose/75-mg/day maintenance dose) with omeprazole (80 mg) given 12 hours later.
Increasing the clopidogrel dose to 600-mg loading/150-mg/day maintenance and omeprazole (80 mg) administered simultaneously.
Clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and pantoprazole (80 mg) administered simultaneously

Results:
Relative to levels after administration of clopidogrel alone in studies 1,2,3, and 4, co administration of PPI decreased the AUC(0-24) of the clopidogrel active metabolite H4 by 40, 47, 41, and 14% (P ≤ 0.002), respectively;
· increased maximal platelet aggregation (MPA) induced by 5 µmol/l adenosine diphosphate (ADP) by 8.0, 5.6, 8.1, and 4.3% (P ≤ 0.014), respectively;
· and increased the vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index (VASP-PRI) by 20.7, 27.1, 19.0 (P < 0.0001), and 3.9% (P = 0.3319), respectively.
The results suggest that a metabolic drug-drug interaction exists between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.

Tuesday, September 21, 2010

Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6)

In the August issue of Lancet, The LEAD-6 trial has been published which had compared Liraglutide and exenatide in patients with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both.

 It was found that Liraglutide reduced mean HbA1c significantly more than did exenatide (−1·12% [SE 0·08] vs −0·79% [0·08]; estimated treatment difference −0·33; 95% CI −0·47 to −0·18; p<0·0001) and more patients achieved a HbA1c value of less than 7% (54% vs 43%, respectively; odds ratio 2·02; 95% CI 1·31 to 3·11; p=0·0015).
Liraglutide reduced mean fasting plasma glucose more than did exenatide (−1·61 mmol/L [SE 0·20] vs −0·60 mmol/L [0·20]; estimated treatment difference −1·01 mmol/L; 95% CI −1·37 to −0·65; p<0·0001) but postprandial glucose control was less effective after breakfast and dinner.
Both drugs promoted similar weight losses (liraglutide −3·24 kg vs exenatide −2·87 kg).
Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0·448, p<0·0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1·93 vs 2·60 events per patient per year; rate ratio 0·55; 95% CI 0·34 to 0·88; p=0·0131; 25·5% vs 33·6% had minor hypoglycaemia).
The authors concluded that Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated.
The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60659-0/fulltext?_eventId=login&elsca1=PPV-TL-AUGUST&elsca2=email&elsca3=segment#

Dabigatran gets approval from FDA

One of cardiology's fondest wishes moved closer to fulfillment as an FDA advisory panel unanimously recommended approval of a potential replacement for warfarin in one of the most common heart disorders. Barring any unforeseen damning revelations about the drug, the FDA's approval of the oral thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim) for stroke prevention in atrial fibrillation (AF) is all but certain.

The panel, with its nine voting members, made the decision based on what's generally seen as the well-designed, solidly executed 18 000-patient Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial, which showed dabigatran was noninferior to warfarin at a lower dosage and superior at a higher one for preventing thromboembolic stroke in paroxysmal or permanent AF.

Debate among the advisory panel throughout the day was tame; there were few criticisms of the RE-LY trial's design, little disappointment in the results, and clear enthusiasm for replacing warfarin in such a widespread indication.

Warfarin is distinguished in being one of the oldest, one of the most widely used, one of the most effective, and one of the most disliked drugs in cardiology: it dramatically cuts ischemic stroke risk in AF but generally requires tight anticoagulation monitoring to get the dosage right, which can be arduous for patients and the healthcare system. Patients must also banish a lot of healthy, vitamin-K-containing foods from their diet.

The kicker with dabigatran, even when "noninferior" to warfarin, is that it doesn't require anticoagulation monitoring—or major diet changes, for that matter. And, as the trial suggested and some panelists agreed, at the higher dose it seems more stroke-preventive than warfarin.

RE-LY compared the two dabigatran dosage levels against a conventional warfarin regimen for the stroke-prevention indication. Dabigatran was noninferior to warfarin at the lower dosage and superior at the higher one, the latter achieving a 34% decline in risk (p<0.001) over a median of two years.

Thursday, September 16, 2010

FDA raises safety issues for Lorcaserin approval

Modest Weight Loss, Safety Issues May Put Lorcaserin Approval in Peril
Modest weight loss and safety questions, including that of a possible link to valvular heart disease, will be at the forefront of today’s advisory committee discussion on whether to recommend approval of Arena’s lorcaserin.
Although the weight loss observed in the lorcaserin-treated patients generally improved their blood pressure, glucose and insulin levels, as well as levels of high sensitivity C-reactive protein, FDA reviewers expressed concerns about the drug’s safety and overall effect on weight loss, according to briefing documents.
Lorcaserin is a new molecular entity that targets activation of the serotonin 5HT2C receptor and is intended to promote weight loss in an obese population. Agonism at the intended target, 5HT2C, is reasonably demonstrated to underlie the anorexigenic effect of lorcaserin. An important aspect of the preclinical development program for lorcaserin was the assessment of receptor selectivity for 5HT2C relative to other serotonin receptor subtypes, particularly other members of the 5HT2 receptor family 5HT2A and 2B. Relative to drug action, the 5HT2A and 2B receptors are implicated in contributing to the hallucinogenic and addictive responses to drugs of abuse (5HT2A), and to drug-induced valvulopathy including that associated with use of dexfenfluramine in humans (5HT2B).

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM225631.pdf

Wednesday, September 15, 2010

Persistence with Statins and Onset of Rheumatoid Arthritis

In the september issue of PloS Medicine, a study showing the association between the use of statins and incidence of Rheumatoid Arthritis has been published.
A retrospective cohort study was done to explore whether persistent use of statins is associated with onset of Rheumatoid Arthritis (RA).
Rheumatoid Arthritis is a chronic systemic inflammatory condition characterized by leukocyte recruitment into synovial tissue. There is growing evidence that statins have anti-inflammatory and immunumodulatory properties, demonstrated by reducing the level of C-reactive protein (CRP) that may play an important role in RA, independent of their cholesterol lowering effects. Some small studies have demonstrated a modest beneficial effect of statins in RA
In contrast, a large US study showed no beneficial effect for statins among 31,451 RA patients as measured by initiation and cessation of oral steroids.
A large study (more than 200,000 patients) with a long follow-up period (average of 10 years) was conducted to discover whether there was any kind of association between persistent use of statins and the onset of rheumatoid arthritis. This was conducted among the members of Maccabi Healthcare Services  in Israel. The cohort covered the period 1998–2007 and included members who were continuously enrolled in the HMO from 1995 to 1998.
New users of statins were identified among all MHS enrollees aged 18 y or older, who from January 1, 1998 to July 1, 2007 had at least one dispensed prescription of 3-hydroxy-3-methylgluraryl coenzyme A (HMG-CoA) reductase inhibitors (e.g., lovastatin, pravastatin, simvastatin, atorvastatin).
Then the incidence of newly diagnosed rheumatoid arthritis was analyzed, recording the date of first diagnostic codes (International Classification of Diseases, 9th revision [ICD-9]) associated with rheumatoid arthritis during the study follow-up period.
To assess any potential effects of “healthy adherer” bias (good adherence to medication in patients with a chronic illness may be more likely to lead to better health and improved survival), the researchers also examined any possible association between persistent statin use and the development of osteoarthritis (OA), a common degenerative joint disease that is unlikely to be affected by statin use
The mean proportion of days covered (PDC) were calculated.
During the study follow-up period, there were 2,578 incident cases of rheumatoid arthritis and 17,878 incident cases of osteoarthritis. The crude incidence density rate of rheumatoid arthritis among patients who did not persistently take statins was 51% higher than that of patients who used statins for at least 80% of the follow-up period.
Furthermore, patients who persistently used statins had a risk ratio of 0.58 for rheumatoid arthritis compared with patients who did not persistently use statins. In the osteoarthritis cohort analysis, high persistence with statin use was associated with a modest decrement in risk ratio (0.85) compared to patients who did not persist with statins.
The authors have themselves compared the strengths and limitations of the study.
Strengths of this study include prospective data collection, the use of administrative databases to avoid the problem of differential recall bias, the systematic and comprehensive collection of personal socio-demographic data, medical history, and utilization of health services prior to the index date, which reduces the possibility for bias due to study outcomes. The present retrospective cohort is one of the largest undertaken to date on the relationship between statin therapy and RA, with respect to the length of follow-up and the size of the study population.
The authors have highlighted the following limitations. The analysis was retrospective in nature and allocation of statin therapy was not randomized. Despite adjustment for baseline differences and an abundance of poor prognostic factors, a higher proportion of days covered with statins could still be a surrogate for other unmeasured variables that reflect a higher quality of care and more aggressive treatment strategies. In the analysis the different temporal variations in patients' use of statins over the study period were not addressed. However, a majority of RA patients (79%) purchased statins at least 3 mo prior to diagnosis. Also, the similarity in study results when limiting the analysis to patients with at least 5 y of follow-up reduces the possible effect of this potential limitation.
The most important methodological limitation in estimating effectiveness in observational studies is the potential for “healthy adherer” bias.  In order to evaluate this potentially important bias in the study, a  analysis with OA as an outcome was conducted. Results indicated that persistent use of statins was associated with a 15% lower OA risk, a relatively small difference compared to RA risk, but one that needs to be noted when considering the results of the study overall. In addition, the reduced risk for OA in patients with high PDC with statins was limited to patients with short follow-up periods and was not found in patients with a follow-up of 5 y or more. This finding supports the notion that most of the RA risk reduction is due to a real biological effect.
In conclusion, this study showed that persistence with statin treatment was associated with an ongoing decrement in the risk for contracting RA. The observed associations were greater than those that would be expected from methodological biases alone. Larger, systematic, controlled, prospective studies with high efficacy statins, particularly in younger adults who are at increased risk for RA, are needed to confirm the findings, and to elucidate the possible biological relationship between adherence to statin therapy and RA onset.
http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000336

Tuesday, September 14, 2010

Results From the Platelet Inhibition and Patient Outcomes (PLATO) Trial

The Platelet Inhibition and Patient Outcomes (PLATO) trial demonstrated that treatment with ticagrelor instead of clopidogrel in a broad population of patients with ACS substantially reduced the risk of death from vascular causes, myocardial infarction, or stroke, and reduced cardiovascular and total mortality at 12 months without increasing the risk of major bleeding.(1) Ticagrelor, a reversibly binding oral P2Y12 receptor antagonist, provides faster, greater, and more consistent (interpatient) P2Y12 inhibition than clopidogrel.
In the recent issue of Circulation (2), the results of PLATO trial in relation to patients with renal disease were presented. Reduced renal function is associated with a poorer prognosis and increased bleeding risk in patients with acute coronary syndromes and may therefore alter the risk-benefit ratio with antiplatelet therapies.
Dose administration in the trial-
Ticagrelor - loading dose of 180 mg followed by 90 mg twice daily.
Clopidogrel- Patients randomized to clopidogrel who had not received clopidogrel for at least 5 days before randomization received a 300-mg loading dose of clopidogrel study drug followed by 75 mg daily. Others continued a maintenance dose of 75 mg daily as clopidogrel study drug.
All patients received acetylsalicylic acid unless intolerant.
Duration- Median duration of study treatment was 9.1 months.
Analyses of primary and secondary efficacy and safety events were performed in patient groups based on the cut point of CrCl of 60 mL/min, the cut point defining Chronic Kideny Disease (CKD) classes 3 and 4.
The numeric absolute (and relative) risk reductions of the primary composite end point and total mortality by ticagrelor versus clopidogrel were 4.7% (23%) and 4.0% (28%) in patients with CKD and 1% (10%) and 0.5% (11%) in patients with normal renal function.
The number needed to treat to prevent an additional event in patients with CKD was 21 (95% confidence interval [CI], 13 to 56) for the primary composite event and 25 (95% CI, 16 to 63) for total mortality.
In fact, ticagrelor reduced the primary composite end point and total mortality versus clopidogrel consistently, regardless of CrCl cutoff value for CKD, with progressively decreasing point estimates of the HR with decreasing cutoffs values of CrCl from 100 to 30 mL/min.
A smaller group, defined as those with CKD, was identified with the Modification of Diet in Renal Disease (MDRD) equation (n=2562). The numeric absolute (and relative) risk reduction of the primary composite end point by ticagrelor versus clopidogrel was 6.0% (29%) in patients with CKD and 1.1% (10%) in patients with normal renal function (P for interaction=0.03). For all-cause mortality, the corresponding numbers were 5.3% (36%) and 0.5% (9%) (P for interaction=0.02). After multivariable adjustment, the interaction term for the primary end point did not remain significant.
Major bleeding increased with decreasing calculated CrCl at entry similarly in the ticagrelor and clopidogrel groups. The incidence of major bleeding did not differ significantly between the ticagrelor and clopidogrel groups in patients with normal renal function or in patients with CKD. The incidence of PLATO-defined major and Thrombolysis in Myocardial Infarction (TIMI) major bleedings not related to CABG increased with lower levels of calculated CrCl at entry with numerically higher rates with ticagrelor versus clopidogrel in patients with CKD.
The incidence of fatal bleeding was numerically lower and the incidence of intracranial bleeding numerically higher in the ticagrelor group versus the clopidogrel group with no significant interactions with renal function. The adjusted HR for major bleeding in patients with CKD was 1.11 (95% CI, 0.91 to 1.37); in patients with normal renal function, the adjusted HR was 1.08 (95% CI, 0.95 to 1.22; P for interaction=0.78).
Dyspnea occurred significantly more often with ticagrelor compared with clopidogrel in patients with CKD (5% absolute increase) and in patients with normal renal function (6.2% absolute increase). The occurrence of ventricular pauses 3 seconds during the first week or 30 days later did not differ significantly between the randomized groups. There was a relative increase in serum creatinine from baseline to 12 months that was higher in patients with normal renal function than in those with CKD and significantly higher in the ticagrelor compared with the clopidogrel group, but there was no difference between the treatment groups at 1 month after the end of treatment . Dyspnea and ventricular pauses, potential adenosine-mediated side effects of ticagrelor, occurred with low frequency and did not increase with reduced renal function. Reduced mortality with ticagrelor occurred despite the fact that patients with CKD who initiated treatment later after randomization discontinued study treatment prematurely more often, leading to a shorter duration of therapy.
The authors have highlighted that the significant benefit of ticagrelor over clopidogrel in patients with CKD contrasts with lack of a benefit of clopidogrel versus placebo. In the Clopidogrel for Reduction of Events During Observation (CREDO) trial, clopidogrel versus placebo reduced the composite of death, myocardial infarction, and stroke in patients with normal renal function, but there was in fact a trend in the opposite direction with an absolute increased event rate in patients with mild or moderate renal dysfunction. In the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, there was also a modest absolute and relative reduction in the primary ischemic end point with clopidogrel versus placebo among patients with renal dysfunction compared with those with normal renal function, although without any significant interaction.The authors have pointed out that the randomization was not stratified for renal function; therefore, some imbalance between the randomized groups may exist among patients with renal dysfunction.
The authors concluded that the present results provide clinical evidence that ticagrelor is a more effective antiplatelet agent than clopidogrel in patients with ACS, regardless of renal function, and that the benefits are larger at poor renal function and without any need for dose reduction to prevent major bleeding.
Ticagrelor provides an important opportunity to substantially improve outcome in patients with ACS and impaired renal function.
(1) http://www.nejm.org/doi/full/10.1056/NEJMoa0904327#ref11
(2) http://circ.ahajournals.org/cgi/content/full/122/11/1056#R1-933796

Saturday, September 11, 2010

Midodrine- withdrawal and approval

The US FDA did a U-turn on its 2-week old decision of withdrawing Midodrine from the market. On August 16, 2010 the U.S. FDA proposed to withdraw approval of the drug Midodrine hydrochloride, used to treat the low blood pressure condition orthostatic hypotension, because required post-approval studies that verify the clinical benefit of the drug have not been done.
It was also mentioned that the patients who currently take this medication should not stop taking it and should consult their health care professional about other treatment options.
The drug, marketed as ProAmatine by Shire Development Inc. and as a generic by others, was approved in 1996 under the FDA’s accelerated approval regulations for drugs that treat serious or life-threatening diseases. That approval required that the manufacturer verify clinical benefit to patients through post-approval studies.
According to the information, till date, neither the original manufacturer nor any generic manufacturer had demonstrated the drug’s clinical benefit, for example, by showing that use of the drug improved a patient’s ability to perform life activities. Orthostatic hypotension is a condition in which patients are unable to maintain blood pressure in the upright position and, therefore, become dizzy or faint when they stand up.
In the same information it was clarified that drug companies that obtain approval under this program are 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 companies do not pursue the required confirmatory trials with due diligence, the FDA can withdraw approval of the drug using expedited procedures.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm222580.htm
The second announcement came after two weeks that the US FDA will make sure that midodrine continues to be available to the 100 000 patients who use the drug while it tries to resolve the issue that originally prompted the planned withdrawal: further post marketing studies . After the withdrawal, extensive lobbying by the physicians and the patients led to a re-think by FDA and earlier announcement was withdrawn.
Although Shire Pharmaceuticals (which holds the new drug application for midodrine under the brand name ProAmatine), did conduct some post marketing trials, the FDA said these were inconclusive and required that additional studies be conducted for the product to maintain its marketing authorization.
http://www.theheart.org/article/1119697.do

Vernakalant cleared in EU for conversion of AF to Sinus Rhythm

Merck and Cardiome Pharma Corp. announced on September 1, 2010 that the intravenous (IV) formulation of BRINAVESS™ (vernakalant) has been granted marketing approval in the European Union (EU), Iceland and Norway.
The approved indication is: “Rapid conversion of recent onset atrial fibrillation to sinus rhythm in adults:
• for non-surgery patients: atrial fibrillation ≤ 7 days duration;
• for post-cardiac surgery patients: atrial fibrillation ≤ 3 days duration.”
Vernakalant hydrochloride is a novel anti-arrhythmic drug that acts preferentially in the atria to prolong atrial refractoriness and to rate-dependently slow the impulse conduction. Vernakalant is the first product in a new class of pharmacologic agents for cardioversion of AF to launch in the EU.
Information on the clinical program for BRINAVESS
The approval of BRINAVESS is based on the results of three randomized, double-blind, placebo controlled studies (ACT I, ACT II, and ACT III) and an active comparator trial (AVRO).
In ACT I and III, the efficacy of BRINAVESS at converting patients from AF to sinus rhythm for a minimum duration of one minute with 90 minutes of initiating therapy was evaluated in 390 haemodynamically stable adult patients with short duration AF (3 hours to 7 days) versus placebo. In ACT I, vernakalant cardioverted 51.0 percent of patients versus 4.0 percent of patients taking placebo (n=74 and 3, respectively; p<0.0001). In ACT III, vernakalant cardioverted 51.2 percent of patients versus 3.6 percent of patients taking placebo (n=44 and 3, respectively; p<0.0001). Conversion of AF to sinus rhythm occurred rapidly; in responders, the median time to conversion was 10 minutes from start of first infusion, based on pooled results from the ACT I and ACT III studies. The efficacy of BRINAVESS was also studied in ACT II in 150 patients with sustained AF (3 hours to 72 hours duration) that occurred between 24 hours and 7 days post coronary artery bypass graft and/or valvular surgery. Treatment with BRINAVESS effectively converted 47.0 percent of patients from AF to sinus rhythm versus 14.0 percent placebo (p=0.0001).
In the AVRO, study BRINAVESS was significantly more effective than amiodarone IV in providing rapid conversion to sinus rhythm within the first 90 minutes of initiating therapy In the AVRO (Active-Controlled, Multi-Center Study of Vernakalant Injection versus Amiodarone in Subjects with Recent Onset Atrial Fibrillation) study, BRINAVESS was demonstrated to be significantly faster than amiodarone IV in converting AF patients to sinus rhythm. In the trial, BRINAVESS was studied in 116 patients with AF (3 hours to 48 hours) versus 116 patients on amiodarone. The amiodarone infusion was given over two hours (i.e., one hour loading dose of 5 mg/kg, followed by one hour maintenance infusion of 50 mg) with the objective to compare rapid conversion to sinus rhythm. The primary endpoint was the proportion of patients that achieved sinus rhythm for a minimum duration of one minute within 90 minutes of the first exposure of the study drug. In this study, treatment with BRINAVESS converted 51.7 percent of patients to sinus rhythm at 90 minutes versus 5.2 percent with amiodarone.
Contraindications:
1. Hypersensitivity to the active substance or to any of the excipients.
2. Severe aortic stenosis, SBP <100 mm Hg, and CHF class NYHA III and NYHA IV.
3. Prolonged QT at baseline (uncorrected >440 msec), severe bradycardia, sinus node dysfunction, or second-degree or third-degree heart block in the absence of a pacemaker.
4. Patients who use intravenous rhythm control antiarrhythmics (class I and class III) within four hours prior to administration of BRINAVESS and patients with acute coronary syndrome (including myocardial infarction) within the last 30 days.
ADVERSE EFFECTS: Hypotension (vernakalant 7.6%, placebo 5.1%), typically occurs early, either during the infusion or early after the end of the infusion. Patients with a history of CHF are at an increased risk of heaving hypotension and ventricular arrhythmias. A higher incidence of ventricular arrhythmia events has been reported in patients with valvular heart disease. Dysgeusia (taste disturbance) (20.1%), sneezing (14.6%), and paraesthesia (9.7%) are the other common adverse effects. Patients should be observed with assessment of vital signs and continuous cardiac rhythm monitoring during and after administration of BRINAVESS, until clinical and ECG parameters have stabilized.
It is preferable to avoid the use of BRINAVESS during pregnancy. It is unknown whether vernakalant/metabolites are excreted in human milk. Caution should be exercised when used in breast-feeding women.

http://www.merck.com/newsroom/news-release-archive/research-and-development/2010_0901.html?WT.svl=content&WT.pi=content+Views


http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001215/smops/Positive/human_smop_000109.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d127&jsenabled=true

Friday, September 10, 2010

Comparative evaluation of the hygienic efficacy of an ultra-rapid hand dryer vs conventional warm air hand dryers

A study published in the Journal of Applied Microbiology (1) was done to compare an ultra-rapid hand dryer against warm air dryers, with regard to: (A) bacterial transfer after drying and (B) the impact on bacterial numbers of rubbing hands during dryer use.
With most hand washing regimens, the numbers of bacteria on the skin surface are lowered, but not eliminated. If hands are not then dried properly, transfer of commensal strains, or transients not eliminated by the wash itself, is more likely to occur. The degree of wetness of hands appears to greatly influence bacterial transfer and dissemination to surfaces and items touched. This probably occurs not only because of the physical aspects of moisture droplets transferring between one surface and another but also because the bacteria may be maintained in a physiological state that makes them better able to survive in the new environment. It is mentioned that by drying the hands, the numbers of bacteria transferred to samples of skin, food or utilities were reduced by an order of 99%.
The four main methods of hand drying are letting the skin dry by evaporation, use of paper towels, cloth towels, or, in more recent times, use of warm air dryers
In this study, fourteen volunteers (seven men and seven women), above the age of 18 years were recruited to take part in the study. The volunteers handled raw chicken, and after a standard handwash and use of one of the different dryers, the transfer of residual bacteria from the fingertips to foil was quantified. Two models of air-dryer and a new Airblade dryer (This is an ultra-rapid dryer that uses two high-pressure ‘knives’ of HEPA-filtered air (at ambient temperature) to strip water from hands that are held apart as they are drawn upwards through the airstream) was used.
It was seen that when a standard drying time of 10 s was applied, the Airblade™ unit performed considerably better (i.e. resulted in less residual bacterial transfer) than all the other methods of drying, with all the results being strongly statistically significant (i.e. P < 0•050). When the manufacturer’s preset device activation times were used with the Turbodry™ and A5 machines, their performance greatly improved (P < 0•050), but was still less than that observed with the Airblade™ unit after just 10 s. For the drying time of 10 s, both the Turbodry™ and A5 machines were associated with higher mean levels of bacterial transfer than when using no dryer at all, but the results were not statistically significant (P > 0•050).
The other parameter studied was the effect of rubbing of hands during drying. In many instances, the bacterial numbers transferred from hands actually increased because of the rubbing action. The results obtained from the rubbing experiments were, in most cases, statistically significantly different from those obtained when holding hands still under the same devices (P < 0•050). When keeping the hands still, there was no statistical difference between any of the dryers, for any anatomical site, and the bacterial reduction in the middle of the fingers was comparable to that obtained with paper towel drying. Rubbing the hands with paper towels proved to be very effective at removing bacteria from the hands, with results that were in most cases statistically significant (P < 0•050). In particular, rubbing with paper towels appeared to be the best means of reducing bacterial loading on the fingertips.
When hands were held stationary (palm up) in the air stream under these units, the reduction in counts of bacteria subsequently transferred from the skin was much greater than when the hands were rubbed together. Indeed, for some sites, the bacterial count increased markedly when hands were rubbed.
The study conclusively demonstrates that effective hand drying is important in preventing the postwash translocation of bacteria from the surface of hands to the next surfaces touched. The results provide an evidence base for the development and enhancement of hygienic hand drying practices. The authors have also concluded that the ultra-rapid Airblade™ hand dryer is superior to the warm air dryers for reducing bacterial transfer. The lack of paper waste, coupled with its short, 10 s drying time and use of HEPA-filtered air should encourage greater compliance with hand drying and thus help reduce the spread of infectious agents by the hand-borne route.
(1)A.M. Snelling, T. Saville, D. Stevens, C.B. Beggs. Comparative evaluation of the hygienic efficacy of an ultra-rapid hand dryer vs conventional warm air hand dryers. Journal of Applied Microbiology. Published onlin 7,September,2010.
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2672.2010.04838.x/full

Vaccines for preventing influenza in healthy adults

A Cochrane review has been published (1) which was conducted with the objective to identify, retrieve and assess all studies evaluating the effects of vaccines against influenza in healthy adults.
The authors have stated the very high cost of yearly vaccination for large parts of the population and the extreme variability of influenza incidence during each ’season’ as the background for this review.
They specified that the majority of viral respiratory disease (influenza-like illness (ILI)) is caused by many different agents which are not clinically distinguishable from one another. A variable proportion of ILI (7% to 15% on average) is caused by influenza viruses and is known as influenza.

Any randomised controlled trial (RCT) or quasi-RCT comparing influenza vaccines in humans with placebo or no intervention or comparing types, doses or schedules of influenza vaccine was included. Only studies assessing protection from exposure to naturally occurring influenza were considered.
Fifty reports were included. Forty (59 sub-studies) were clinical trials of over 70,000 people. Eight were comparative non-RCTs and assessed serious harms. Two were reports of harms which could not be introduced in the data analysis. In the relatively uncommon circumstance of vaccine matching the viral circulating strain and high circulation, 4% of unvaccinated people versus 1% of vaccinated people developed influenza symptoms (risk difference (RD) 3%, 95% confidence interval (CI) 2% to 5%). The corresponding figures for poor vaccine matching were 2% and 1% (RD 1, 95% CI 0% to 3%). These differences were not likely to be due to chance. Inactivated vaccines caused local harms and an estimated 1.6 additional cases of Guillain-Barré Syndrome per million vaccinations. The harms evidence base is limited.
The combined results of these trials showed that under ideal conditions (vaccine completely matching circulating viral configuration) 33 healthy adults need to be vaccinated to avoid one set of influenza symptoms.
In average conditions (partially matching vaccine) 100 people need to be vaccinated to avoid one set of influenza symptoms. Vaccine use did not affect the number of people hospitalised or working days lost but caused one case of Guillian-Barré syndrome (a major neurological condition leading to paralysis) for every one million vaccinations.
Parenterally administered influenza vaccines appear significantly better than their comparators and can reduce the risk of developing influenza symptoms by around 4%, if the WHO recommendations are adhered to and the match is right. However, whilst the vaccines do prevent influenza symptoms, this is only one part of the spectrum of “clinical effectiveness” as they reduce the risk of total “clinical” seasonal influenza (i.e. influenza-like illness) symptoms by around 1%. When the results are expressed as RD the effect appears minimal. This is remarkable as healthy adults are the population in which inactivated vaccines perform best. No evidence was found that vaccines prevent viral transmission or complications. None of the studies included in the review presented results evaluating the ability of this vaccination to interrupt the spread of the disease.
Some studies presented data on reduction of working days lost and showed a very limited effect. Similarly a very limited effect was found on morbidity and no effect was found on hospitalization.
It was also concluded that it is not possible to give a definite indication on the practical use of live aerosol vaccines, because the assessment of their effectiveness is based on a limited number of studies presenting conflicting results. The effectiveness, according to WHO criteria, appears relatively low.

Inactivated influenza vaccines decrease the risk of symptoms of influenza and time off work, but their effects are minimal, especially if the vaccines and the circulating viruses are mismatched. There is no evidence that they affect complications or transmission. Efforts to update and enhance these vaccines should have priority.

The review conclusions are uncertain about the safety profile of inactivated vaccines which is a reflection of the size of the evidence base. The authors also conclude that the results may be an optimistic estimate because company-sponsored influenza vaccines trials tend to produce results favorable to their products and some of the evidence comes from trials carried out in ideal viral circulation and matching conditions and because the harms evidence base is limited.
(1)Jefferson T, Di Pietrantonj C, Rivetti A, Bawazeer GA, Al-Ansary LA, Ferroni E. Vaccines for preventing influenza in healthy adults. Cochrane Database of Systematic Reviews 2010, Issue 7. Art. No.: CD001269. DOI: 10.1002/14651858.CD001269.pub4
http://www.cochranejournalclub.com/vaccines-for-preventing-influenza-clinical/pdf/CD001269_full.pdf

Thursday, September 9, 2010

FDA approves pediatric use of chemical poisoning treatment (Protopam)

The U.S. Food and Drug Administration has approved the pediatric use of Protopam Chloride (pralidoxime chloride), a drug used to treat poisoning by organophosphate pesticides and chemicals (e.g., nerve agents). The drug is approved to be administered either by intravenous (IV) or intramuscular (IM) injections.

Improving the drug’s label with new dosing information for children will give health care professionals better guidance on how to use this drug safely and effectively.
It can be difficult to use IV drugs in children, particularly in emergency situations, so having the new option of IM injection may help health care professionals use this medicine quickly and accurately, informed Dianne Murphy, M.D., director of the FDA's Office of Pediatric Therapeutics.

Organophosphate pesticides are typically used in the farm setting and by professional exterminators. A person poisoned with organophosphate pesticides or chemicals (e.g., nerve agents) can have mild symptoms, such as a runny nose, teary eyes, or vomiting, to more serious symptoms such as difficulty breathing, weakness and convulsions.
Protopam Chloride was approved by the FDA in 1964 to treat various types of pesticide and chemical poisoning in adults. The drug works as an antidote to pesticides and chemicals of the organophosphate class by slowing the attachment of the chemical to nerve endings.

Adverse reactions that have been reported in pediatric and adult use of the drug include: blurred vision, double vision, dizziness, headache, drowsiness, nausea, difficulty breathing, increased heart rate and increased blood pressure.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm225347.htm

Guidelines for the management of atrial fibrillation:The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC)

The European Society of Cardiology issued new guidelines for management of Atrial Fibrillation at the ESC 2010. The guidelines  were issued after a gap of 4 years.
The guidelines have been compiled under various headings-Preamble, Introduction, Detection, Natural history and acute management, management and specific populations.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, occurring in 1–2% of the general population. Over 6 million Europeans suffer from this arrhythmia, and its prevalence is estimated to at least double in the next 50 years as the population ages.
AF confers a 5-fold risk of stroke, and one in five of all strokes is attributed to this arrhythmia. Ischaemic strokes in association with AF are often fatal, and those patients who survive .
Full text of the guidelines are available at:

http://eurheartj.oxfordjournals.org/content/early/2010/08/28/eurheartj.ehq278.long

Wednesday, September 8, 2010

NSAID use associated with future stroke in healthy population

At the last week's European Society of Cardiology (ESC) 2010 Congress, Dr Gunnar Gislason  presented a study that the short-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an increased risk of stroke in a Danish population study including only healthy individuals and said that the results could have "massive public-health implications."

"First we found an increased risk of MI with NSAIDs. Now we are finding the same thing for stroke. This is very serious, as these drugs are very widely used, with many available over the counter," Gislason raised a concern about the findings.

In this study, Gislason and colleagues examined the risk of stroke and NSAID use in healthy individuals living in Denmark. His team started with the whole population of Denmark aged over 10 years. To select just the healthy individuals, they excluded anyone admitted to the hospital within the past five years or those prescribed chronic medications for more than two years. This left a population of around half a million, who were included in the study.
By linking to prescribing registries, the researchers found that 45% of these healthy individuals had received at least one prescription for an NSAID between 1997 and 2005. They then used stroke data from further hospitalization and death registries and estimated the risk of fatal and nonfatal stroke associated with the use of NSAIDs by Cox proportional-hazard models and case-crossover analyses.

Results showed that NSAID use was associated with an increased risk of stroke. This increased risk ranged from about 30% with ibuprofen and naproxen to 86% with diclofenac.
There was also a dose-relationship found, with the increased risk of stroke reaching 90% (HR 1.90) with doses of ibuprofen over 200 mg and 100% (HR 2.0) with diclofenac doses over 100 mg.

The authors also concludeded that the harmful effects of these agents are relevant to huge numbers of people. "If half the population takes these drugs, even on an occasional basis, then this could be responsible for a 50% to 100% increase in stroke risk. It is an enormous effect."

http://www.theheart.org/article/1119849.do

Magic mushrooms

Magic Mushrooms’ Drug Can Improve the Lives of Cancer Patients
A psychedelic “magic mushroom” drug can be used to safely improve the lives of patients with advanced cancer, a study shows.

http://www.telegraph.co.uk/health/healthnews/7984313/Magic-mushrooms-can-improve-the-lives-of-cancer-patients.html

SHIFT: Adding HR-slowing agent ivabradine to HF meds cuts mortality, hospitalization

The findings from the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT)(1), presented at ESC 2010, signal a new potential direction for the treatment of heart failure characterized by an elevated heart rate as a therapeutic target.
Ivabradine is a selective inhibitor of a sodium-potassium channel highly expressed in the sinoatrial node, on which it has a mild dampening effect. The drug has few other, if any, known cardiac effects.

In the RCT cardiovascular outcomes in the placebo (n=3264) and ivabradine groups (n=3241) of this  trial, divided by quintiles of baseline heart rate in the placebo groups were analyzed.
The primary composite endpoint was cardiovascular death or hospital admission for worsening heart failure. In the ivabradine group, heart rate achieved at 28 days was also analysed in relation to subsequent outcomes. Analysis adjusted to change in heart rate was used to study heart-rate reduction as mechanism for risk reduction by ivabradine directly.
The results show that in the placebo group, patients with the highest heart rates (≥87 beats per min [bpm], n=682, 286 events) were at more than two-fold higher risk for the primary composite endpoint than were patients with the lowest heart rates (70 to <72 bpm, n=461, 92 events; hazard ratio [HR] 2·34, 95% CI 1·84—2·98, p<0·0001). Risk of primary composite endpoint events increased by 3% with every beat increase from baseline heart rate and 16% for every 5-bpm increase. In the ivabradine group, there was a direct association between heart rate achieved at 28 days and subsequent cardiac outcomes.
Patients with heart rates lower than 60 bpm at 28 days on treatment had fewer primary composite endpoint events during the study (n=1192; event rate 17·4%, 95% CI 15·3—19·6) than did patients with higher heart rates. The effect of ivabradine is accounted for by heart-rate reduction, as shown by the neutralisation of the treatment effect after adjustment for change of heart rate at 28 days (HR 0·95, 0·85—1·06, p=0·352).
The authors describe ivabradine as being "well tolerated" despite a 10% rate of bradycardia, which prompted withdrawal from the study by 1% of patients receiving the drug.The authors concluded that high heart rate is a risk factor in heart failure. Selective lowering of heart rates with ivabradine improves cardiovascular outcomes. Heart rate is an important target for treatment of heart failure.

Issues raised:
1.The population of the trial is younger than most patients with heart failure in the US, mostly white, sinus rhythm only, and status post-heart-failure hospitalization within the prior 12 months of enrollment."

Moreover, "the majority of the patients in this study were not only 'outside US' but also 'outside Western Europe.'
2.Dr John R Teerlink (2) focuses on the trial's beta-blocker dosing as a major reason not to consider the trial a conclusive test of ivabradine in chronic heart failure. Conceivably, a significant reduction in the primary end point might not have emerged had beta blockers—which also reduce heart rate—been more consistently given "at or near target doses," he speculates.
Would these benefits have occurred if the dose of beta blocker had been more consistently closer to the recommended doses in the patients studied

(1) http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61259-7/abstract
(2)http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61314-1/fulltext

Tuesday, September 7, 2010

Background, Incidence, and Predictors of Antiplatelet Therapy Discontinuation During the First Year After Drug-Eluting Stent Implantation

In a prospective study predictors of antiplatelet therapy discontinuation (ATD) during the first year after drug-eluting stent implantation were studied.
A 3-, 6-, 9-, and 12-month follow-up of patients receiving at least 1 drug-eluting stent between January and April 2008 in 29 hospitals was done. Individual- and hospital-level predictors of ATD were assessed by hierarchical-multinomial regression analysis. A total of 234 patients (14.4%) interrupted at least 1 antiplatelet therapy drug, predominantly clopidogrel (n=182, 11.8%). Bleeding events or invasive procedures led to ATD in 109 patients. This was predicted by renal impairment (odds ratio [OR] 2.81, 95% confidence interval [CI] 1.48 to 5.34), prior major hemorrhage (OR 3.77, 95% CI 1.41 to 10.03), and peripheral arterial disease (OR 1.78, 95% CI 1.01 to 3.15).
Medical decisions led to ATD in 70 patients; this was predicted by long-term use of anticoagulant therapy (OR 3.88, 95% CI 1.26 to 11.98), undergoing the procedure in a private hospital (OR 13.3, 95% CI 1.69 to 105), and not receiving instructions about medication (OR 2.8, 95% CI 1.23 to 6.36). Thirty-nine patients interrupted ATD on their own initiative, mainly immigrants (OR 3.78, 95% CI 1.2 to 11.98) and consumers of psychotropic drugs (OR 2.58, 95% CI 1.3 to 5.12).

Conclusions— ATD during the first year after drug-eluting stent implantation is based mainly on patient decision or a medical decision not associated with major bleeding events or major surgical procedures. Individual- and hospital-level variables are important to predict ATD
http://circ.ahajournals.org/cgi/content/abstract/122/10/1017?view=short&fp=1017&vol=122&lookupType=volpage

Ten-Year Follow-Up Survival of the Medicine, Angioplasty, or Surgery Study (MASS II)

MASS-II study compared the 10-year follow-up of percutaneous coronary intervention (PCI), coronary artery surgery (CABG), and medical treatment (MT) in patients with multivessel coronary artery disease, stable angina, and preserved ventricular function.

In the randomized controlled trial at a single institution, 611 patients were randomly assigned to CABG (n=203), PCI (n=205), or MT (n=203). The 10-year survival rates were 74.9% with CABG, 75.1% with PCI, and 69% with MT (P=0.089).
The 10-year rates of myocardial infarction were 10.3% with CABG, 13.3% with PCI, and 20.7% with MT (P<0.010).
The 10-year rates of additional revascularizations were 7.4% with CABG, 41.9% with PCI, and 39.4% with MT (P<0.001). Relative to the composite end point, Cox regression analysis showed a higher incidence of primary events in MT than in CABG (hazard ratio 2.35, 95% confidence interval 1.78 to 3.11) and in PCI than in CABG (hazard ratio 1.85, 95% confidence interval 1.39 to 2.47). Furthermore, 10-year rates of freedom from angina were 64% with CABG, 59% with PCI, and 43% with MT (P<0.001).

Conclusions— Compared with CABG, MT was associated with a significantly higher incidence of subsequent myocardial infarction, a higher rate of additional revascularization, a higher incidence of cardiac death, and consequently a 2.29-fold increased risk of combined events.
PCI was associated with an increased need for further revascularization, a higher incidence of myocardial infarction, and a 1.46-fold increased risk of combined events compared with CABG. Additionally, CABG was better than MT at eliminating anginal symptoms.
http://circ.ahajournals.org/cgi/content/abstract/122/10/949?view=short&fp=949&vol=122&lookupType=volpage

Calcium supplements and the risk of MI?

The meta-analysis to investigate whether the calcium supplements increase the risk of cardiovascular events published recently in BMJ(1) has concluded that Calcium supplements (without coadministered vitamin D) are associated with an increased risk of myocardial infarction. As calcium supplements are widely used these modest increases in risk of cardiovascular disease might translate into a large burden of disease in the population. A reassessment of the role of calcium supplements in the management of osteoporosis is warranted.
The findings of the meta-analysis were consistent across trials, with an increased relative risk of myocardial infarction with calcium observed in six of the seven trials in which at least one event occurred, although no individual trial reported a statistically significant effect. The risk of myocardial infarction with calcium tended to be greater in those with dietary calcium intake above the median but was independent of age, sex, and type of supplement
The studies that compared coadministered calcium and vitamin D supplements with placebo were not included. The results therefore may not apply to coadministered calcium and vitamin D supplements.
In an editorial accompanying the article, Dr John Cleland and colleagues (2) wonder why calcium supplements should increase cardiovascular risk, as found in this meta-analysis. "Accumulation of calcium in the arterial wall leading to reduced compliance would be expected to take years, but the increased risk of myocardial infarction reported by Bolland and colleagues occurred early after calcium supplementation (median follow-up of 3.6 years)." They suggest that the increased risk of MI may not be a true effect, because the increased risk of MI was not accompanied by an increase in mortality. "Calcium supplements could simply be causing gastrointestinal symptoms that could be misdiagnosed as cardiac chest pain
It was concluded that patients with osteoporosis should generally not be treated with calcium supplements, either alone or with vitamin D, unless they are also receiving an effective treatment for osteoporosis for a recognized indication." They add that research on whether such supplements are needed in addition to effective osteoporosis treatment is "urgently required".
1. http://www.bmj.com/content/341/bmj.c3691.long
2. http://www.bmj.com/content/341/bmj.c3856.long

US FDA has approved Tekamlo (aliskiren and amlodipine) tablets for hypertension

US FDA approved the use of Tekamlo (aliskiren/amlodipine) 150 mg/5 mg, 150 mg/10 mg, 300 mg/5 mg and 300 mg/10 mg Tablets for treatment of hypertension as initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals and in patients not adequately controlled with monotherapy.
Tekamlo is a combination of aliskiren, a renin inhibitor, and amlodipine, a dihydropyridine calcium channel blocker, indicated for the treatment of hypertension.

http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022545s000lbl.pdf
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/022184s000ltr.pdf

FDA Approves Lumigan 0.01% Ophthalmic Solution

US FDA approved the use of the use of Lumigan (bimatoprost ophthalmic solution), 0.01%, for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension on August 31, 2010.

Lumigan 0.01% is a once-daily prescription eye drop that provides effective and sustained IOP lowering.

Lumigan 0.01% will be available in the fourth quarter of 2010, and is the newest addition to Allergan's comprehensive glaucoma portfolio

Read more: http://www.drugs.com/newdrugs/allergan-inc-receives-fda-approval-lumigan-0-01-first-line-therapy-indicated-reduction-elevated-2283.html#ixzz0ypZpVPBW

Monday, September 6, 2010

Tygacil

FDA reminded healthcare professionals of an increased mortality risk associated with the use of the intravenous antibacterial Tygacil (tigecycline) compared to that of other drugs used to treat a variety of serious infections.

The increased risk was seen most clearly in patients treated for hospital-acquired pneumonia, especially ventilator-associated pneumonia, but was also seen in patients with complicated skin and skin structure infections, complicated intra-abdominal infections and diabetic foot infections.

Tygacil is not approved for the treatment of hospital-acquired pneumonia (including ventilator-associated pneumonia) or diabetic foot infection.

Tygacil is approved by FDA for the treatment of complicated skin and skin structure infections, complicated intra-abdominal infections, and community acquired pneumonia.
Read at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm224626.htm