DEFINE ( Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) trial

The results of the DEFINE ( Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) trial were presented at the recent AHA meet. It was a double-blind randomized trial in which patients received either 100 mg of anacetrapib or matching placebo daily. Anacetrapib is an orally active, potent, selective CETP inhibitor that has had an acceptable side-effect profile in initial studies involving healthy volunteers and patients with hyperlipidemia.

The primary efficacy end points were the percentage change from baseline in LDL cholesterol after 24 weeks of treatment and the safety and side-effect assessments (i.e., assessment of adverse events; laboratory testing related to safety, including measurement of electrolyte and aldosterone levels; and assessment of vital signs, including blood-pressure measurement, electrocardiography, and physical examination) throughout the 76-week treatment period. Secondary efficacy end points included the change in LDL cholesterol from baseline to week 76 and the levels of HDL cholesterol, non-HDL cholesterol, apolipoprotein B, and apolipoprotein A-I after 24 and 76 weeks of treatment.

By 24 weeks, LDL cholesterol levels had decreased from 81 mg per deciliter to 45 mg per deciliter (1.2 mmol per liter) in the anacetrapib group, as compared with a change from 82 mg per deciliter (2.1 mmol per liter) to 77 mg per deciliter (2.0 mmol per liter) in the placebo group — a 39.8% reduction with anacetrapib beyond that seen with placebo (P<0.001).

HDL cholesterol levels had increased from 41 mg per deciliter to 101 mg per deciliter (2.6 mmol per liter) in the anacetrapib group, as compared with a change from 40 mg per deciliter (1.0 mmol per liter) to 46 mg per deciliter (1.2 mmol per liter) in the placebo group — a 138.1% increase with anacetrapib beyond that seen with placebo (P<0.001).

In the anacetrapib group, apolipoprotein B levels decreased by 21.0% and apolipoprotein A-I levels increased by 44.7% beyond the changes seen in the placebo group (P<0.001).

 Treatment with anacetrapib was associated with a 31.7% reduction in non-HDL cholesterol, a 36.4% reduction in lipoprotein(a) levels, and a 6.8% reduction in triglyceride levels, beyond the changes seen in the placebo group. All the changes in lipid levels were sustained throughout the 76-week treatment period. There were no significant differences in C-reactive protein levels between the two treatment groups.

Adverse events: There were no appreciable differences between the anacetrapib group and the placebo group in the percentage of patients with adverse events that were thought to be related to the study drug or that led to its discontinuation. There were also no significant differences between the two groups in the mean change in systolic or diastolic blood pressure or in the percentage of patients with a reported increase in blood pressure.

There were no cases of rhabdomyolysis in either study group and no significant differences in the percentages of patients with myalgias or other muscle symptoms or with elevations in creatine kinase.

In the current study, anacetrapib treatment did not alter blood pressure, electrolyte levels, or serum aldosterone levels, and the distribution of cardiovascular events between the two treatment groups provided a 94% predictive probability (confidence) that treatment with anacetrapib is not associated with the rate of adverse cardiovascular effects reported with torcetrapib. These findings have opened the door to retesting the hypothesis that inhibition of CETP is cardioprotective.

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1009744

CTT meta-analysis: Safety and efficacy of more intensive lowering of LDL cholesterol with statin therapy.

In the  Cholesterol Treatment Trialists  Collaboration (CTT) meta-analysis all those trials were eligible for inclusion if: the main effect of the intervention was to lower LDL cholesterol; no other differences in risk factor modification were intended; and at least 1000 participants were to be recruited with at least 2 years' scheduled treatment duration. Five trials comparing more intensive with less intensive LDL-C lowering were taken and 21 trials were of comparison of statin therapy with control.

Overall, among the 39 612 participants in five trials, the weighted mean baseline LDL cholesterol concentration was estimated to be 2·53 mmol/L, the weighted mean difference at one year was 0·51 mmol/L, and the weighted median follow-up duration among survivors was 5·1 years (2·1 years for patients with acute coronary syndrome and 5·8 years for those with stable disease).

First major vascular events were recorded in the five trials of more versus less intensive statin therapy in 3837 (4·5% per annum) of 19 829 participants allocated more intensive versus 4416 (5·3% per annum) of 19 783 allocated less intensive therapy, corresponding to a highly significant further proportional risk reduction of 15% (95% CI 11—18; p<0·0001) associated with the mean 0·51 mmol/L further LDL cholesterol reduction.

In the updated meta-analysis of 21 trials of statin versus control, 7136 (2·8% per annum) of 64 744 participants allocated statin therapy had first major vascular events versus 8934 (3·6% per annum) of 64 782 allocated control, corresponding to a highly significant 22% (95% CI 19—24; p<0·0001) risk reduction with a 1·07 mmol/L LDL cholesterol reduction. Overall, the weighted average reduction in major vascular events was 21% (95% CI 19—23; p<0·0001) per 1·0 mmol/L reduction in LDL cholesterol.

Taking all 26 trials together, the risk reduction was 22% (95% CI 20—24; p<0·0001) per 1·0 mmol/L reduction in LDL cholesterol at 1 year, with a significant 12% reduction during the first year after randomisation (p<0·0001) and highly significant reductions of about a quarter during each subsequent year (all p<0·0001).

In the trials of more versus less intensive statin therapy, the weighted mean further reduction in LDL cholesterol at 1 year was 0·51 mmol/L. Compared with less intensive regimens, more intensive regimens produced a highly significant 15% (95% CI 11—18; p<0·0001) further reduction in major vascular events, consisting of separately significant reductions in coronary death or non-fatal myocardial infarction of 13% (95% CI 7—19; p<0·0001), in coronary revascularisation of 19% (95% CI 15—24; p<0·0001), and in ischaemic stroke of 16% (95% CI 5—26; p=0·005). Per 1·0 mmol/L reduction in LDL cholesterol, these further reductions in risk were similar to the proportional reductions in the trials of statin versus control.

Across all 26 trials, all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction (RR 0·90, 95% CI 0·87—0·93; p<0·0001), largely reflecting significant reductions in deaths due to coronary heart disease (RR 0·80, 99% CI 0·74—0·87; p<0·0001) and other cardiac causes (RR 0·89, 99% CI 0·81—0·98; p=0·002), with no significant effect on deaths due to stroke (RR 0·96, 95% CI 0·84—1·09; p=0·5) or other vascular causes (RR 0·98, 99% CI 0·81—1·18; p=0·8). No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 0·97, 95% CI 0·92—1·03; p=0·3) or on cancer incidence (RR 1·00, 95% CI 0·96—1·04; p=0·9), even at low LDL cholesterol concentrations.

Overall, there was a 22% proportional reduction in the risk of major vascular events for each 1 mmol/L reduction in LDL cholesterol, which implies that, at least within the range of LDL cholesterol studied to date, a 2 mmol/L reduction would reduce the risk by about 40% (since the combination of risk ratios of 0·78×0·78 yields a risk ratio of about 0·6), and a 3 mmol/L reduction could reduce the risk by about 50%.

In the combined meta-analysis coronary mortality was reduced by about a fifth per 1·0 mmol/L LDL cholesterol reduction, but the reduction in cardiac deaths that were not attributed to coronary disease was only about half as large.

There was no evidence in the analyses of an increase in incidence of cancer.The lowering of LDL cholesterol with statin therapy was associated with a non-significant excess (257 vs 220; p=0·2 of incidence of haemorrhagic strokes

These findings suggest that the primary goal for patients at high risk of occlusive vascular events should be to achieve the largest LDL cholesterol reduction possible without materially increasing myopathy risk.

Current therapeutic guidelines tend to emphasise the need to reach a particular LDL cholesterol target—for example, US National Cholesterol Education Program guidelines suggest that the objective in high-risk patients should generally be to reduce LDL cholesterol to below 100 mg/dL (2·6 mmol/L) or, optionally, for very high risk patients, to below 70 mg/dL (1·8 mmol/L).

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61350-5/fulltext#

SEARCH trial

The results of SEARCH trial have been published in the November issue of Lancet.(1) It was a double blind randomized trial involving 12 064 men and women aged 18—80 years with a history of myocardial infarction. Participants were either currently on or had clear indication for statin therapy, and had a total cholesterol concentration of at least 3·5 mmol/L if already on a statin or 4·5 mmol/L if not.

The primary endpoint was major vascular events, defined as coronary death, myocardial infarction, stroke, or arterial revascularisation. Analysis was by intention to treat. 

Aim was to establish reliably the balance of efficacy and safety of more intensive LDL-cholesterol-lowering therapy by comparing long-term treatment with 80 mg versus 20 mg simvastatin daily in a large population of patients at high risk of cardiovascular events.

Mean follow-up duration was 6·7 (SD 1·5) person-years: 40 129 person-years in those allocated 80 mg and 40 158 person-years in those allocated 20 mg simvastatin daily.

Compliance: Among participants allocated 80 mg simvastatin, 5275 (90%) were compliant after 12 months, and 2555 (77%) after 84 months. Compliance in patients on 20 mg simvastatin was similar after 12 months, but had dropped to 69% by 84 months, with an increasing proportion of patients having started a non-study statin. The main reason for discontinuation of study treatment in participants was medical advice, generally because of a perceived need for more intensive cholesterol-lowering therapy. By contrast, slightly more of the patients allocated 80 mg simvastatin were likely to stop because of raised liver or muscle enzyme concentrations or to have reported muscle pain or weakness.

At 2 months, LDL cholesterol was reduced by 0·51 (SE 0·06) mmol/L more in those allocated 80 mg simvastatin (as originally anticipated), but that difference had decreased to 0·34 (0·02) mmol/L by 84 months (mainly because of increasing non-compliance with the allocated treatment), yielding a weighted average difference during the study of 0·35 (0·01) mmol/L.

Major vascular events occurred during the scheduled treatment period in 1477 (24·5%) of the 6031 participants allocated 80 mg simvastatin versus 1553 (25·7%) of the 6033 allocated 20 mg simvastatin. This non-significant reduction in risk did not increase significantly with duration of treatment (p value for trend=0·7). Among participants in the low, middle, and high thirds of baseline LDL cholesterol, allocation to 80 mg simvastatin produced further average reductions in LDL cholesterol of 0·30 (SE 0·02), 0·37 (0·02), and 0·36 (0·02) mmol/L, respectively, but no significant difference between the major vascular event reductions.

The numbers of deaths attributed to vascular causes (565 [9·4%] vs 572 [9·5%]) or non-vascular causes (399 [6·6%] vs 398 [6·6%]) did not differ significantly between the treatment groups.

Persistent increases of alanine aminotransferase to four times the upper limit of normal were rare, and no significant difference was found between the treatment groups. Myopathy was confirmed in 53 (1%) participants and two participants in 80 mg simvastatin and 20 mg simvastatin groups respectively.

In the larger and longer SEARCH trial, LDL cholesterol was reduced from an average of 2·52 mmol/L to an average of 2·17 mmol/L for about 7 years and, again, there were similar numbers of non-vascular deaths in both groups (399 [6·6%] on 80 mg simvastatin vs 398 [6·6%] on 20 mg simvastatin), as well as similar numbers with incident cancer (640 [10·6%] vs 677 [11·2%]). The higher absolute rate of non-vascular mortality in SEARCH reflects both the older age of the participants and the longer study duration.

(1)

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60310-8/fulltext

World Diabetes Day 14th November, 2010

The European Society of Cardiology marked the World Diabetes Day by emphasizing the simple steps for diabetics.

The press release highlights that the forecast of 330 million diabetes cases worldwide by 2050. This figure represents a staggering 3% of the predicted global population.

The mechanisms that link the onset of diabetes with subsequent development of CVD include above-average lipid levels, inflammation of vascular walls, high blood pressure, and an excess of ‘bad’ cholesterol produced by the liver. 

Additionally, the effects of continuing to smoke are particularly potent for diabetics, with a dramatic increase in mortality rates being an inevitable outcome.  Despite this, most diabetics can greatly alleviate the symptoms of CVD by making sensible diet and lifestyle choices.

The members said that the the impact of growing obesity levels is pushing Type 2 diabetes into an epidemic.  It is a very serious problem for healthcare providers due to the cost of treatment, but also for cardiologists who now see diabetes prevention as one of the main health challenges.

Around 60% of cardiovascular patients nowadays are pre-diabetic or diabetic, a significant increase from our experience of 20 years ago.”

Diabetics with CVD are urged to follow the ESC recommendations for patients which, quite simply, are summarised as:

• Eat a healthy diet
• Exercise more
• Stop smoking
• Limit alcohol intake

Following this common sense advice will have a very positive impact on the progression of CVD.  They stressed that the complications of CVD when added to the underlying effects of diabetes are a dangerous combination that should be avoided at all costs.  That is why it is important to manage the diet and lifestyle changes to prevent the progression of CVD.

The press release also highlighted the pioneering work done by “Chronic Disease Alliance” organization in Europe.

http://www.escardio.org/about/press/press-releases/pr-10/Pages/World-Diabetes-Day.aspx

Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines:ACCF/ACG/AHA 2010

ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use

Conclusions are:

1.     The Assessment of Epidemiologic Evidence Supporting a Significant Clinical Interaction Between PPIs and Thienopyridines.  

a.     The magnitude of association in positive observational studies reviewed is small to moderate (HR or OR: <2), but associations of this magnitude in nonrandomized observational studies may be due to residual differences in patient characteristics between study groups. The only available randomized trial showed no significant association of omeprazole with CV events, but the confidence limits on this null finding include the possibility of up to a 44% relative increase in CV risk.

b.     A significant association between PPI use and increased CV events has been inconsistently demonstrated in observational studies, with the majority of studies showing no association.

c.       Although clinical studies with CV events as endpoints are not definitive, the proposed mechanism is biologically plausible, given that a) clopidogrel users with reduced-function genetic polymorphisms in CYP2C19 metabolism have increased rates of CV events; and b) in vitro testing suggests that PPIs may inhibit CYP2C19 metabolism.

d.     Experimental pharmacodynamic data consistently indicate that omeprazole diminishes the effect of clopidogrel on platelets. Other pharmacodynamic studies have failed to demonstrate a significant effect of other PPIs on clopidogrel.

2.     Risk/Benefit Balance: GI Bleed Risk Versus CV Event Risk.   All prescription drugs have favorable and unfavorable effects, and treatment decisions must be based on whether the potential for benefit outweighs the potential for harm.

PPIs are coprescribed with antiplatelet drugs for 1 reason—to reduce the increased risk of GI complications caused by antiplatelet drugs.  Prior upper GI bleeding is the strongest and most consistent risk factor for GI bleeding on antiplatelet therapy. Patients with ACS and prior upper GI bleeding are at substantial CV risk, so dual antiplatelet therapy with concomitant use of a PPI may provide the optimal balance of risk and benefit.

Among stable patients undergoing coronary revascularization, a history of GI bleeding should inform the choice of revascularization method; if a coronary stent is selected to treat such patients, the risk/benefit tradeoff may favor concomitant use of dual antiplatelet therapy and a PPI.

Advanced age; concomitant use of warfarin, steroids, or NSAIDs; or H. pylori infection all raise the risk of GI bleeding with antiplatelet therapy. The risk reduction with PPIs is substantial in patients with risk factors for GI bleeding and may outweigh any potential reduction in the CV efficacy of antiplatelet treatment because of a drug–drug interaction. Patients without these risk factors for GI bleeding receive little if any absolute risk reduction from a PPI, and the risk/benefit balance would seem to favor use of antiplatelet therapy without concomitant PPI. The reduction of GI symptoms by PPIs (i.e., treatment of dyspepsia) may also prevent patients from discontinuing their antiplatelet treatment. The discontinuation of antiplatelet therapy in patients with GI bleeding may increase the risk of CV events.

3.     Are H2RAs a Reasonable Alternative and in Which Population?.   Available data suggest PPIs are superior to H2RAs, but H2RAs may be a reasonable alternative in patients at lower risk for GI bleeding, and in those who do not require PPI for refractory gastroesophageal reflux disease. Cimetidine can competitively inhibit CYP2C19, so other H2RAs might be a better choice in patients treated with clopidogrel.

http://content.onlinejacc.org/cgi/content/full/j.jacc.2010.09.010#top

    

Egrifta gets FDA approval

On 11^th November 2010, US FDA approved Egrifta (tesamorelin) to treat HIV patients with lipodystrophy. It is the first FDA-approved treatment for lipodystrophy .

Lipodystrophy , also called fat redistribution , is a  disturbance in the way the body produces, uses, and stores fat. There are two different kinds of lipodystrophy-lipoatrophy, and hyperadiposity. The condition is associated with many antiretroviral drugs used to treat HIV.

Egrifta, the first FDA-approved treatment for lipodystrophy, is a growth hormone releasing factor (GRF) drug that is administered in a once-daily injection.

Presently it is not known whether Egrifta decreases the risk of cardiovascular disease or improves compliance with antiretroviral drugs has not been studied.

Egrifta was evaluated in two clinical trials involving 816 HIV-infected adult men and women with lipodystrophy and excess abdominal fat. Of these, 543 patients received Egrifta during a 26-week, placebo-controlled period. In both studies, patients treated with Egrifta experienced greater reductions in abdominal fat as measured by CT scan, compared with patients receiving another injectable solution (placebo). Some patients reported improvements in their self image. 

The most commonly reported side effects in the studies included joint pain (arthralgia), skin redness and rash at the injection site (erythema and pruritis), stomach pain, swelling, and muscle pain (myalgia). Worsening blood sugar control occurred more often in patients treated with Egrifta than with placebo.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm233516.htm

Docosahexaenoic Acid Supplementation and Cognitive Decline in Alzheimer Disease

A study published in the recent issue of JAMA has shown the relation between the use of Docosahexaenoic acid DHA and cognitive functions in Alzheimers disease.

DHA is an omega-3 fatty acid identified as a potential treatment for Alzheimer disease. Epidemiological studies have shown that omega-3 fatty acid consumption reduces Alzheimer disease risk and DHA modifies the expression of Alzheimer-like brain pathology in mouse models.

A randomized, double-blind, placebo-controlled trial was conducted by the Alzheimer’s Disease Cooperative Study (ADCS) a consortium of academic medical centers and private Alzheimer disease clinics funded by the National Institute on Aging to conduct clinical trials on Alzheimer disease. Participants were recruited between February and November 2007 and the Clinical activity was completed in May 2009.

Inclusion criteria: Individuals with probable Alzheimer disease, if they had the following: (1) their Mini-Mental State Examination (MMSE) score was between 14 and 26, (2) they were medically stable, (3) they consumed on average no more than 200 mg/d of DHA (as assessed by a brief 7-item food frequency questionnaire), and (4) they were not taking DHA or omega-3 fatty acid supplements.

Exclusion criteria: if they were taking drugs with central anticholinergic effects or sedatives or were receiving any investigational treatment for Alzheimer disease. Stable use ( 3 months) of cholinesterase inhibitors or memantine was permitted.

Study drug: Aalgal-derived DHA (Martek Biosciences, Columbia, Maryland) administered as capsules, dosed as 1 g twice per day for a total daily dose of 2 g. Algal DHA contains approximately 45% to 55% of DHA by weight and does not contain eicosapentaenoic acid.

Two Primary outcome measures: The rate of change over 18 months on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and on the Clinical Dementia Rating (CDR) sum of boxes.

The primary analysis was an intent-to-treat analysis including all randomized participants. That is, participants were analyzed in the group to which they were randomized, regardless of medication adherence. All available assessments for ADAS-cog and CDR sum of boxes were used in the analysis for individuals who discontinued medication.

Results: Plasma phospholipid DHA increased in the DHA treatment group from 3.18 weight percentage at baseline to 9.80 weight percentage at 6 months, 10.20 weight percentage at 12 months, and 9.82 weight percentage at 18 months (207% increase, P < .001) with no significant change in plasma phospholipid DHA in the placebo group.

Subgroup of 44 participants volunteering for cerebrospinal fluid collection at baseline and 18 months (DHA group: 29; placebo group: 15), a significant 38% increase in cerebrospinal fluid DHA was observed in the DHA group (2.53 weight percentage at baseline and 3.46 weight percentage at 18 months; P < .001) but not in the placebo group.

The rate of mean change in ADAS-cog score over 18 months was 8.27 points  for the placebo group compared with 7.98 points for the DHA group (linear mixed-effects model: P = .41). The rate of points change on CDR sum of boxes over 18 months was 2.93 (95% CI, 2.44-3.42) for the placebo group compared with 2.87 (95% CI, 2.44-3.30) for the DHA group. The linear mixed-effects analysis revealed a rate of decline on the ADCS-ADL of 11.51 (95% CI, 9.57 to 13.45) points change over 18 months for the DHA group compared with the points change of 10.43 (95% CI, 8.41 to 12.45) for the placebo group.

The hypothesis that DHA slows the progression of mild to moderate Alzheimer disease was not supported, so there is no basis for recommending DHA supplementation for patients with Alzheimer disease.  A large proportion of randomized participants (28% of the DHA group and 24% of the placebo group) did not complete the study.

The authors concluded that the supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate Alzheimer disease.

^{http://jama.ama-assn.org/cgi/content/full/304/17/1903}

  

Pharmacodynamics of Clonidine Therapy in Pregnancy

A retrospective cohort study was performed in patients cared for at the University of Washington Obstetric Hypertension Clinic.

The authors have highlighted the following aims:

·  To describe the pharmacodynamics of clonidine in pregnancy with particular attention to differences in individual hemodynamic responses.

·  To determine whether differences in individual hemodynamic responses had an impact on fetal growth and birth weight.

·  Finally to determine whether the pattern of hemodynamic response could be predicted by maternal characteristics or by baseline hemodynamic parameters that could be ascertained without noninvasive measurement of CO.

Charts were reviewed from 1997 to 2007 to identify subjects started on clonidine monotherapy after 16 weeks gestational age.

Results: Seventy-two women were identified who had been treated with clonidine monotherapy. One was excluded for acute pre-eclampsia.

Hemodynamic response to clonidine: Normative data from 89 nulliparous women who developed neither gestational hypertension nor pre-eclampsia are included for comparison. With all data combined, a decrease in MAP was associated with a decrease in TPR and a modest rise in CO.

The ↓CO Group experienced a substantial reduction in heart rate (HR) with an associated reduction in CO and a very modest change in TPR. Pretreatment hemodynamic profile (e.g., MAP, CO, HR, stroke volume, TPR), did not predict response as demonstrated by the similar starting point of each response vector.

Many women delivered prior to term, and the cohort experienced a high rate of pre-eclampsia. Mean birth weight percentile was lower in the ↓CO Group (26.1), compared to the ↓TPR Group (43.6), P = 0.02.

The ↓CO Group was less likely to be associated with a higher birth weight compared to the ↓TPR Group (relative risk ratio 0.81; 95% confidence interval 0.66–0.98) for an increase in birth weight by 100 g. The Mixed Group exhibited a trend toward a lower birth weight baby relative to the ↓TPR Group (relative risk ratio 0.83; 95% confidence interval 0.64–1.07). Women whose response was characterized by a reduction in CO delivered infants with a lower birth rate percentile and an increased incidence of birth weight <10th percentile.

In the study, Clonidine was found to have heterogeneous hemodynamic effects when used to treat hypertension in pregnancy. Fifty two percentage of patients experienced a primary reduction in vascular resistance.

In this report, women treated with clonidine experienced a heterogeneous response. Women in the ↓CO Group delivered babies with a lower birth weight percentile (26.1 vs. 43.6, P = 0.02) compared to the ↓TPR Group. The differential effect on fetal growth may be attributable to the differential hemodynamic effects of the drug. Alternatively, unknown factors intrinsically associated with the different responses could be responsible for the observed effect on growth.

A higher dose of clonidine occurred more commonly in the ↓CO Group. A higher maternal plasma clonidine concentration could be a determinant of the type of response group. But, there were no serum clonidine levels in this cohort to evaluate this hypothesis.

The heterogeneous response to treatment with clonidine seems to be associated with an impact on fetal growth. Similar fetal growth findings with clonidine that has a different mechanism of action than atenolol, suggest that the effect is due to the common effect on maternal hemodynamics.

As might be expected, a reduction in HR characterized the ↓CO Group with 20/22 women (91%) having a change in HR <0. All babies in this group with birth weights <10th percentile were delivered to women with a reduction in HR. In the entire cohort, a ΔHR <0 identified 12/14 babies born at <10th percentile. However, 41/64 women (64%) of the entire cohort had a ΔHR <0. While a decrease in HR was sensitive in predicting response group and small babies, it was not very specific.

Recommendations: First, by limiting the dose of clonidine to 0.15 mg/day and adding a second agent such as hydralazine when an additional reduction in BP is needed, the chance of a ↓CO effect will be reduced.

Second, if a decrease in HR is observed with clonidine, addition of a vasodilator such as hydralazine should again be considered. While this strategy would again decrease the chance of a ↓CO response, 33% of women whose treatment was altered might not have needed an additional agent to avoid a ↓CO response. If BP was not excessively reduced, this strategy would not be likely to have adverse effects.

http://www.nature.com/ajh/journal/v23/n11/full/ajh2010159a.html

FDA Approves Teflaro for Bacterial Infections

The U.S. Food and Drug Administration today approved Teflaro (ceftaroline fosamil), an injectable antibiotic to treat adults with community acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI), including methicillin-resistant Staphylococcus aureus (MRSA).

Teflaro is an antibacterial agent in a class of drugs known as cephalosporins, which act by interfering with the bacterial cell wall.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm231594.htm

FDA approves new indication for Afinitor (everolimus)

The U.S. Food and Drug Administration approved the cancer drug Afinitor (everolimus) on Friday to treat patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS), a rare genetic disorder.
This approval was for treatments of SEGA that can not be treated with surgery.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm231793.htm

Acetaminophen Increases Blood Pressure in Patients With Coronary Artery Disease

The safety of acetaminophen in patients with coronary artery disease has been evaluated in a randomized, double-blind, placebo-controlled, crossover study.

A total of  33 patients with coronary artery disease  received acetaminophen (1 g TID) on top of standard cardiovascular therapy for 2 weeks.

 Ambulatory blood pressure, heart rate, endothelium-dependent and -independent vasodilatation, platelet function, endothelial progenitor cells, markers of the renin-angiotensin system, inflammation, and oxidative stress were determined at baseline and after each treatment period.

Treatment with acetaminophen resulted in a significant increase in mean systolic (from 122.4±11.9 to 125.3±12.0 mm Hg P=0.02 versus placebo) and diastolic (from 73.2±6.9 to 75.4±7.9 mm Hg P=0.02 versus placebo) ambulatory blood pressures.

 On the other hand, heart rate, endothelial function, early endothelial progenitor cells, and platelet function did not change.

The authors have concluded that the study demonstrates for the first time that acetaminophen induces a significant increase in ambulatory blood pressure in patients with coronary artery disease.

Thus, the use of acetaminophen should be evaluated as rigorously as traditional nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors, particularly in patients at increased cardiovascular risk.

http://circ.ahajournals.org/cgi/content/abstract/122/18/1789