Day: 09/03/2013

Use of Oral Fluconazole during Pregnancy and the Risk of Birth Defects.

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BACKGROUND

Case reports suggest that long-term, high-dose fluconazole treatment for severe fungal infections during pregnancy causes a pattern of birth defects. It is unclear whether commonly used lower doses increase the risk of specific birth defects.

METHODS

In a registry-based cohort of liveborn infants in Denmark, we evaluated first-trimester oral fluconazole exposure and the risk of birth defects overall and of birth defects previously linked to azole antifungal agents.

RESULTS

The majority of fluconazole-exposed pregnancies were in women who received common therapeutic doses of 150 mg (56% of pregnancies) or 300 mg (31%). Oral fluconazole exposure was not associated with an increased risk of birth defects overall (210 birth defects among 7352 fluconazole-exposed pregnancies [prevalence, 2.86%] and 25,159 birth defects among 968,236 unexposed pregnancies [prevalence, 2.60%]; adjusted prevalence odds ratio, 1.06; 95% confidence interval [CI], 0.92 to 1.21). In addition, oral fluconazole exposure was not associated with a significantly increased risk of 14 of 15 types of birth defects previously linked to azole antifungal agents: craniosynostosis, other craniofacial defects, middle-ear defects, cleft palate, cleft lip, limb defects, limb-reduction defects, polydactyly, syndactyly, diaphragmatic hernia, heart defects overall, pulmonary-artery hypoplasia, ventricular septal defects, and hypoplastic left heart. A significantly increased risk of tetralogy of Fallot was observed (7 cases in fluconazole-exposed pregnancies [prevalence, 0.10%] as compared with 287 cases in unexposed pregnancies [prevalence, 0.03%]; adjusted prevalence odds ratio, 3.16; 95% CI, 1.49 to 6.71).

CONCLUSIONS

Oral fluconazole was not associated with a significantly increased risk of birth defects overall or of 14 of the 15 specific birth defects of previous concern. Fluconazole exposure may confer an increased risk of tetralogy of Fallot.

Source: NEJM

 

 

 

 

 

Safety and Efficacy of RNAi Therapy for Transthyretin Amyloidosis.

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BACKGROUND

Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin.

METHODS

We identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN-TTR02, respectively. Each formulation was studied in a single-dose, placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers.

RESULTS

Rapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P<0.001 for all comparisons). These reductions were shown to be RNAi-mediated. Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN-TTR02, respectively.

CONCLUSIONS

ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAi therapy targeting messenger RNA transcribed from a disease-causing gene.

Source: NEJM

 

Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension.

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Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point. We assessed the efficacy of macitentan, a new dual endothelin-receptor antagonist, using a primary end point of morbidity and mortality in a long-term trial.

METHODS

We randomly assigned patients with symptomatic pulmonary arterial hypertension to receive placebo once daily, macitentan at a once-daily dose of 3 mg, or macitentan at a once-daily dose of 10 mg. Stable use of oral or inhaled therapy for pulmonary arterial hypertension, other than endothelin-receptor antagonists, was allowed at study entry. The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension.

RESULTS

A total of 250 patients were randomly assigned to placebo, 250 to the 3-mg macitentan dose, and 242 to the 10-mg macitentan dose. The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 (97.5% confidence interval [CI], 0.52 to 0.96; P=0.01), and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39 to 0.76; P<0.001). Worsening of pulmonary arterial hypertension was the most frequent primary end-point event. The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline. Adverse events more frequently associated with macitentan than with placebo were headache, nasopharyngitis, and anemia.

CONCLUSIONS

Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study.

Source: NEJM

 

Oral Apixaban for the Treatment of Acute Venous Thromboembolism.

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BACKGROUND

Apixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism.

METHODS

In this randomized, double-blind study, we compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding.

RESULTS

The primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], −0.4 percentage points; 95% CI, −1.3 to 0.4). Apixaban was noninferior to conventional therapy (P<0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (<1.80) and difference in risk (<3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P<0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P<0.001). Rates of other adverse events were similar in the two groups.

CONCLUSIONS

A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding

Source: NEJM

The Cardiovascular Safety of Diabetes Drugs — Insights from the Rosiglitazone Experience.

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The management of type 2 diabetes has been challenged by uncertainty about possible cardiovascular effects related to treatment intensity and choice of drug. Although the Food and Drug Administration (FDA) considers a decrease in glycated hemoglobin an approvable end point, very intensive glycemic control is associated with increased cardiovascular and all-cause mortality.1 The safety of specific drugs for type 2 diabetes — particularly the thiazolidinediones — has also been questioned. After rosiglitazone had been approved in the United States in 1999 and in Europe in 2000, a highly publicized meta-analysis in 2007 reported a 43% increase in myocardial infarction (P=0.03) and a 64% increase in death from cardiovascular causes (P=0.06).2 This report and subsequent FDA advisory committee reviews led to a boxed warning of myocardial ischemia in 2007 and highly restricted access to rosiglitazone in 2010. In 2010, the FDA placed a full clinical hold on the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial (ClinicalTrials.gov number, NCT00879970), a large cardiovascular-outcome trial designed to evaluate the benefit of rosiglitazone and pioglitazone as compared with placebo (superiority hypothesis) and the safety of rosiglitazone as compared with pioglitazone (noninferiority hypothesis). In part owing to the rosiglitazone experience, the FDA issued an updated Guidance for Industry in 2008 requiring that preapproval and postapproval studies for all new antidiabetic drugs rule out excess cardiovascular risk, defined as an upper bound of the two-sided 95% confidence interval for major adverse cardiovascular events (MACE) of less than 1.80 and less than 1.30, respectively.3 Regardless of the presence or absence of preclinical or clinical signals of cardiovascular risk, the guidance has been applied broadly to all new diabetes drugs, creating substantial challenges in the drug development and approval process.

On June 5 and 6, 2013, the FDA held a joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee (on which we serve) and the Drug Safety and Risk Management Advisory Committee to further evaluate the cardiovascular safety of rosiglitazone. When rosiglitazone was approved in Europe, the European Medicines Agency raised concern about the cardiovascular risks of the thiazolidinedione class, including fluid retention, heart failure, and increased levels of low-density lipoprotein cholesterol. This concern led to a postmarketing requirement that cardiovascular-outcome trials be conducted for both pioglitazone and rosiglitazone, and these were reviewed at subsequent FDA meetings. Although the results of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study (NCT00379769) did not suggest an increased risk of MACE,4issues with trial design and data integrity led the FDA to require the sponsor to perform an independent readjudication of the data. This extensive exercise, performed by the Duke Clinical Research Institute, had a minimal effect on the overall point estimates and confidence intervals for MACE, which remained at less than 1.30. The result was consistent with the FDA guidance and provided reassurance that rosiglitazone was not associated with excess cardiovascular risk.

Two groups of authors (Scirica et al. and White et al.) now report in the Journal the results of large, placebo-controlled, cardiovascular-outcome trials, these involving saxagliptin and alogliptin, members of the incretin drug class. Neither of these drugs had shown increased cardiovascular risk in its development program. Both trials were designed to first rule out excess cardiovascular risk by means of noninferiority testing; if that was shown, superiority testing followed, on the assumption that better glycemic control might yield cardiovascular benefit. Both trials clearly met the FDA 2008 guidance for cardiovascular safety, but neither showed a reduction in cardiovascular events. Saxagliptin was associated with an unexpected increased risk of hospitalization for heart failure and a high frequency of hypoglycemia. Neither trial showed any increased risk of pancreatic adverse events, including cancer.

Before rosiglitazone, the cardiovascular safety of diabetes drugs had not been well studied. The initial concern with rosiglitazone arose from observational and case–control epidemiologic studies that generated a legitimate signal of possible cardiovascular harm, but every study had substantial methodologic shortcomings, including multiplicity, which meant that a statistically positive finding might be a false positive result.5 Meta-analyses were also performed with preapproval studies that had been designed to show a positive glycemic effect as the primary end point. These studies enrolled patients at low cardiovascular risk, were short in duration, used both placebo and active controls, and did not prospectively adjudicate cardiovascular safety events. In such situations, comparison of a new drug with an active agent is challenged by the uncertain cardiovascular risk of the active comparator. In contrast, a placebo-controlled design may lead to imbalances in background therapy (as was the case with saxagliptin) that could influence the cardiovascular outcomes. Meta-analyses of these premarketing trials from phase 3 development programs were therefore relatively insensitive in assessing cardiovascular risk, making dedicated postmarketing cardiovascular-outcome trials such as the RECORD study necessary to substantiate any risk signals. But the design of the RECORD study had substantial limitations that precluded a complete assessment of the cardiovascular safety of rosiglitazone.

In 2010, the FDA took a cautious stance and limited exposure to rosiglitazone, given the numerous alternative therapies that were available. But this position did not acknowledge the uncertainty of cardiovascular risk associated with other diabetes drugs on the market, and the FDA decision may have had unintended consequences. The intense publicity about the ischemic cardiac risk of rosiglitazone may have diverted attention from the better-established risk of heart failure that is common to the drug class. Restricted access led patients to switch from rosiglitazone to other diabetes drugs of unproven cardiovascular safety. Patients who had a myocardial infarction while taking rosiglitazone may have concluded that the drug was the cause, adversely affecting their perceptions of their doctor, drug companies, and the FDA. And placing a hold on the TIDE trial, although arguably justifiable, prevented any further clarification of the cardiovascular risks or benefits of the thiazolidinedione drug class. The rosiglitazone experience also raises the question of how to define a regulatory standard for withdrawing drugs from the market. New drug approvals are based on “substantial evidence” of drug safety and efficacy. But there is little guidance on what constitutes substantial evidence of harm that is sufficient to justify market withdrawal or the imposition of severe market restrictions.

What have we learned from the rosiglitazone experience? Clearly, the presumed cardiovascular risks of rosiglitazone led to a major change in FDA policy regarding the approval of all new diabetes drugs. From a cardiovascular perspective, rosiglitazone, saxagliptin, and alogliptin appear to be relatively safe. It is disappointing, however, that neither intensive glycemic control nor the use of specific diabetes medications is associated with any suggestion of cardiovascular benefit. Thus the evidence does not support the use of glycated hemoglobin as a valid surrogate for assessing either the cardiovascular risks or the cardiovascular benefits of diabetes therapy.

Patients with type 2 diabetes and their physicians currently have numerous treatment options, and additional drugs are in development. Perhaps the recent experience with rosiglitazone will allow the FDA to become more targeted in its adjudication of the cardiovascular safety of new diabetes drugs, focusing the considerable resources needed to rule out a cardiovascular concern only on drugs with clinical or preclinical justification for that expenditure. New therapies targeting glycemic control may have cardiovascular benefit, but this has yet to be shown. The optimal approach to the reduction of cardiovascular risk in diabetes should focus on aggressive management of the standard cardiovascular risk factors rather than on intensive glycemic control.

Source: NEJM

 

r�a>�,� �b� n> At 2.5 years, the rate of repeat revascularization was less frequent in the immediate– and staged–preventive PCI groups combined, as compared with the group receiving no preventive PCI (11% and 33%, respectively), and there was a nonsignificant decrease in the rate of cardiac death (5% and 12%, respectively). These studies were limited by a lack of statistical power and a reliance on repeat revascularization as an outcome, which, as indicated above, may be subject to bias. However, the results of these studies are consistent with those of our study.

 

Current guidelines on the management of STEMI recommend infarct-artery-only PCI in patients with multivessel disease, owing to a lack of evidence with respect to the value of preventive PCI.2-5 This uncertainty has led to variations in practice, with some cardiologists performing immediate preventive PCI in spite of the guidelines, some delaying preventive PCI until recovery from the acute episode, and others limiting the procedure to patients with recurrent symptoms or evidence of ischemia. The results of this trial help resolve the uncertainty by making clear that preventive PCI is a better strategy than restricting a further intervention to those patients with refractory angina or a subsequent myocardial infarction. However, our findings do not address the question of immediate versus delayed (staged) preventive PCI, which would need to be clarified in a separate trial.

Several questions remain. First, are the benefits of preventive PCI applicable to patients with non-STEMI?21 Such patients tend to be difficult to study because, unlike those with STEMI (in whom the infarct artery is invariably identifiable), there is often uncertainty over which artery is the culprit. Second, do the benefits extend to coronary-artery stenoses of less than 50%? There is uncertainty over the level of stenosis at which the risks of PCI outweigh the benefits. Third, would a physiological measure of blood flow, such as fractional flow reserve,22,23 offer an advantage over angiographic visual assessment in guiding preventive PCI? Further research is needed to answer these questions.

In conclusion, in this randomized trial, we found that in patients undergoing emergency infarct-artery PCI for acute STEMI, preventive PCI of stenoses in noninfarct arteries reduced the risk of subsequent adverse cardiovascular events, as compared with PCI limited to the infarct artery.

 

Source: NEJM

 

 

 

Randomized Trial of Preventive Angioplasty in Myocardial Infarction.

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Patients with acute ST-segment elevation myocardial infarction (STEMI) are effectively treated with emergency angioplasty, hereafter called percutaneous coronary intervention (PCI), to restore blood flow to the coronary artery that is judged to be causing the myocardial infarction (infarct artery, also known as culprit artery).1-5 These patients may have major stenoses in coronary arteries that were not responsible for the myocardial infarction,6 but the value of performing PCI in such arteries for the prevention of future cardiac events is not known.

Some physicians have taken the view that stenoses in noninfarct arteries may cause serious adverse cardiac events that could be avoided by performing preventive PCI during the initial procedure.7-12Others have suggested that medical therapy with antiplatelet, lipid-lowering, and blood-pressure–lowering drugs is sufficient and that the risks of preventive PCI outweigh the benefits.2-4,13-17

The aim of our single-blind, randomized study, called the Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) trial, was to determine whether performing preventive PCI as part of the procedure to treat the infarct artery would reduce the combined incidence of death from cardiac causes, nonfatal myocardial infarction, or refractory angina.

DISCUSSION

The results of this trial show that in patients with acute STEMI, the use of preventive PCI to treat noninfarct coronary-artery stenoses immediately after PCI in the infarct artery conferred a substantial advantage over not performing this additional procedure. The combined rate of cardiac death, nonfatal myocardial infarction, or refractory angina was reduced by 65%, an absolute risk reduction of 14 percentage points over 23 months. The effect was similar in magnitude and remained highly significant when the analysis was limited to cardiac death and nonfatal myocardial infarction.

In this trial, all decisions regarding the treatment of patients, other than the random assignments to the two study groups, were left to the discretion of the clinicians involved. The rates of use of drug-eluting stents and medical therapy were similar in the two groups. In the group receiving no preventive PCI, ischemia testing was performed in about one third of patients: 44 tests in asymptomatic patients (usually ≤6 weeks after the myocardial infarction) and 37 tests in patients with chest pain. In the preventive-PCI group, ischemia testing was performed in about one sixth of patients: 8 tests in asymptomatic patients and 31 tests in patients with chest pain. Although such testing was not a prespecified trial outcome, these findings suggest that preventive PCI may lead to less ischemia testing and that when such testing is performed, it tends to be in patients with symptoms.

Although refractory angina is a more subjective outcome than myocardial infarction or cardiac death, it was included as a component of the primary outcome because it is a serious symptomatic condition that warrants prevention. We sought to reduce bias in the assessment of this outcome by requiring that the diagnosis be confirmed with objective evidence of ischemia. The benefit of preventive PCI was also evident when the less subjective outcomes of cardiac death and nonfatal myocardial infarction were considered alone.

We decided against using revascularization as a primary outcome, since subsequent revascularization procedures could be prompted by the identification of stenosis in a noninfarct artery in the group receiving no preventive PCI during the initial procedure. This factor would also tend to underestimate the effect of preventive PCI on primary-outcome events by reducing the treatment difference between the two study groups. However, revascularization was retained as a secondary outcome to record the number of subsequent procedures in each group.

In our study, 13 patients did not receive their assigned treatment. In the group receiving no preventive PCI, 2 patients underwent PCI in a noninfarct artery (1 for unknown reasons and 1 because the operator treated what turned out to be a noninfarct right coronary artery and then had to treat the infarct circumflex artery). In the preventive-PCI group, 11 patients underwent PCI only in the infarct artery because the preventive PCI could not be completed owing to insufficient time (because of competing emergency PCIs) in 3 patients, failure of the noninfarct-artery PCI in 5 patients, and other complications in 3 patients. These deviations from the assigned treatment mean that the intention-to-treat analysis, adopted to ensure comparability of the two study groups, will tend to underestimate the benefit of preventive PCI. However, the results of the as-treated analysis were consistent with those of the intention-to-treat analysis.

In two other randomized trials, investigators have specifically assessed the value of preventive PCI in patients with acute STEMI undergoing PCI in the infarct artery. In one study, 69 patients were randomly assigned (in a 3:1 ratio) to preventive PCI (52 patients) or no preventive PCI (17 patients).20 At 1 year, in the preventive-PCI group, there were nonsignificant reductions in the rates of repeat revascularization (17% and 35%, respectively) and cardiac death or myocardial infarction (4% and 6%, respectively). In the other trial, 214 patients were randomly assigned to one of three groups: no preventive PCI (84 patients), immediate preventive PCI (65 patients), and staged preventive PCI performed during a second procedure about 40 days later (65 patients).7 At 2.5 years, the rate of repeat revascularization was less frequent in the immediate– and staged–preventive PCI groups combined, as compared with the group receiving no preventive PCI (11% and 33%, respectively), and there was a nonsignificant decrease in the rate of cardiac death (5% and 12%, respectively). These studies were limited by a lack of statistical power and a reliance on repeat revascularization as an outcome, which, as indicated above, may be subject to bias. However, the results of these studies are consistent with those of our study.

Current guidelines on the management of STEMI recommend infarct-artery-only PCI in patients with multivessel disease, owing to a lack of evidence with respect to the value of preventive PCI.2-5 This uncertainty has led to variations in practice, with some cardiologists performing immediate preventive PCI in spite of the guidelines, some delaying preventive PCI until recovery from the acute episode, and others limiting the procedure to patients with recurrent symptoms or evidence of ischemia. The results of this trial help resolve the uncertainty by making clear that preventive PCI is a better strategy than restricting a further intervention to those patients with refractory angina or a subsequent myocardial infarction. However, our findings do not address the question of immediate versus delayed (staged) preventive PCI, which would need to be clarified in a separate trial.

Several questions remain. First, are the benefits of preventive PCI applicable to patients with non-STEMI?21 Such patients tend to be difficult to study because, unlike those with STEMI (in whom the infarct artery is invariably identifiable), there is often uncertainty over which artery is the culprit. Second, do the benefits extend to coronary-artery stenoses of less than 50%? There is uncertainty over the level of stenosis at which the risks of PCI outweigh the benefits. Third, would a physiological measure of blood flow, such as fractional flow reserve,22,23 offer an advantage over angiographic visual assessment in guiding preventive PCI? Further research is needed to answer these questions.

In conclusion, in this randomized trial, we found that in patients undergoing emergency infarct-artery PCI for acute STEMI, preventive PCI of stenoses in noninfarct arteries reduced the risk of subsequent adverse cardiovascular events, as compared with PCI limited to the infarct artery.

 

Source: NEJM

 

 

 

Dabigatran versus Warfarin in Patients with Mechanical Heart Valves.

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Prosthetic heart-valve replacement is recommended for many patients with severe valvular heart disease and is performed in several hundred thousand patients worldwide each year.1 Mechanical valves are more durable than bioprosthetic valves2 but typically require lifelong anticoagulant therapy. The use of vitamin K antagonists provides excellent protection against thromboembolic complications in patients with mechanical heart valves3 but requires restrictions on food, alcohol, and drugs and lifelong coagulation monitoring. Because of the limitations of vitamin K antagonists, many patients opt for a bioprosthesis rather than a mechanical valve, despite the higher risk of premature valve failure requiring repeat valve-replacement surgery with bioprostheses.

Dabigatran etexilate (dabigatran) is an oral direct thrombin inhibitor that was shown to be effective as an anticoagulant in the treatment of patients with atrial fibrillation in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study.4-6 Prompted by these data and the promising results of studies in animals, which showed the efficacy of dabigatran in preventing valve thrombosis,7-9 we conducted the Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement (RE-ALIGN). The primary aim of RE-ALIGN was to validate a new regimen for the administration of dabigatran to prevent thromboembolic complications in patients with mechanical heart valves

DISCUSSION

The primary goal of RE-ALIGN was to validate a new dabigatran dosing regimen for the prevention of thromboembolic complications in patients with mechanical heart valves. However, the trial was stopped early because of an excess of thromboembolic and bleeding events in the dabigatran group, as compared with the warfarin group. Most thromboembolic events among patients in the dabigatran group occurred in population A (patients who had started a study drug within 7 days after valve surgery), with fewer occurring in population B (patients who had undergone valve implantation more than 3 months before randomization). Excess bleeding events among patients receiving dabigatran occurred in the two study populations.

Possible explanations for the increase in thromboembolic complications with dabigatran include inadequate plasma levels of the drug and a mechanism of action that differs from that of warfarin. Trough plasma levels of dabigatran in population A were lower during the first few weeks after surgery than they were subsequently, and low drug levels soon after valve surgery may have allowed for early formation of blood clots that were not clinically manifested until later. However, thromboembolic events also occurred among patients with higher trough plasma levels of dabigatran early after surgery and among those in population B who had higher plasma levels than those in population A, suggesting that lower-than-expected drug levels cannot fully explain the increase in the rate of thromboembolic events.

The choice of a target trough plasma level of 50 ng of dabigatran per milliliter was primarily based on data from the RE-LY trial, in which dabigatran at a dose of 150 mg twice daily, as compared with warfarin, had superior efficacy and similar safety in patients with atrial fibrillation. We cannot exclude the possibility that targeting a higher trough level of dabigatran would have been more effective for the prevention of thromboembolic complications. At the same time, it is likely that the use of higher dabigatran doses would have led to unacceptably high bleeding rates, since dabigatran caused excess bleeding at the doses studied. It is also possible that more frequent administration of dabigatran (e.g., three times a day) without an increase in the total daily dose might have resulted in higher trough and lower peak levels, thereby increasing antithrombotic efficacy and reducing bleeding, but this approach was not tested.

Differences in the mechanisms of action of dabigatran and warfarin may also in part explain our findings. In patients with atrial fibrillation, thrombi form in the left atrial appendage under low-flow, low-shear conditions in which thrombin generation is believed to be triggered by stasis and endothelial dysfunction.19 In contrast, in patients with a mechanical heart valve, coagulation activation and thrombin generation induced by the release of tissue factor from damaged tissues during surgery may partly explain the high risk of early thromboembolic complications. In addition, thrombin generation can be triggered by exposure of the blood to the artificial surface of the valve leaflets and sewing ring, which induce activation of the contact pathway of coagulation. The majority of thrombi in patients with prosthetic heart valves appear to arise from the sewing ring,20 which does not undergo endothelialization for at least several weeks after surgery. It is thought that the sewing ring becomes less thrombogenic once endothelial tissue has formed around it. Warfarin is likely to be more effective than dabigatran at suppressing coagulation activation because it inhibits the activation of both tissue factor–induced coagulation (by inhibiting the synthesis of coagulation factor VII) and contact pathway–induced coagulation by inhibiting the synthesis of factor IX), as well as inhibiting the synthesis of factor X and thrombin in the common pathway,21 whereas dabigatran exclusively inhibits thrombin.22 If contact activation is intense, the resulting thrombin generation may overwhelm local levels of dabigatran, which can lead to thrombus formation on the surface of the valve and related embolic complications.

RE-ALIGN was an open-label trial and thus subject to reporting biases. However, clinical outcomes were prespecified, objectively defined, and independently adjudicated by experts who were unaware of the study-group assignments, all factors that minimize the potential for bias.

The results of our study indicate that dabigatran is not appropriate as an alternative to warfarin for the prevention of thromboembolic complications in patients who require anticoagulation after the implantation of a prosthetic heart valve. The results may also be relevant to studies of other new oral anticoagulants in patients with mechanical heart valves. Like dabigatran, the direct factor Xa inhibitors are effective for stroke prevention in patients with atrial fibrillation,23,24 but these data cannot be extrapolated to patients with mechanical heart valves because the mechanisms of thrombosis are different. Rivaroxaban has been successfully tested for the prevention of thromboembolic complications associated with mechanical heart valves in preclinical studies,25 but our study did not provide evidence of the safety and efficacy of the selected dosing algorithm, despite favorable results of preclinical studies.7-9

In conclusion, the results of our phase 2 study indicate that at the doses tested, dabigatran was not as effective as warfarin for the prevention of thromboembolic complications in patients with mechanical heart valves and was associated with an increased risk of bleeding. These results might be explained by the relative inability of dabigatran to suppress activation of coagulation that occurs when blood is exposed to the artificial surfaces of the valve prosthesis. The use of dabigatran has no positive value and was associated with excess risk in patients with mechanical heart valves.

 

Source: NEJM

 

Pazopanib versus Sunitinib in Metastatic Renal-Cell Carcinoma.

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BACKGROUND

Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy.

METHODS

We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life.

RESULTS

Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22), meeting the predefined noninferiority margin (upper bound of the 95% confidence interval, <1.25). Overall survival was similar (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs. 55%), the hand–foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60%, vs. 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P<0.05 for all 11 comparisons).

CONCLUSIONS

Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib

Source: NEJM

10 Things That Need to Be Found on Your Daily To Do List.

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When my children were small I had to incessantly nag them to do the most obvious and mundane things that would ultimately prevent illness and promote health. I had to bribe them to brush their teeth, plead with them to take a bath, and practically beg them to eat their green vegetables. As they grew older, their resistance turned to habit, and they are now grown adults with the ability to “remember” these things on their own. As I reflect back however, I wonder if there weren’t a few less obvious things I could have reminded them to do on a daily basis.

Our lives are busy, and we focus on getting stuff done all day long. I have come to realize that even as adults we need to be reminded to do a few things that can truly effect how we live and feel. I guess we are never beyond needing a little nudge now and then, and it’s never too late to begin living with a sense of intention and purpose toward optimal health.

Here are 10 things you need to be doing every day to prevent, maintain and sustain your health and happiness.

1. Breath

It sounds crazy, but most of us definitely forget to breathe. Breath is supposed to happen without conscious attention, but none of us breathe deeply enough.  Our bodies are designed to pull our breathe deep into our diaphragms, but instead we breath shallowly neglecting our natural need to get air deep into our bodies. Remember to breathe deep into your belly every day to feed your body the oxygen it needs to work so hard for you.

2. Get Sunlight

Most of us are deficient in Vitamin D simply because we don’t get enough sunlight, and it’s hard to get this nutrient from food. If you find yourself saying, “Wow, I never made it outside today” then you need to make this more of a priority. Just putting your face into the sun for a few minutes will benefit your mood and your body. Feeling the warmth of the sun will lift your mood, and warm your heart.

3. Read

I hate to say it but blogs don’t count here. Reading words on a paper page exercises your eyes and enriches your soul. The very act of sitting down to read has its benefits because it forces you to take a time out. Even if it’s just a page before bed, reading is essential to the health of your mind and body. Reading is also a way to connect with others whether it’s reading a passage out loud to your partner, or sharing a bed time story with your children.

4. Eat

Skip lunch often? Eating in your car between appointments? The leisurely act of sitting down to a meal has become rare in our culture. Shoving food in our bodies while on the go leads to poor digestion, and increased stress. Take time out of your day to eat something delicious while mindfully paying attention. This will add nourishment to your body, while forcing you to pause and focus. Give yourself the time you deserve for a healthy meal each and every day.

5. Sleep

When you were little you most like had to be told to go to bed. Now that you are an adult, you need to hit the hay on your own without the nudging of a concerned parent. Everyone has a different level of required sleep, but even if you are a night owl, make sure you are sneaking in a nap to rejuvenate your cells, and replenish your energy. Too little sleep has been connected to illness, poor performance and irritability.

6. Laugh

Don’t let one day go by without laughing. Laughter has been scientifically proven to improve mood, increase emotional connection, and to release tension. If you aren’t around funny people, watch a clip from a movie or pick up a New Yorker and read the comics. You don’t have to wait for the “pee your pants” laugh-a-thon. Just a simple chuckle will do.

7. Connect

We are evolutionarily wired to be connected to others. When we don’t feel connected we become depressed and lonely. Make sure you are connecting with someone meaningful every day. Connecting through social media is great, but it doesn’t replace the positive effects of social connection we get in real time. If you have been “thinking about calling” a friend, do it. Or talk to a stranger in line getting coffee. Reach out and reap the benefits of social interaction on a daily basis.

8. Journal

You may think that journals are for tween girls, but writing in a private notebook has benefits. The act of writing accesses your left-brain, which is analytical and rational. While your left-brain is occupied, your right brain is free to create, intuit and feel. Journaling is also great for getting thoughts out of your head, and can help you work through difficult emotions.

9. Exercise

Exercising daily is essential for your health. It’s easy to make excuses about why you can’t do it, but to maintain your mood and a positive perspective on life you need to get moving. Taking the stairs, stretching at your desk and walking around the block all count. You will love those endorphins once they kick in.

10. Pray

Prayer is a healing and healthy habit that doesn’t always have to be associated with religion. Prayer is about expressing gratitude, and silently sharing wishes and hopes for yourself and others. Even if it’s thoughts in your head that don’t cross your lips, a poem that offers meaning or the lyrics to a song you love, you can turn it into a prayer. Try adding a small prayer to your daily routine, and watch as it manifests in the world.

Source: purposefairy.com

How To Find and Keep Your Balance.

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Happiness is not a matter of intensity but of balance, order, rhythm and harm. ~Thomas Merton

When our resilience is low it’s often because we’re focussing our energies on one area of our lives over the others – usually some stressful event, work, or a collection of things that are taxing. What goes out of the window are the counter balancers – the things that are soothing, the slow, the easy going, the nourishing.

BALANCEEE

I once had an amazing yoga teacher who would change the focus of her classes each week. We’d never know what each class’s emphasis would be until we got there so there was always an air of excitement and anticipation as to what we’d find.

Sometimes they would be 2 hour, intense workouts that would leave us drenched in sweat with muscles crying out for their Mummy’s.

Other times she would have us do laughing yoga and headstands against the wall like when we were at school.

And at other times the movements would be so gentle, the poses held for so long that it was almost like we were working in slow motion; languid, soothing and elastic.

One thing I remember her talking about was the fact that yoga is all about balance – when we stretch one side of the body we must stretch the other or our muscles will be out of whack. When we’re energetic one day, we must be calm another.

But in our modern lives we don’t get this. We get overwhelmed, run on empty or adrenaline long past the point where every fibre of our bodies is telling us to cool it, take a break, have a rest. We tell ourselves we can’t just yet, we will when we get the chance, once things calm down, as soon as this project’s out of the way, after the holidays, when I’m earning a bit more money ….etc.

We all know what it’s like to have a vacation and immediately fall ill. We know what it’s like to spend our vacations feeling so exhausted we can barely function, or to spend the first week getting into the ‘zone’ of not being on the go all the time, only to spend the second week getting revved up for it again.

If sounds like you then I have news for you – you’re completely out of balance.

Just like in yoga, our minds need periods of activity and calm. We need to feel inspired and totally unplugged at different times. Think of it like an elastic band – if you keep it taut all the time it’s eventually going to snap. But if you stretch and release, stretch and release, it will last a lifetime.

What You Can Do

What are you doing to stay busy that you could drop right now? Be honest with yourself – do the kitchen cupboards need to be washed down every day? Do you need to iron the underwear (I mean, who’d know if you didn’t?) How many calls do you make or emails you write that make no real contribution to you productivity and output?

Here’s another question to ask yourself – if you we suddenly told you were invited onto the Oprah show/Top Gear/X-factor (delete depending on which one rocks your boat the most!) but had to be on a plan by lunchtime tomorrow to get there – what would you drop from your schedule? What could you delegate/postpone/outsource? Of the things you definitely HAD to do, how much more quickly would you get them done if you knew you only had a limited timescale?

What would you do with an extra hour a day?

What would you do if you ONLY had one hour a day? (This will help you get super focused on what’s really essential to you.)

Imagine you’re looking back one year from now. What would you regret not doing more/less of?

Once you have the answers to these questions list 3 things you are GOING TO DO in the next 7 days to get more balance in your life and if you feel comfortable, share them with us in the comment section bellow. It could be doing less housework, spending more time in nature, eating out for dinner once per week so that you’ve some extra time with your family.

Theory is great but if you don’t put some of it into action it’s for nothing – and nothing will change. So choose 3 things, share them with us if you feel comfortable in the comment section bellow, commit to them and regain your equilibrium.

Source: purposefairy.com