Wall Street Journal - July 20, 2007
Novartis’s Hypertension Combo Works, With Risks
When you sell as many blood pressure drugs as Novartis, it’s natural to get creative, mixing and matching medicines to create new combinations.
But while combinations may lower blood pressure more effectively than a single drug, they may also heighten risk, as a [1] study published in this week’s Lancet shows.
The company’s blood pressure drugs already include single agents Tekturna and Diovan, as well as combination pills Exforge and Lotrel. (For an analysis of the sales of all these drugs, see [2] this Health Blog post.)
The new study enrolled 1797 patients and compared a combination of Tekturna and Diovan against each drug individually and against placebo. Diastolic blood pressure (the second number in a blood pressure reading) went down an average of 12.2 millimeters of mercury for patients who received the combination, compared with 9.7 mm Hg for Diovan, 9.0 mm Hg for Tekturna and 4.1 mm Hg for placebo. The study was funded by Novartis, which also paid medical writers to edit the manuscript.
The authors note that the percentage of patients with a high level of potassium in the blood was higher for patients who received the combination — 4%, compared with 3% for placebo and 2% for each of the single drugs. But they point out that the increase was not associated with serious medical problems and tended to return to normal by the study’s eight-week endpoint.
“Physicians have managed these mild increases in potassium very successfully for over 20 years,” the study’s [3] lead author, Suzanne Oparil of the University of Alabama Birmingham, said in a [4] statement issued by Novartis.
But a [5] commentary accompanying the study strikes a more cautious note about the heightened potassium levels, which, the authors note, can be associated with severe complications including paralysis and cardiac arrest. (One of the commentary’s authors, Willem H Birkenhäger of Erasmus University Rotterdam, claims no conflicts of interest; the other, Jan A Staessen of University of Leuven, reports funding from AstraZeneca and Pfizer, among other companies.)
The commentary argues that there may be a small group of patients suited to the Tekturna-Diovan combination. “However,” they conclude, “because of the potential life-threatening side-effects, which require biochemical monitoring, this concept of treatment is unlikely to make it to general practice or even to primary prevention in specialist care.”
Showing posts with label Pharmacology. Show all posts
Showing posts with label Pharmacology. Show all posts
Friday, July 20, 2007
Thursday, July 12, 2007
Beta-Blockers and Coronary Artery Disease
Beta-Blockers Slow, Even Reverse Coronary Artery Disease
Cleveland Clinic Study Shows - 12 Jul 2007
A Cleveland Clinic study is reporting that beta-blockers, a class of drugs used to lower blood pressure and prevent symptoms in a variety of heart conditions, can slow progression and can even induce regression of coronary artery disease.
The study appears in the July 3, 2007, issue of the Annals of Internal Medicine and suggests that all patients with coronary disease can benefit from this class of agents.
Coronary artery disease or clogging of vessels supplying the heart is one of the most common causes of death in the United States and other developed countries. Currently, more than 15 million Americans have coronary artery disease.
Researchers aimed to identify whether beta-blockers have any effect on progression of coronary disease in a group of more than 1,500 patients with this disease.
They began by measuring the amount of fatty plaque found in the arteries of these patients, using high-resolution intravascular ultrasound.
This required the insertion of tiny ultrasonic transducers in the coronary arteries to provide a baseline examination. Subsequently, the ultrasound examination was repeated after 18 to 24 months and the progression rate of coronary disease was compared in patients who were treated with beta-blockers and those who were not treated with these agents.
The researchers found that patients treated with beta-blockers had a significant reduction in the amount of fatty plaque at the follow-up examination, whereas those not on a beta-blocker experienced no change in the amount of plaque. "Our results have important implications," said Ilke Sipahi, M.D., F.A.C.C., a Cardiologist at the Cleveland Clinic and the study's lead author. "Up to now, we thought that beta-blockers were beneficial only to preserve heart muscle function in patients with a previous injury to their heart due to a heart attack. Now we learn that these drugs also have favorable effects on the coronary arteries by reducing clogging of these vessels in a similar fashion to cholesterol-lowering statin drugs. Our results indicate that all patients with coronary disease, such as those with coronary stents, previous bypass surgery and even patients with earlier stages of coronary artery disease can benefit from treatment with beta-blockers."
Thursday, June 28, 2007
Guidelines Updated for Treatment of Pulmonary Arterial Hypertension
Guidelines Updated for Treatment of Pulmonary Arterial Hypertension
June 19, 2007 — The American College of Chest Physicians provides an update of the evidence-based treatment recommendations for patients with pulmonary arterial hypertension. The new guidelines are published in the June issue of Chest.
"Pulmonary arterial hypertension (PAH), defined as a mean pulmonary artery pressure (PAPm) ≥ 25 mm Hg with a pulmonary capillary wedge pressure ≤ 15 mm Hg measured by cardiac catheterization, is a disorder that may occur either in the setting of a variety of underlying medical conditions or as a disease that uniquely affects the pulmonary circulation," write David B. Badesch, MD, FCCP, from the University of Colorado Health Sciences Center in Denver, and colleagues. "Irrespective of its etiology, PAH is a serious and often progressive disorder that results in right ventricular dysfunction and impairment in activity tolerance, and may lead to right-heart failure and death. The pathogenesis of PAH is complex and incompletely understood, but includes both genetic and environmental factors that alter vascular structure and function."
Since a consensus panel convened by the American College of Chest Physicians developed guidelines for PAH treatment that were published in 2004, several important clinical trials have been published and new treatments have received regulatory approval. Add-on and combination therapy are being explored as potential new therapeutic options.
These updated guidelines, taking into consideration studies published before September 1, 2006, provide a summary of the original guidelines, a discussion of new studies, and a revised treatment algorithm taking into account recent developments in therapy.
"Due to the complexity of the diagnostic evaluation required and the treatment options available, referral of patients with PAH to a specialized center continues to be strongly recommended," the authors write. "The pace of developments in the treatment for PAH has quickened, with several important clinical trials having been published over the past 2 years that have led to regulatory approval of newer drugs and experience with combinations of existing drugs. These advances are likely to impact on the way physicians should now approach the treatment of PAH."
The treatment algorithm provided summarizes the current approach to therapy for PAH, based on functional class. However, the authors note that functional class is difficult to quantify, may vary among patients and care providers, and may not always correlate with other indexes of disease severity, although it does correlate with outcome (in patients with IPAH [idiopathic PAH]).
When making decisions regarding treatment, one should therefore consider not only functional class but also cardiopulmonary hemodynamics, 6-minute walk distance, signs and symptoms of right-sided heart failure, adverse effect profile, and drug-drug interactions, as well as cost.
Functional class II: The only treatments currently approved for patients with PAH in functional class II are sildenafil and subcutaneous and intravenous treprostinil. Because of the ease of administration and relative efficacy, sildenafil may be the first choice for most of these patients. Clinical trials with sitaxsentan and ambrisentan have included patients with PAH in functional class II, and a trial with bosentan is ongoing. Patients should be encouraged to enroll in clinical trials.
Functional class III: For the treatment of patients with PAH in functional class III, there are now 5 drugs approved by the US Food and Drug Administration, in 3 therapeutic classes, allowing rational therapeutic decisions based on available evidence, knowledge of an individual patient's specific situation, clinical judgment, and patient preferences.
For patients with "early" PAH in functional class III, most experts now consider 1 of the 2 approved oral therapies (bosentan or sildenafil, listed in no specific order). When choosing between these agents, one should take into account relative toxicities (eg, patients with hepatic abnormalities may do better with sildenafil, whereas patients with ocular disease or recurrent epistaxis may do better with bosentan). Sildenafil is generally less expensive.
Patients with more advanced class III disease may need a prostanoid, such as intravenous epoprostenol or treprostinil, inhaled iloprost, or subcutaneous treprostinil. While awaiting additional evidence regarding the use of add-on and combination therapy, one might consider these in the context of enrollment into clinical trials.
Functional class IV: All currently labeled therapies are approved for patients with PAH in functional class IV. However, based on the quality of the evidence and the net risk-benefit profile, the guidelines strongly recommend intravenous epoprostenol as the treatment of choice. Most experts are familiar with how to titrate intravenous epoprostenol in the acute setting, and it has a rapid and predictable onset of action.
As experience with intravenous treprostinil is accumulating, this may be a suitable alternative to intravenous epoprostenol in some cases. Except for patients who refuse intravenous therapy or who are not capable of managing the complex delivery system, oral, subcutaneous, and inhaled agents should generally not be used as first-line therapy for patients with PAH in functional class IV.
"Recommendations regarding therapy obviously need to be applied in light of the individual patient's specific situation," the authors conclude. "The importance of a thorough diagnostic evaluation, looking for underlying causes and contributing factors, cannot be overemphasized. Educational efforts have contributed to improved recognition of PAH, facilitating earlier initiation of therapy [which] should contribute to better clinical outcomes."
Some of the authors have disclosed various financial relationships with pharmaceutical companies and organizations, including the National Institutes of Health, GlaxoSmithKline, United Therapeutics/LungRx, and Actelion. A complete listing of financial relationships is available in the original article.
Chest. 2007;131:1917-1928.
Clinical Context
PAH is defined by a mean pulmonary artery pressure of at least 25 mm Hg along with a pulmonary capillary wedge pressure of 15 mm Hg or less. PAH may be an intrinsic process within the pulmonary vasculature, or it may be secondary to other disease states such as connective tissue disease or congenital heart conditions.
The American College of Chest Physicians last published guidelines for the management of PAH in 2004. Since then, new research has mandated a rethinking of treatment of PAH. The current clinical practice guidelines highlight this research.
Study Highlights
An expert panel reviewed pertinent literature published prior to September 1, 2006, to shape the current guidelines. Only studies published in English were included, and the authors focused on trials of prostanoids, endothelin receptor antagonists, and phosphodiesterase inhibitors. The etiology of PAH was not considered in the decision whether to include a study in the literature review.
Patients with PAH and a favorable response to short-term vasodilator testing during cardiac catheterization, defined as a decrease in mean pulmonary artery pressure of at least 10 mm Hg to a level of 40 mm Hg or below, may be amenable to therapy with calcium channel blockers.
The authors recommend long-acting nifedipine or diltiazem along with amlodipine for this small subgroup of patients, but verapamil should be avoided. If the patient does not improve to functional class I or II following 3 months of treatment with calcium channel blockers, other therapy should be considered.
Treprostinil and sildenafil are indicated for the treatment of patients with PAH in functional class II. Because sildenafil is delivered orally and treprostinil via either the subcutaneous or intravenous route, sildenafil might be preferred by most patients. Trials of sitaxsentan, ambrisentan, and bosentan for patients with PAH in functional class II are underway.
Sildenafil or bosentan may be considered for patients with PAH in functional class III whose symptoms are not too severe. The authors recommend consideration of the toxicities of these agents in choosing treatment. Patients with headache, epistaxis, and ocular disease should avoid therapy with sildenafil if possible. Also, patients with liver disease should preferably not receive bosentan. Sildenafil is somewhat more affordable than bosentan.
Patients with more advanced PAH in functional class III should receive epoprostenol, treprostinil, or iloprost. There is little evidence regarding the benefits for combination therapy with different treatments if monotherapy is insufficient, and this management strategy may be considered in the context of enrollment into clinical trials.
The authors strongly recommend intravenous epoprostenol for the treatment of patients with PAH in functional class IV. Intravenous epoprostenol has a rapid and predictable onset of action, and many clinicians have good experiences with this medication. Evidence of the efficacy of intravenous treprostinil is increasing, and this medication may be considered as an alternative to epoprostenol. The use of oral, subcutaneous, or inhaled agents among patients with PAH in functional class IV is discouraged.
Pearls for Practice
Treprostinil and sildenafil are indicated for the treatment for patients with PAH in functional class II, and sildenafil may be the preferred agent because of ease of administration and cost.
Intravenous epoprostenol as the first-line treatment for patients with PAH in functional class IV is strongly recommended.
Friday, June 22, 2007
Lowering Blood Pressure Improves Diastolic Function, Regardless of Regimen
Lowering Blood Pressure Improves Diastolic Function, Regardless of Regimen
Reductions in blood pressure lead to improved diastolic function — regardless of the antihypertensive drugs used — reports a study in Lancet.
Researchers sought to determine whether the angiotensin-receptor blocker valsartan would be more effective than other antihypertensives at improving diastolic function. They randomized nearly 400 patients with hypertension and evidence of diastolic dysfunction to receive either the ARB or placebo. The patients also received other classes of antihypertensive agents to lower blood pressure to below 135/80 mm Hg.
After 38 weeks, tissue Doppler imaging showed improved diastolic function in both valsartan and placebo recipients, but there was no significant difference between the groups.
Authors of an accompanying commentary note that valsartan might have an advantage in patients with more advanced left ventricular remodeling. Nevertheless, they add, "the good news is that lowering blood pressure improves diastolic function, irrespective of the antihypertensive regimen used."
Lancet article (Free abstract with one-time registration; full text requires subscription)
Lancet comment (Subscription required)
ABSTRACT
The Lancet 2007; 369:2079-2087
Articles
Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: a randomised trial
Dr Scott D SolomonMD, et al
Summary
Background
Diastolic dysfunction might represent an important pathophysiological intermediate between hypertension and heart failure. Our aim was to determine whether inhibitors of the renin-angiotensin-aldosterone system, which can reduce ventricular hypertrophy and myocardial fibrosis, can improve diastolic function to a greater extent than can other antihypertensive agents.
Methods
Patients with hypertension and evidence of diastolic dysfunction were randomly assigned to receive either the angiotensin receptor blocker valsartan (titrated to 320 mg once daily) or matched placebo. Patients in both groups also received concomitant antihypertensive agents that did not inhibit the renin-angiotensin system to reach targets of under 135 mm Hg systolic blood pressure and under 80 mm Hg diastolic blood pressure. The primary endpoint was change in diastolic relaxation velocity between baseline and 38 weeks as determined by tissue doppler imaging. Analyses were done by intention to treat.
Findings
186 patients were randomly assigned to receive valsartan; 198 were randomly assigned to receive placebo. 43 patients were lost to follow-up or discontinued the assigned intervention. Over 38 weeks, there was a 12·8 (SD 17·2)/7·1 (9·9) mm Hg reduction in blood pressure in the valsartan group and a 9·7 (17·0)/5·5 (10·2) mm Hg reduction in the placebo group. The difference in blood pressure reduction between the two groups was not significant. Diastolic relaxation velocity increased by 0·60 (SD 1·4) cm/s from baseline in the valsartan group (p<0·0001) and 0·44 (1·4) cm/s from baseline in the placebo group (p<0·0001) by week 38. However, there was no significant difference in the change in diastolic relaxation velocity between the groups (p=0·29).
Interpretation
Lowering blood pressure improves diastolic function irrespective of the type of antihypertensive agent used.
Reductions in blood pressure lead to improved diastolic function — regardless of the antihypertensive drugs used — reports a study in Lancet.
Researchers sought to determine whether the angiotensin-receptor blocker valsartan would be more effective than other antihypertensives at improving diastolic function. They randomized nearly 400 patients with hypertension and evidence of diastolic dysfunction to receive either the ARB or placebo. The patients also received other classes of antihypertensive agents to lower blood pressure to below 135/80 mm Hg.
After 38 weeks, tissue Doppler imaging showed improved diastolic function in both valsartan and placebo recipients, but there was no significant difference between the groups.
Authors of an accompanying commentary note that valsartan might have an advantage in patients with more advanced left ventricular remodeling. Nevertheless, they add, "the good news is that lowering blood pressure improves diastolic function, irrespective of the antihypertensive regimen used."
Lancet article (Free abstract with one-time registration; full text requires subscription)
Lancet comment (Subscription required)
ABSTRACT
The Lancet 2007; 369:2079-2087
Articles
Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: a randomised trial
Dr Scott D SolomonMD, et al
Summary
Background
Diastolic dysfunction might represent an important pathophysiological intermediate between hypertension and heart failure. Our aim was to determine whether inhibitors of the renin-angiotensin-aldosterone system, which can reduce ventricular hypertrophy and myocardial fibrosis, can improve diastolic function to a greater extent than can other antihypertensive agents.
Methods
Patients with hypertension and evidence of diastolic dysfunction were randomly assigned to receive either the angiotensin receptor blocker valsartan (titrated to 320 mg once daily) or matched placebo. Patients in both groups also received concomitant antihypertensive agents that did not inhibit the renin-angiotensin system to reach targets of under 135 mm Hg systolic blood pressure and under 80 mm Hg diastolic blood pressure. The primary endpoint was change in diastolic relaxation velocity between baseline and 38 weeks as determined by tissue doppler imaging. Analyses were done by intention to treat.
Findings
186 patients were randomly assigned to receive valsartan; 198 were randomly assigned to receive placebo. 43 patients were lost to follow-up or discontinued the assigned intervention. Over 38 weeks, there was a 12·8 (SD 17·2)/7·1 (9·9) mm Hg reduction in blood pressure in the valsartan group and a 9·7 (17·0)/5·5 (10·2) mm Hg reduction in the placebo group. The difference in blood pressure reduction between the two groups was not significant. Diastolic relaxation velocity increased by 0·60 (SD 1·4) cm/s from baseline in the valsartan group (p<0·0001) and 0·44 (1·4) cm/s from baseline in the placebo group (p<0·0001) by week 38. However, there was no significant difference in the change in diastolic relaxation velocity between the groups (p=0·29).
Interpretation
Lowering blood pressure improves diastolic function irrespective of the type of antihypertensive agent used.
Estrogen therapy decreases coronary artery calcification
Estrogen therapy decreases coronary artery calcification
N Engl J Med 2007; 356: 2591-2602
MedWire News: Postmenopausal women receiving estrogen therapy have a lower build up of calcium plaque in their coronary arteries than women who do not take hormone replacement therapy (HRT), study findings show.
Calcified plaque in the coronary arteries is a marker for atheromatous plaque burden, and is predictive of future risk of cardiovascular events.
Results from the Women's Health Initiative (WHI) randomized trial of conjugated equine estrogens indicated a reduced need for coronary revascularization among women aged 50-59 years, but not older women, who were receiving estrogen compared with those on the placebo group.
JoAnn Manson (Harvard Medical School, Boston, Massachusetts, USA) and colleagues carried out a substudy shortly after the WHI trial ended to determine whether the coronary artery calcium burden differed according to group assignment among 1064 women, aged 50-59 years, after a mean of 7.4 years of treatment.
After trial completion, women receiving estrogen had lower mean coronary artery calcium scores than those receiving placebo, at 83.1 versus 123.1 (p=0.02).
Michael Mendelsohn and Richard Karas, from Tufts University School of Medicine, Boston, wrote in a related editorial that these findings support the "potentially beneficial cardiovascular effects of HRT in younger menopausal women receiving the therapy for symptoms."
They added, however, that "it remains important to continue to emphasize that HRT should not be considered as a strategy to prevent cardiovascular disease in women; there are proven therapies for cardiovascular disease that remain underused in women."
"Clear and striking" cardioprotective effect of estrogen in young women requires confirmation"
ABSTRACT
Estrogen Therapy and Coronary-Artery Calcification
JoAnn E. Manson, M.D., Dr.P.H., Matthew A. Allison, M.D., M.P.H., Jacques E. Rossouw, M.D., J. Jeffrey Carr, M.D., Robert D. Langer, M.D., M.P.H., Judith Hsia, M.D., Lewis H. Kuller, M.D., Dr.P.H., Barbara B. Cochrane, Ph.D., Julie R. Hunt, Ph.D., Shari E. Ludlam, M.P.H., Mary B. Pettinger, M.S., Margery Gass, M.D., Karen L. Margolis, M.D., M.P.H., Lauren Nathan, M.D., Judith K. Ockene, Ph.D., Ross L. Prentice, Ph.D., John Robbins, M.D., Marcia L. Stefanick, Ph.D., for the WHI and WHI-CACS Investigators
Background Calcified plaque in the coronary arteries is a marker for atheromatous-plaque burden and is predictive of future risk of cardiovascular events. We examined the relationship between estrogen therapy and coronary-artery calcium in the context of a randomized clinical trial.
Methods In our ancillary substudy of the Women's Health Initiative trial of conjugated equine estrogens (0.625 mg per day) as compared with placebo in women who had undergone hysterectomy, we performed computed tomography of the heart in 1064 women aged 50 to 59 years at randomization. Imaging was conducted at 28 of 40 centers after a mean of 7.4 years of treatment and 1.3 years after the trial was completed (8.7 years after randomization). Coronary-artery calcium (or Agatston) scores were measured at a central reading center without knowledge of randomization status.
Results The mean coronary-artery calcium score after trial completion was lower among women receiving estrogen (83.1) than among those receiving placebo (123.1) (P=0.02 by rank test). After adjustment for coronary risk factors, the multivariate odds ratios for coronary-artery calcium scores of more than 0, 10 or more, and 100 or more in the group receiving estrogen as compared with placebo were 0.78 (95% confidence interval, 0.58 to 1.04), 0.74 (0.55 to 0.99), and 0.69 (0.48 to 0.98), respectively. The corresponding odds ratios among women with at least 80% adherence to the study estrogen or placebo were 0.64 (P=0.01), 0.55 (P<0.001), and 0.46 (P=0.001). For coronary-artery calcium scores of more than 300 (vs. <10), the multivariate odds ratio was 0.58 (P=0.03) in an intention-to-treat analysis and 0.39 (P=0.004) among women with at least 80% adherence.
Conclusions Among women 50 to 59 years old at enrollment, the calcified-plaque burden in the coronary arteries after trial completion was lower in women assigned to estrogen than in those assigned to placebo. However, estrogen has complex biologic effects and may influence the risk of cardiovascular events and other outcomes through multiple pathways.
N Engl J Med 2007; 356: 2591-2602
MedWire News: Postmenopausal women receiving estrogen therapy have a lower build up of calcium plaque in their coronary arteries than women who do not take hormone replacement therapy (HRT), study findings show.
Calcified plaque in the coronary arteries is a marker for atheromatous plaque burden, and is predictive of future risk of cardiovascular events.
Results from the Women's Health Initiative (WHI) randomized trial of conjugated equine estrogens indicated a reduced need for coronary revascularization among women aged 50-59 years, but not older women, who were receiving estrogen compared with those on the placebo group.
JoAnn Manson (Harvard Medical School, Boston, Massachusetts, USA) and colleagues carried out a substudy shortly after the WHI trial ended to determine whether the coronary artery calcium burden differed according to group assignment among 1064 women, aged 50-59 years, after a mean of 7.4 years of treatment.
After trial completion, women receiving estrogen had lower mean coronary artery calcium scores than those receiving placebo, at 83.1 versus 123.1 (p=0.02).
Michael Mendelsohn and Richard Karas, from Tufts University School of Medicine, Boston, wrote in a related editorial that these findings support the "potentially beneficial cardiovascular effects of HRT in younger menopausal women receiving the therapy for symptoms."
They added, however, that "it remains important to continue to emphasize that HRT should not be considered as a strategy to prevent cardiovascular disease in women; there are proven therapies for cardiovascular disease that remain underused in women."
"Clear and striking" cardioprotective effect of estrogen in young women requires confirmation"
ABSTRACT
Estrogen Therapy and Coronary-Artery Calcification
JoAnn E. Manson, M.D., Dr.P.H., Matthew A. Allison, M.D., M.P.H., Jacques E. Rossouw, M.D., J. Jeffrey Carr, M.D., Robert D. Langer, M.D., M.P.H., Judith Hsia, M.D., Lewis H. Kuller, M.D., Dr.P.H., Barbara B. Cochrane, Ph.D., Julie R. Hunt, Ph.D., Shari E. Ludlam, M.P.H., Mary B. Pettinger, M.S., Margery Gass, M.D., Karen L. Margolis, M.D., M.P.H., Lauren Nathan, M.D., Judith K. Ockene, Ph.D., Ross L. Prentice, Ph.D., John Robbins, M.D., Marcia L. Stefanick, Ph.D., for the WHI and WHI-CACS Investigators
Background Calcified plaque in the coronary arteries is a marker for atheromatous-plaque burden and is predictive of future risk of cardiovascular events. We examined the relationship between estrogen therapy and coronary-artery calcium in the context of a randomized clinical trial.
Methods In our ancillary substudy of the Women's Health Initiative trial of conjugated equine estrogens (0.625 mg per day) as compared with placebo in women who had undergone hysterectomy, we performed computed tomography of the heart in 1064 women aged 50 to 59 years at randomization. Imaging was conducted at 28 of 40 centers after a mean of 7.4 years of treatment and 1.3 years after the trial was completed (8.7 years after randomization). Coronary-artery calcium (or Agatston) scores were measured at a central reading center without knowledge of randomization status.
Results The mean coronary-artery calcium score after trial completion was lower among women receiving estrogen (83.1) than among those receiving placebo (123.1) (P=0.02 by rank test). After adjustment for coronary risk factors, the multivariate odds ratios for coronary-artery calcium scores of more than 0, 10 or more, and 100 or more in the group receiving estrogen as compared with placebo were 0.78 (95% confidence interval, 0.58 to 1.04), 0.74 (0.55 to 0.99), and 0.69 (0.48 to 0.98), respectively. The corresponding odds ratios among women with at least 80% adherence to the study estrogen or placebo were 0.64 (P=0.01), 0.55 (P<0.001), and 0.46 (P=0.001). For coronary-artery calcium scores of more than 300 (vs. <10), the multivariate odds ratio was 0.58 (P=0.03) in an intention-to-treat analysis and 0.39 (P=0.004) among women with at least 80% adherence.
Conclusions Among women 50 to 59 years old at enrollment, the calcified-plaque burden in the coronary arteries after trial completion was lower in women assigned to estrogen than in those assigned to placebo. However, estrogen has complex biologic effects and may influence the risk of cardiovascular events and other outcomes through multiple pathways.
Drugs To Prevent Heart Complications During Surgery
Questions Over Drugs To Prevent Heart Complications During Surgery
The use of drugs to prevent heart complications during surgery is called into question in this week's BMJ.
Globally, about 100 million adults have non-cardiac surgery (ie. on any part of the body other than the heart) each year. Around 1% are at risk of cardiac complications, such as heart attacks and strokes, and about one in four will die each year.
Two types of drugs - Beta blockers and statins - are regularly given to patients to prevent such complications. They are given shortly before, during, or after surgery (the perioperative stage) to help lower blood pressure
But doctors in Australia now warn that the benefit of using these drugs at this time remains unclear.
They cite several large international studies that found no benefit from perioperative Beta blockers.
Two studies from Denmark and the UK reported no reduction in death or several other serious complications, such as heart attack, heart failure, and stroke 30 days after surgery in patients receiving Beta blockers. Another study found no benefit six months after surgery, and a trial currently underway has so far not reported any beneficial effects.
However, all studies did report significantly higher rates of important side effects with Beta blockers, including slow heart beat (bradycardia) and very low blood pressure (hypotension).
This has led to calls to examine the widespread use of perioperative Beta blocking drugs.
Like Beta blockers, statins have also been advocated to reduce the risk of perioperative cardiac complications, write the authors. Non-randomised trials suggest that statins confer benefit, but the evidence remains weak, and to prove a strong overall survival benefit would require a 'gold-standard' randomised controlled trial of more than 12,000 patients.
The benefits of statins in reducing cardiac complications in the general population and high risk patients are well known, but robust evidence to confirm that these drugs are valuable in routine perioperative use has not been published, they say.
So, on the basis of the evidence currently available, what should practising clinicians do?
They suggest that patients already receiving Beta blockers or statins before surgery should continue with treatment. But no patient should start taking statins or Beta blockers in the perioperative period specifically to reduce the likelihood of perioperative cardiac events.
Editorial: Beta blockers and statins in non-cardiac surgeryBMJ Volume 334 pp 1283-4http://www.bmj.com
Article URL: http://www.medicalnewstoday.com/medicalnews.php?newsid=74894
The use of drugs to prevent heart complications during surgery is called into question in this week's BMJ.
Globally, about 100 million adults have non-cardiac surgery (ie. on any part of the body other than the heart) each year. Around 1% are at risk of cardiac complications, such as heart attacks and strokes, and about one in four will die each year.
Two types of drugs - Beta blockers and statins - are regularly given to patients to prevent such complications. They are given shortly before, during, or after surgery (the perioperative stage) to help lower blood pressure
But doctors in Australia now warn that the benefit of using these drugs at this time remains unclear.
They cite several large international studies that found no benefit from perioperative Beta blockers.
Two studies from Denmark and the UK reported no reduction in death or several other serious complications, such as heart attack, heart failure, and stroke 30 days after surgery in patients receiving Beta blockers. Another study found no benefit six months after surgery, and a trial currently underway has so far not reported any beneficial effects.
However, all studies did report significantly higher rates of important side effects with Beta blockers, including slow heart beat (bradycardia) and very low blood pressure (hypotension).
This has led to calls to examine the widespread use of perioperative Beta blocking drugs.
Like Beta blockers, statins have also been advocated to reduce the risk of perioperative cardiac complications, write the authors. Non-randomised trials suggest that statins confer benefit, but the evidence remains weak, and to prove a strong overall survival benefit would require a 'gold-standard' randomised controlled trial of more than 12,000 patients.
The benefits of statins in reducing cardiac complications in the general population and high risk patients are well known, but robust evidence to confirm that these drugs are valuable in routine perioperative use has not been published, they say.
So, on the basis of the evidence currently available, what should practising clinicians do?
They suggest that patients already receiving Beta blockers or statins before surgery should continue with treatment. But no patient should start taking statins or Beta blockers in the perioperative period specifically to reduce the likelihood of perioperative cardiac events.
Editorial: Beta blockers and statins in non-cardiac surgeryBMJ Volume 334 pp 1283-4http://www.bmj.com
Article URL: http://www.medicalnewstoday.com/medicalnews.php?newsid=74894
Tuesday, June 19, 2007
Lipitor or simvastatin? - Lipitor is not superior
Pfizer Backtracks on Lipitor’s Edge Over Rival
Posted by Jacob Goldstein
Earlier this year, Pfizer issued a press release trumpeting an analysis that suggested the company’s cholesterol-lowering drug Lipitor helped patients more than simvastatin, a cheaper generic competitor originally sold by Merck as Zocor.
Today Pfizer filed a two-paragraph statement with the SEC explaining that those results were wrong. By the study’s primary measure of cardiovascular risks, patients who took Lipitor didn’t fare significantly better than those who took simvastatin.
That’s quite a rowback by Pfizer, which is fighting in the medical trenches to keep Lipitor sales humming. The March press release by Pfizer quoted a study author as saying the “analysis is important for physicians, employers and formulary directors at managed care companies who are making real-world treatment decisions for patients” because it “further supports the cardiovascular benefits previously seen with Lipitor.” There was no corrective press release issued today.
Generic simvastatin has been stealing market share from Lipitor since it became available last year.
The flawed study analyzed data from about 80,000 members of a managed care organization who had taken either Lipitor or simvastatin. The primary analysis compared the rate of serious cardiovascular problems, such as heart attacks and strokes, in patients who had been taking either drug for at least three months. The study found that, after adjusting for differences in doses of the medicines, the risk of cardiovascular events was 14% lower in patients who took Lipitor.
But according to the SEC filing today, “a subsequent review by the Company” found that the difference was in fact only 10% — not enough to be considered statistically significant, the standard test of scientific validity, Pfizer said.
The mistake was due to a “programming error” and came to light after the manuscript was submitted for publication in a medical journal, Pfizer spokeswoman Vanessa Aristide told the Health Blog this afternoon. Initial results from the study were presented at an American Heart Association epidemiology and prevention conference in March.
A secondary analysis included in the study looked at the difference between patients on Lipitor and simvastatin starting on the first day they took the drugs. That analysis found that Lipitor reduced cardiovascular risk by 26% more than simvastatin. The revised findings issued today said that difference was also lower than originally reported, but at 22% it was still enough to be statistically significant.
Update: We just got Pfizer senior vice president Michael Berelowitz on the phone. He explained that the mistake occurred because the initial analysis incorrectly included some data from 2005. The study was supposed to be limited to data from between 2002 and 2004.
The error was discovered while researchers were re-analyzing the data at the request of an expert who was reviewing the manuscript, which had been submitted for publication in a journal. Berelowitz declined to name the publication.
So is Lipitor superior to simvastatin or not, we asked? “We have clinical trial data and real-world data that are intriguing, and I think it should be followed up on,” said Berelowitz, citing a previous study, called IDEAL, that directly compared the two drugs. But that study also narrowly failed to show that Lipitor was superior to simvastatin in reducing heart attacks and heart-related deaths among patients who have already had heart attacks.
He wouldn’t say whether Pfizer is funding additional head-to-head studies of the two drugs. But he encouraged those who control the preferred-drug lists known as formularies to make the comparison for themselves. “People who make formulary decisions should look at their data and see how it plays out in their world.”
LINK: http://blogs.wsj.com/health/
Posted by Jacob Goldstein
Earlier this year, Pfizer issued a press release trumpeting an analysis that suggested the company’s cholesterol-lowering drug Lipitor helped patients more than simvastatin, a cheaper generic competitor originally sold by Merck as Zocor.
Today Pfizer filed a two-paragraph statement with the SEC explaining that those results were wrong. By the study’s primary measure of cardiovascular risks, patients who took Lipitor didn’t fare significantly better than those who took simvastatin.
That’s quite a rowback by Pfizer, which is fighting in the medical trenches to keep Lipitor sales humming. The March press release by Pfizer quoted a study author as saying the “analysis is important for physicians, employers and formulary directors at managed care companies who are making real-world treatment decisions for patients” because it “further supports the cardiovascular benefits previously seen with Lipitor.” There was no corrective press release issued today.
Generic simvastatin has been stealing market share from Lipitor since it became available last year.
The flawed study analyzed data from about 80,000 members of a managed care organization who had taken either Lipitor or simvastatin. The primary analysis compared the rate of serious cardiovascular problems, such as heart attacks and strokes, in patients who had been taking either drug for at least three months. The study found that, after adjusting for differences in doses of the medicines, the risk of cardiovascular events was 14% lower in patients who took Lipitor.
But according to the SEC filing today, “a subsequent review by the Company” found that the difference was in fact only 10% — not enough to be considered statistically significant, the standard test of scientific validity, Pfizer said.
The mistake was due to a “programming error” and came to light after the manuscript was submitted for publication in a medical journal, Pfizer spokeswoman Vanessa Aristide told the Health Blog this afternoon. Initial results from the study were presented at an American Heart Association epidemiology and prevention conference in March.
A secondary analysis included in the study looked at the difference between patients on Lipitor and simvastatin starting on the first day they took the drugs. That analysis found that Lipitor reduced cardiovascular risk by 26% more than simvastatin. The revised findings issued today said that difference was also lower than originally reported, but at 22% it was still enough to be statistically significant.
Update: We just got Pfizer senior vice president Michael Berelowitz on the phone. He explained that the mistake occurred because the initial analysis incorrectly included some data from 2005. The study was supposed to be limited to data from between 2002 and 2004.
The error was discovered while researchers were re-analyzing the data at the request of an expert who was reviewing the manuscript, which had been submitted for publication in a journal. Berelowitz declined to name the publication.
So is Lipitor superior to simvastatin or not, we asked? “We have clinical trial data and real-world data that are intriguing, and I think it should be followed up on,” said Berelowitz, citing a previous study, called IDEAL, that directly compared the two drugs. But that study also narrowly failed to show that Lipitor was superior to simvastatin in reducing heart attacks and heart-related deaths among patients who have already had heart attacks.
He wouldn’t say whether Pfizer is funding additional head-to-head studies of the two drugs. But he encouraged those who control the preferred-drug lists known as formularies to make the comparison for themselves. “People who make formulary decisions should look at their data and see how it plays out in their world.”
LINK: http://blogs.wsj.com/health/
Sunday, June 17, 2007
Aspirin Resistance
Landmark Study On Aspirin Resistance
Aspirin is used by millions of patients for the prevention and treatment of coronary artery disease, the single leading cause of death in the world. In the largest study to date on the effectiveness of aspirin, researchers at the Center for Thrombosis Research at Sinai Hospital of Baltimore recently demonstrated that aspirin resistance is rare, less than 5 percent, at all doses (81 mg, 162 mg and 325 mg) in patients with heart disease. The results of study were recently published in the June 11 issue of Circulation, a journal of the American Heart Association (DOI: 10.1161/CIRCULATIONAHA.106.675587).
Most coronary artery disease deaths are caused by platelets sticking together and forming blood clots (thrombosis) that block blood flow within arteries, resulting in a heart attack. By inhibiting clotting, aspirin keeps platelets from sticking together by specifically blocking an important enzyme, COX-1.
"The occurrence of clotting in patients taking aspirin therapy has been attributed to the failure of aspirin blocking its target and is a hot topic in cardiovascular disease today," said Paul Gurbel, MD, lead investigator for the study and director of the Center for Thrombosis Research at Sinai Hospital of Baltimore. "However, our data suggest that aspirin blocks COX-1 with high efficiency."
The team at the Center for Thrombosis Research at Sinai Hospital studied 125 patients with a history of coronary artery disease treated with aspirin. All patients were randomly placed on 81 mg, 162 mg and 325 mg of aspirin daily for four weeks each for a total of 12 weeks. Then the response to aspirin was tested by multitude methods. When measuring the ability of aspirin to block its target, COX-1, it was found highly effective at all dose levels.
"The research also shows that aspirin may be effective at blocking other pathways that promote platelet activation, independent of COX-1. Further research is now under way to better understand these additional pathways that may cause clotting in patients in an effort to continue to improve patient outcomes," said Gurbel.
This investigator-initiated study was funded by an unrestricted educational grant from Bayer HealthCare LLC and Sinai Hospital of Baltimore.
Tuesday, June 12, 2007
Prostate cancer therapy may worsen heart threat
Prostate cancer therapy may worsen heart threat
Men at high cardiac risk should remedy those problems before tumor treatment starts, researchers say.
June 9, 2007
Standard treatment for prostate cancer — shutting off the body's production of androgen hormones — can shorten by 2 1/2 years the lives of men who are at high risk of developing heart disease, Boston researchers reported Friday.
The drugs used to suppress the hormones produce anemia, weight gain and insulin resistance, a constellation of factors known as metabolic syndrome.
These effects can sharply increase the risk of a fatal heart attack, especially in men already at high risk, Dr. Anthony D'Amico of Brigham and Women's Hospital in Boston reported in the Journal of Clinical Oncology.
Because the drugs can slow or halt the progression of a prostate tumor, researchers are not advocating that physicians stop using them.
Instead, they say, prostate cancer patients should be screened for cardiovascular risk, and those with risk factors should be aggressively treated for their potential heart disease before cancer therapy begins.
The medical field has come to realize "in the last year or two that hormone therapy has cardiovascular side effects and we need to pay attention to it," said Dr. Eric Klein of the Cleveland Clinic, who was not involved in the study. "I've already changed my practice."
The risk factors, he added, "are correctable and need to be corrected before treatment or concurrently."
The new study grew from a clinical trial of androgen suppression conducted by D'Amico. "I observed that there were a few men receiving treatment who died quickly of a heart attack," he said.
The 206-man sample in his study was not large enough, so he combined his results with data from studies in Canada, Australia and New Zealand. That brought the total number of men to 1,372, about half of whom received both radiation and hormone suppression therapy and half of whom received only radiation.
During the five years the men were tracked, 51 had fatal heart attacks, half of whom had had hormone suppression therapy. But the older men who received the therapy suffered their heart attacks about 2 1/2 years earlier, on average, than those who had not received it.
The heart attacks "occurred within the first six months to two years after treatment," D'Amico said.
"There wasn't an increased number of heart attacks, it is just that they occurred sooner."
The heart attacks affected about 2.5% of the men receiving treatment, he said.
The primary risk factors were diabetes and smoking. Obesity, high cholesterol levels and high blood pressure were also predictive.
D'Amico said he had begun referring high-risk cardiac patients for therapy, which includes aspirin, cholesterol-lowering statins, angioplasty and, for some, open-heart surgery.
"Hormonal therapy in men who need it is lifesaving," he said. But the cure rate "could be even higher if we screen the appropriate men for coronary risk factors."
Experts noted that oncologists had previously used estrogen in prostate cancer patients to suppress androgen hormones, but that use was abandoned in the late 1980s when clinical trials showed an increase in the risk of heart attacks.
Men at high cardiac risk should remedy those problems before tumor treatment starts, researchers say.
June 9, 2007
Standard treatment for prostate cancer — shutting off the body's production of androgen hormones — can shorten by 2 1/2 years the lives of men who are at high risk of developing heart disease, Boston researchers reported Friday.
The drugs used to suppress the hormones produce anemia, weight gain and insulin resistance, a constellation of factors known as metabolic syndrome.
These effects can sharply increase the risk of a fatal heart attack, especially in men already at high risk, Dr. Anthony D'Amico of Brigham and Women's Hospital in Boston reported in the Journal of Clinical Oncology.
Because the drugs can slow or halt the progression of a prostate tumor, researchers are not advocating that physicians stop using them.
Instead, they say, prostate cancer patients should be screened for cardiovascular risk, and those with risk factors should be aggressively treated for their potential heart disease before cancer therapy begins.
The medical field has come to realize "in the last year or two that hormone therapy has cardiovascular side effects and we need to pay attention to it," said Dr. Eric Klein of the Cleveland Clinic, who was not involved in the study. "I've already changed my practice."
The risk factors, he added, "are correctable and need to be corrected before treatment or concurrently."
The new study grew from a clinical trial of androgen suppression conducted by D'Amico. "I observed that there were a few men receiving treatment who died quickly of a heart attack," he said.
The 206-man sample in his study was not large enough, so he combined his results with data from studies in Canada, Australia and New Zealand. That brought the total number of men to 1,372, about half of whom received both radiation and hormone suppression therapy and half of whom received only radiation.
During the five years the men were tracked, 51 had fatal heart attacks, half of whom had had hormone suppression therapy. But the older men who received the therapy suffered their heart attacks about 2 1/2 years earlier, on average, than those who had not received it.
The heart attacks "occurred within the first six months to two years after treatment," D'Amico said.
"There wasn't an increased number of heart attacks, it is just that they occurred sooner."
The heart attacks affected about 2.5% of the men receiving treatment, he said.
The primary risk factors were diabetes and smoking. Obesity, high cholesterol levels and high blood pressure were also predictive.
D'Amico said he had begun referring high-risk cardiac patients for therapy, which includes aspirin, cholesterol-lowering statins, angioplasty and, for some, open-heart surgery.
"Hormonal therapy in men who need it is lifesaving," he said. But the cure rate "could be even higher if we screen the appropriate men for coronary risk factors."
Experts noted that oncologists had previously used estrogen in prostate cancer patients to suppress androgen hormones, but that use was abandoned in the late 1980s when clinical trials showed an increase in the risk of heart attacks.
Sunday, June 10, 2007
Statins added to WHO list of “essential” drugs ??????
Colin Rose said:
Statins added to WHO list of “essential” drugs
June 8th, 2007
Well, it finally happened. The statin peddlers convinced WHO to add statins to the list of essential drugs.
But look at who was behind the initiative, Dr Gotto
Dr. Gotto receives many thousands of dollars from statin peddlers.
Here is a disclosure statement from a recent publication
“Antonio M. Gotto, Jr., MD, DPhil, serves as a consultant forAstraZeneca, Bristol-Myers Squibb, Johnson & Johnson-Merck, KosPharmaceuticals, Kowa, Merck & Co., Inc., Merck-Schering Plough,Novartis, Pfizer Inc, and Reliant Pharmaceuticals.”
Surely this should have been mentioned in the Cornell press release.
Personally, I refuse to take any advice from anyone who receives even one cent from a drug dealer.
I completely agree with Dr Kishore’s statement:
“Increasingly, ‘Western’ high-fat diets, tobacco use and urbanization havehelped make heart disease a bigger killer than ‘The Big Three’—HIV/AIDS,tuberculosis and malaria—combined.”
Indeed, high risk individuals have high risk lifestyles.
But the FIRST thing to do is change the diet and eliminate tobacco BEFORE labeling statins essential drugs. To do otherwise will reduce any incentive to improve lifestyle and make the obesity and diabetes pandemic even worse.
Do you think that the “developing” world is going to be happy with generic simvastatin? Not likely. They are going to start demanding patented Crestor and Vytorin, just like the rich Americans.
Cubans take no statins but live longer than Americans? If statins are not essential in Cuba, why should they be in Africa?
Link: http://panaceia-or-hygeia.com/medicalmyths/?p=12
Statins added to WHO list of “essential” drugs
June 8th, 2007
Well, it finally happened. The statin peddlers convinced WHO to add statins to the list of essential drugs.
But look at who was behind the initiative, Dr Gotto
Dr. Gotto receives many thousands of dollars from statin peddlers.
Here is a disclosure statement from a recent publication
“Antonio M. Gotto, Jr., MD, DPhil, serves as a consultant forAstraZeneca, Bristol-Myers Squibb, Johnson & Johnson-Merck, KosPharmaceuticals, Kowa, Merck & Co., Inc., Merck-Schering Plough,Novartis, Pfizer Inc, and Reliant Pharmaceuticals.”
Surely this should have been mentioned in the Cornell press release.
Personally, I refuse to take any advice from anyone who receives even one cent from a drug dealer.
I completely agree with Dr Kishore’s statement:
“Increasingly, ‘Western’ high-fat diets, tobacco use and urbanization havehelped make heart disease a bigger killer than ‘The Big Three’—HIV/AIDS,tuberculosis and malaria—combined.”
Indeed, high risk individuals have high risk lifestyles.
But the FIRST thing to do is change the diet and eliminate tobacco BEFORE labeling statins essential drugs. To do otherwise will reduce any incentive to improve lifestyle and make the obesity and diabetes pandemic even worse.
Do you think that the “developing” world is going to be happy with generic simvastatin? Not likely. They are going to start demanding patented Crestor and Vytorin, just like the rich Americans.
Cubans take no statins but live longer than Americans? If statins are not essential in Cuba, why should they be in Africa?
Link: http://panaceia-or-hygeia.com/medicalmyths/?p=12
Saturday, June 9, 2007
Low serum K tied to increased mortality risk in heart failure
Low serum K tied to increased mortality risk in heart failure
Hypokalemia is associated with an increased mortality risk independently of NYHA functional class, drugs used in therapy, and use of potassium supplements, according to a post hoc analysis of data from a randomized trial conducted in the 1990s.
Low serum potassium in HF may be caused by diuretic therapy or may be a marker of increased neurohormonal activity and disease progression according to the authors, who say their study has implications for contemporary HF management. Its findings argue against the use of diuretics in euvolemic patients with milder HF and for an emphasis on potassium-sparing diuretics in those with more symptomatic disease and volume overload, write Dr Ali Ahmed (University of Alabama, Birmingham) and associates.
Their analysis, which defined hypokalemia as a serum potassium <4 mEq/L, is based on patients followed for 32 months in the US-Canadian Digitalis Investigation Group (DIG) trial who had levels <5.5 mEq/L. The DIG trial, which predated the recommended use of beta blockers in heart failure, had entered patients with chronic systolic or diastolic HF of any etiology. The current report appears in the June 2007 issue of the European Heart Journal.
The cohort's 1187 patients with serum potassium <4 mEq/L were matched with the same number who had higher levels based on propensity scores encompassing a broad range of demographic, clinical, and treatment-related factors. Nearly all of those features became covariates in an analysis that showed low potassium to be independently associated with increased all-cause and cardiovascular mortality and death due to progressive HF. Similar but nonsignificant trends were seen for all-cause, cardiovascular, and MI- and stroke-related hospitalization.
Mortality risks associated with serum potassium <4 mEq/L in heart failure
ALL-CAUSE MORTALITY: HR 1.25 95% CI 1.07 – 1.46 p 0.006
CV MORTALITY: HR 1.27 95% CI 1.06 – 1.51 p 0.009
DEATH FROM PROGRESIVE HF: HR 1.36 95% CI 1.05 – 1.75 p 0.020
Hypokalemia hasn't been well defined in heart failure, although in the hypertension literature the definition has been variously said to be serum potassium of <3.5 mEg/L or <4.0 mEq/L, according to Ahmed. The current analysis supports a minimum of 4 mEq/L up to at least 5.5 mEq/L as the optimal safe range for HF patients, consistent with other proposals in the literature, he told heartwire.
Based on their findings and the established evidence base, Ahmed and his colleagues recommend the following treatment approaches:
Avoid diuretics in patients in NYHA class 1-2 who are receiving contemporary recommended drug therapy and have adequate fluid balance.
Patients in NYHA 3-4 heart failure with volume overload should receive diuretics, which could include spironolactone (or potentially eplerenone for post-MI patients) to help prevent hypokalemia.
Potassium supplements may be an alternative to aldosterone antagonists.
"But we think it might be safer to give spironolactone [instead of potassium supplements] because of its proven benefit in terms of reducing mortality," Ahmed said. "No one knows what potassium supplements will do [in heart failure]."
How relevant are findings based on the vintage DIG trial to today's generation of heart-failure patients who, unlike those in DIG, are taking beta blockers or are generally supposed to be taking them? Those drugs are grossly underused in heart failure today, Ahmed noted, observing that about one half of HF is chronic and only about one half of HF patients who should receive beta blockers actually get them. That, he said, would mean the drugs are today used in only about one fourth of HF patients and, therefore, the DIG analysis likely applies to about three fourths of heart failure today. "That's the way I look at it."
SOURCES:
Ahmed A, Zannad F, Love TE, et al. A propensity-matched study of the association of low serum potassium levels and mortality in chronic heart failure. Eur Heart J 2007;
Hypokalemia is associated with an increased mortality risk independently of NYHA functional class, drugs used in therapy, and use of potassium supplements, according to a post hoc analysis of data from a randomized trial conducted in the 1990s.
Low serum potassium in HF may be caused by diuretic therapy or may be a marker of increased neurohormonal activity and disease progression according to the authors, who say their study has implications for contemporary HF management. Its findings argue against the use of diuretics in euvolemic patients with milder HF and for an emphasis on potassium-sparing diuretics in those with more symptomatic disease and volume overload, write Dr Ali Ahmed (University of Alabama, Birmingham) and associates.
Their analysis, which defined hypokalemia as a serum potassium <4 mEq/L, is based on patients followed for 32 months in the US-Canadian Digitalis Investigation Group (DIG) trial who had levels <5.5 mEq/L. The DIG trial, which predated the recommended use of beta blockers in heart failure, had entered patients with chronic systolic or diastolic HF of any etiology. The current report appears in the June 2007 issue of the European Heart Journal.
The cohort's 1187 patients with serum potassium <4 mEq/L were matched with the same number who had higher levels based on propensity scores encompassing a broad range of demographic, clinical, and treatment-related factors. Nearly all of those features became covariates in an analysis that showed low potassium to be independently associated with increased all-cause and cardiovascular mortality and death due to progressive HF. Similar but nonsignificant trends were seen for all-cause, cardiovascular, and MI- and stroke-related hospitalization.
Mortality risks associated with serum potassium <4 mEq/L in heart failure
ALL-CAUSE MORTALITY: HR 1.25 95% CI 1.07 – 1.46 p 0.006
CV MORTALITY: HR 1.27 95% CI 1.06 – 1.51 p 0.009
DEATH FROM PROGRESIVE HF: HR 1.36 95% CI 1.05 – 1.75 p 0.020
Hypokalemia hasn't been well defined in heart failure, although in the hypertension literature the definition has been variously said to be serum potassium of <3.5 mEg/L or <4.0 mEq/L, according to Ahmed. The current analysis supports a minimum of 4 mEq/L up to at least 5.5 mEq/L as the optimal safe range for HF patients, consistent with other proposals in the literature, he told heartwire.
Based on their findings and the established evidence base, Ahmed and his colleagues recommend the following treatment approaches:
Avoid diuretics in patients in NYHA class 1-2 who are receiving contemporary recommended drug therapy and have adequate fluid balance.
Patients in NYHA 3-4 heart failure with volume overload should receive diuretics, which could include spironolactone (or potentially eplerenone for post-MI patients) to help prevent hypokalemia.
Potassium supplements may be an alternative to aldosterone antagonists.
"But we think it might be safer to give spironolactone [instead of potassium supplements] because of its proven benefit in terms of reducing mortality," Ahmed said. "No one knows what potassium supplements will do [in heart failure]."
How relevant are findings based on the vintage DIG trial to today's generation of heart-failure patients who, unlike those in DIG, are taking beta blockers or are generally supposed to be taking them? Those drugs are grossly underused in heart failure today, Ahmed noted, observing that about one half of HF is chronic and only about one half of HF patients who should receive beta blockers actually get them. That, he said, would mean the drugs are today used in only about one fourth of HF patients and, therefore, the DIG analysis likely applies to about three fourths of heart failure today. "That's the way I look at it."
SOURCES:
Ahmed A, Zannad F, Love TE, et al. A propensity-matched study of the association of low serum potassium levels and mortality in chronic heart failure. Eur Heart J 2007;
Friday, June 8, 2007
Blood-pressure changes with acupuncture comparable to ACE-inhibitor monotherapy
Blood-pressure changes with acupuncture comparable to ACE-inhibitor monotherapy
Erlangen, Germany - A study billed as the first rigorous, randomized trial in the West to test acupuncture against a sham needle technique to treat hypertension suggests that, performed properly, acupuncture may produce blood-pressure changes on a par with monotherapy in mild to moderate hypertension.
"It's certainly not like a wonder drug; it's not a massive effect, but it's a clear effect," lead investigator Dr Frank A Flachskampf (Universitätsklinikum Erlangen, Germany) told heartwire.
Smaller randomized trials have been performed in China, with mixed results, while one randomized study in the West found no difference in blood-pressure lowering between traditional Chinese acupuncture, standardized acupuncture, and a sham procedure, the authors note. This earlier study did not use ambulatory blood-pressure measurements, believed to be superior to office-based measurements.
Results of their study are published online June 4, 2007 in Circulation.
Needlework
For the study, 160 outpatients with uncomplicated, mild to moderate hypertension were randomized to six weeks of acupuncture performed by Chinese medicine practitioners, trained in China, or to a sham procedure. In both arms, patients underwent 22 sessions, each 30 minutes in length. By the end of the six weeks, 24-hour ambulatory systolic and diastolic blood pressures were significantly reduced from baseline in the acupuncture-treated patients (5.4 mm Hg and 3.0 mm Hg, respectively), and this change was also significantly different from values in the sham-treated patients, in whom no meaningful changes were seen.
After three and six months, however, the blood-pressure reductions disappeared, leading investigators to conclude that ongoing acupuncture treatments would be required to maintain the blood-pressure reductions.
"The main finding is that for the first time in a reasonably sized but still relatively small randomized study, this establishes beyond a reasonable doubt that acupuncture lowers blood pressure," Flachskampf commented. "It's a modest but undeniable effect on both systolic and diastolic blood pressure."
The extent of the blood-pressure reductions are comparable to those seen with ACE-inhibitor monotherapy or aggressive lifestyle changes, including radical salt restrictions, he added.
A "demanding" alternative to drugs
Flachskampf had some caveats, acknowledging that the regular acupuncture sessions used in the study represent a significant time investment: each acupuncture session lasted 30 minutes—not including transportation and administrative time—and took place several times a week. The study subjects were also reasonably healthy, with no other major risk factors and with only mild to moderate hypertension.
"This is clearly something that would probably not work as well with very sick people or people with blood pressure at dangerous levels," he said. "We cannot easily extrapolate to people, for example, with complicated hypertension who have had a myocardial infarction."
Flachskampf believes, however, that acupuncture likely represents an attractive option in specific patients, particularly those averse to taking medical therapy who are open to so-called "alternative" medicine.
"This is probably only for people who somehow relate to this spiritually, who say I am profoundly against taking drugs and I'm very fond of Oriental wisdom or things like that," Flachskampf told heartwire. "I don't want to make a joke about this, but this certainly needs more compliance than taking two or three pills a day. It's much more demanding."
Unlike drugs, acupuncture appeared to have few or no side effects, although two people complained that the needles were painful. "Clearly, many millions of Chinese get acupuncture without any major problems so I think this is really a minor point," Flachskampf observed.
Source:
Flachskampf FA, Gallasch J, Gefeller O, et al. Randomized trial of acupuncture to lower blood pressure. Circulation 2007; DOI: 10.1161/CIRCULATIONAHA.106.661140. Available at: http://www.theheart.org/viewDocument.do?document=http%3A%2F%2Fwww.circulationaha.org.
Erlangen, Germany - A study billed as the first rigorous, randomized trial in the West to test acupuncture against a sham needle technique to treat hypertension suggests that, performed properly, acupuncture may produce blood-pressure changes on a par with monotherapy in mild to moderate hypertension.
"It's certainly not like a wonder drug; it's not a massive effect, but it's a clear effect," lead investigator Dr Frank A Flachskampf (Universitätsklinikum Erlangen, Germany) told heartwire.
Smaller randomized trials have been performed in China, with mixed results, while one randomized study in the West found no difference in blood-pressure lowering between traditional Chinese acupuncture, standardized acupuncture, and a sham procedure, the authors note. This earlier study did not use ambulatory blood-pressure measurements, believed to be superior to office-based measurements.
Results of their study are published online June 4, 2007 in Circulation.
Needlework
For the study, 160 outpatients with uncomplicated, mild to moderate hypertension were randomized to six weeks of acupuncture performed by Chinese medicine practitioners, trained in China, or to a sham procedure. In both arms, patients underwent 22 sessions, each 30 minutes in length. By the end of the six weeks, 24-hour ambulatory systolic and diastolic blood pressures were significantly reduced from baseline in the acupuncture-treated patients (5.4 mm Hg and 3.0 mm Hg, respectively), and this change was also significantly different from values in the sham-treated patients, in whom no meaningful changes were seen.
After three and six months, however, the blood-pressure reductions disappeared, leading investigators to conclude that ongoing acupuncture treatments would be required to maintain the blood-pressure reductions.
"The main finding is that for the first time in a reasonably sized but still relatively small randomized study, this establishes beyond a reasonable doubt that acupuncture lowers blood pressure," Flachskampf commented. "It's a modest but undeniable effect on both systolic and diastolic blood pressure."
The extent of the blood-pressure reductions are comparable to those seen with ACE-inhibitor monotherapy or aggressive lifestyle changes, including radical salt restrictions, he added.
A "demanding" alternative to drugs
Flachskampf had some caveats, acknowledging that the regular acupuncture sessions used in the study represent a significant time investment: each acupuncture session lasted 30 minutes—not including transportation and administrative time—and took place several times a week. The study subjects were also reasonably healthy, with no other major risk factors and with only mild to moderate hypertension.
"This is clearly something that would probably not work as well with very sick people or people with blood pressure at dangerous levels," he said. "We cannot easily extrapolate to people, for example, with complicated hypertension who have had a myocardial infarction."
Flachskampf believes, however, that acupuncture likely represents an attractive option in specific patients, particularly those averse to taking medical therapy who are open to so-called "alternative" medicine.
"This is probably only for people who somehow relate to this spiritually, who say I am profoundly against taking drugs and I'm very fond of Oriental wisdom or things like that," Flachskampf told heartwire. "I don't want to make a joke about this, but this certainly needs more compliance than taking two or three pills a day. It's much more demanding."
Unlike drugs, acupuncture appeared to have few or no side effects, although two people complained that the needles were painful. "Clearly, many millions of Chinese get acupuncture without any major problems so I think this is really a minor point," Flachskampf observed.
Source:
Flachskampf FA, Gallasch J, Gefeller O, et al. Randomized trial of acupuncture to lower blood pressure. Circulation 2007; DOI: 10.1161/CIRCULATIONAHA.106.661140. Available at: http://www.theheart.org/viewDocument.do?document=http%3A%2F%2Fwww.circulationaha.org.
Thursday, June 7, 2007
FDA & GLITAZONES (AVANDIA and ACTOS)
FDA Asks for Black-Box Warning on Heart Failure Risk with Glitazones
In Congressional testimony yesterday, the FDA commissioner revealed that the agency has requested that the manufacturers of rosiglitazone (Avandia) and pioglitazone (Actos) add black-box warnings about the risk for heart failure with these drugs.
The commissioner indicated that the request was made because although the drugs currently carry warnings about potential heart failure, they are still sometimes prescribed to patients with this condition.
The request was only made public yesterday but was made to the companies on May 23, a couple of days after the publication of a meta-analysis that raised questions about the potential risk for heart attacks with rosiglitazone. The manufacturers have indicated that they are in negotiations with the agency over the new warnings.
Link: New York Times story (One-time registration required)
Link: Wall Street Journal story (Subscription required)
Link: Physician's First Watch coverage of interim analysis (Free)
Published in Physician's First Watch June 7, 2007
In Congressional testimony yesterday, the FDA commissioner revealed that the agency has requested that the manufacturers of rosiglitazone (Avandia) and pioglitazone (Actos) add black-box warnings about the risk for heart failure with these drugs.
The commissioner indicated that the request was made because although the drugs currently carry warnings about potential heart failure, they are still sometimes prescribed to patients with this condition.
The request was only made public yesterday but was made to the companies on May 23, a couple of days after the publication of a meta-analysis that raised questions about the potential risk for heart attacks with rosiglitazone. The manufacturers have indicated that they are in negotiations with the agency over the new warnings.
Link: New York Times story (One-time registration required)
Link: Wall Street Journal story (Subscription required)
Link: Physician's First Watch coverage of interim analysis (Free)
Published in Physician's First Watch June 7, 2007
Monday, June 4, 2007
Treatment-risk paradox
Treatment-risk paradox highlighted
04 June 2007
Arch Intern Med 2007; 167: 1009-1016; 1019-1025
MedWire News:
Two studies in the Archives of Internal Medicine highlight concerns that high-risk heart disease patients who are most likely to benefit from evidence-based therapy are the least likely to receive it.
Andrew Yan (University of Toronto, Ontario, Canada) and colleagues studied the use of in-hospital cardiac catheterization in relation to risk among non-ST-elevation acute coronary syndrome (NSTE-ACS) patients in the prospective, multicenter, Canadian ACS Registry 1 and Registry 2, which enrolled patients between 1999 and 2001 and 2002 and 2003, respectively.
The team stratified 4414 patients into low-, intermediate-, and high-risk groups based on tertiles of the Global Registry of Acute Coronary Events (GRACE) score.
The recommendation by the American College of Cardiology and American Heart Association of an early-invasive strategy in the management of NSTE-ACS patients appears to have been effective, with in-hospital use of cardiac catheterization increasing significantly from 38.8% in ACS Registry 1 to 63.5% in Registry 2 (p<0.001). color="#000099">In the second study, Finlay McAlister (University of Alberta, Edmonton, Canada) and team explored why clinicians are less likely to prescribe new therapies in low-risk than high-risk coronary artery disease (CAD) patients.
They studied 3871 patients diagnosed with CAD by angiography at three cardiac centers in Alberta between February 2004 and December 2005. The team defined patients as being at low, medium, or high risk according to the Duke Coronary Index.
The results showed that at 1 month after an angiogram, high-risk patients were less likely to be taking angiotensin-converting enzyme inhibitors, aspirin, and statins than lower-risk patients (25.8% vs 32.3%, odds ratio=0.73; risk ratio=0.80).
A similar relationship was seen across individual drug classes, although the strongest association was seen with statins.
However, adjusting for exertional capacity and depressive symptoms caused the relationship between risk and level and use of medications to almost completely disappear.
The authors report that there was no relationship between risk and symptom-relieving anti-anginal medications in unadjusted analyses and that it is therefore unlikely that clinicians preferentially avoid treating these patients. The more likely explanation, they say, is that patients who have depression, poor functional status, or both are less likely than those without to adhere to therapy.
"The treatment-risk paradox reported in administrative database analyses is attributable to clinical factors not typically captured in these databases," the authors write.
In an accompanying editorial, John Spertus and Mark Furman (University of Massachusetts, Worcester, USA) argued: "To overcome this paradox, what is needed is a transparent method for objectively calculating the risks of an adverse prognosis in our patients and, ideally, the expected benefits of treatment."
They said that barriers to the deployment of current models include: the complexity of employing multivariable regression models; the absence of data projecting the outcomes as a function of alternative treatment strategies; the limited range of meaningful outcomes predicted; and clinical inertia in substituting complex decision aids for anecdotal decision making.
They propose the creation of a national research agenda to "instill a new model of clinical practice."
Journal
04 June 2007
Arch Intern Med 2007; 167: 1009-1016; 1019-1025
MedWire News:
Two studies in the Archives of Internal Medicine highlight concerns that high-risk heart disease patients who are most likely to benefit from evidence-based therapy are the least likely to receive it.
Andrew Yan (University of Toronto, Ontario, Canada) and colleagues studied the use of in-hospital cardiac catheterization in relation to risk among non-ST-elevation acute coronary syndrome (NSTE-ACS) patients in the prospective, multicenter, Canadian ACS Registry 1 and Registry 2, which enrolled patients between 1999 and 2001 and 2002 and 2003, respectively.
The team stratified 4414 patients into low-, intermediate-, and high-risk groups based on tertiles of the Global Registry of Acute Coronary Events (GRACE) score.
The recommendation by the American College of Cardiology and American Heart Association of an early-invasive strategy in the management of NSTE-ACS patients appears to have been effective, with in-hospital use of cardiac catheterization increasing significantly from 38.8% in ACS Registry 1 to 63.5% in Registry 2 (p<0.001). color="#000099">In the second study, Finlay McAlister (University of Alberta, Edmonton, Canada) and team explored why clinicians are less likely to prescribe new therapies in low-risk than high-risk coronary artery disease (CAD) patients.
They studied 3871 patients diagnosed with CAD by angiography at three cardiac centers in Alberta between February 2004 and December 2005. The team defined patients as being at low, medium, or high risk according to the Duke Coronary Index.
The results showed that at 1 month after an angiogram, high-risk patients were less likely to be taking angiotensin-converting enzyme inhibitors, aspirin, and statins than lower-risk patients (25.8% vs 32.3%, odds ratio=0.73; risk ratio=0.80).
A similar relationship was seen across individual drug classes, although the strongest association was seen with statins.
However, adjusting for exertional capacity and depressive symptoms caused the relationship between risk and level and use of medications to almost completely disappear.
The authors report that there was no relationship between risk and symptom-relieving anti-anginal medications in unadjusted analyses and that it is therefore unlikely that clinicians preferentially avoid treating these patients. The more likely explanation, they say, is that patients who have depression, poor functional status, or both are less likely than those without to adhere to therapy.
"The treatment-risk paradox reported in administrative database analyses is attributable to clinical factors not typically captured in these databases," the authors write.
In an accompanying editorial, John Spertus and Mark Furman (University of Massachusetts, Worcester, USA) argued: "To overcome this paradox, what is needed is a transparent method for objectively calculating the risks of an adverse prognosis in our patients and, ideally, the expected benefits of treatment."
They said that barriers to the deployment of current models include: the complexity of employing multivariable regression models; the absence of data projecting the outcomes as a function of alternative treatment strategies; the limited range of meaningful outcomes predicted; and clinical inertia in substituting complex decision aids for anecdotal decision making.
They propose the creation of a national research agenda to "instill a new model of clinical practice."
Journal
Friday, June 1, 2007
Caution With All Pain Medications
Use Caution With All Pain Medications, Reports The 'Harvard Heart Letter'
Not long ago, choosing a pain reliever meant finding one that eased your pain without being too hard on the stomach. Now, research suggests that some commonly used pain medications -- not just the now-banned Vioxx -- can raise the risk of having a heart attack or stroke. New step-by-step recommendations from the American Heart Association (AHA) can help you choose a pain reliever that's good for both the heart and stomach, reports the June 2007 issue of the "Harvard Heart Letter."
The AHA suggests starting with aspirin or acetaminophen (Tylenol) to quell muscle or joint pain. Aspirin is good for the heart, and acetaminophen doesn't affect blood clotting. If they don't work, the next step for most people would be a nonsteroidal anti-inflammatory drug (NSAID). Try naproxen (Aleve) first, then ibuprofen (Advil). Next is diclofenac, but more caution is needed with this drug (which is available only by prescription). Celebrex, the only drug in the class known as COX-2 inhibitors that remains on the market, should be the last resort for managing pain. In addition to the side effect of increasing the risk of clots in the bloodstream, COX-2 inhibitors can also reduce blood flow through the kidneys and raise blood pressure. For short-term pain in some people, a narcotic pain reliever such as tramadol (Ultram), codeine, or fentanyl (Actiq, Duragesic) may be an option.
The "Harvard Heart Letter" notes that you shouldn't be afraid to take aspirin, Tylenol, Advil, or Aleve for occasional aches and pains. But if you need a pain reliever several times a week, pay closer attention to your choices and talk with your doctor.
Harvard Heart Letter
http://www.health.harvard.edu/heart
Not long ago, choosing a pain reliever meant finding one that eased your pain without being too hard on the stomach. Now, research suggests that some commonly used pain medications -- not just the now-banned Vioxx -- can raise the risk of having a heart attack or stroke. New step-by-step recommendations from the American Heart Association (AHA) can help you choose a pain reliever that's good for both the heart and stomach, reports the June 2007 issue of the "Harvard Heart Letter."
The AHA suggests starting with aspirin or acetaminophen (Tylenol) to quell muscle or joint pain. Aspirin is good for the heart, and acetaminophen doesn't affect blood clotting. If they don't work, the next step for most people would be a nonsteroidal anti-inflammatory drug (NSAID). Try naproxen (Aleve) first, then ibuprofen (Advil). Next is diclofenac, but more caution is needed with this drug (which is available only by prescription). Celebrex, the only drug in the class known as COX-2 inhibitors that remains on the market, should be the last resort for managing pain. In addition to the side effect of increasing the risk of clots in the bloodstream, COX-2 inhibitors can also reduce blood flow through the kidneys and raise blood pressure. For short-term pain in some people, a narcotic pain reliever such as tramadol (Ultram), codeine, or fentanyl (Actiq, Duragesic) may be an option.
The "Harvard Heart Letter" notes that you shouldn't be afraid to take aspirin, Tylenol, Advil, or Aleve for occasional aches and pains. But if you need a pain reliever several times a week, pay closer attention to your choices and talk with your doctor.
Harvard Heart Letter
http://www.health.harvard.edu/heart
Thursday, May 31, 2007
BAFTA: Warfarin bests aspirin for stroke prevention in elderly AF patients
BAFTA: Warfarin bests aspirin for stroke prevention in elderly AF patients
Glasgow, Scotland - Results of the Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) trial show that even among elderly patients with atrial fibrillation (AF), anticoagulation with warfarin was superior to aspirin for primary stroke prevention [1].
The benefit of treatment was not at the cost of more major hemorrhage, the rates of which were similar between groups. The results were presented here at the 16th European Stroke Conference.
"Use of anticoagulation rather than aspirin in over-75s in our study will prevent one primary event for every 50 patients treated for a year, or 25 treated for two years," Dr Jonathan W Mant (University of Birmingham, UK) told attendees here. "Our conclusion is that warfarin could be safely used much more widely in the elderly than it is at the moment, and age itself should not be regarded as a contraindication to warfarin therapy."
Glasgow, Scotland - Results of the Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) trial show that even among elderly patients with atrial fibrillation (AF), anticoagulation with warfarin was superior to aspirin for primary stroke prevention [1].
The benefit of treatment was not at the cost of more major hemorrhage, the rates of which were similar between groups. The results were presented here at the 16th European Stroke Conference.
"Use of anticoagulation rather than aspirin in over-75s in our study will prevent one primary event for every 50 patients treated for a year, or 25 treated for two years," Dr Jonathan W Mant (University of Birmingham, UK) told attendees here. "Our conclusion is that warfarin could be safely used much more widely in the elderly than it is at the moment, and age itself should not be regarded as a contraindication to warfarin therapy."
Saturday, May 19, 2007
Rimonabant: A novel selective cannabinoid-1 receptor antagonist
Rimonabant: A novel selective cannabinoid-1 receptor antagonist for treatment of obesity
American Journal of Health-System Pharmacy, Vol. 64, Issue 5, 481-489
PRITI N. PATEL, PHARM.D., BCPS, is Assistant Clinical Professor, College of Pharmacy and Allied Health Professions, and Director, Drug Information Center, St. John’s University, Queens, NY. ROLEE PATHAK, PHARM.D., BCPS, is Clinical Assistant Professor, Ernest Mario College of Pharmacy, Rutgers University, Piscataway, NJ, and Clinical Coordinator, Englewood Hospital and Medical Center, Englewood, NJ.
Purpose. The pharmacology, pharmacokinetics, clinical efficacy, safety, drug interactions, and dosage and administration of rimonabant in the treatment of obesity and related metabolic factors are reviewed.
Summary. Discovery of the cannabinoid receptors has led to the development of rimonabant, a cannabinoid-1 (CB1) antagonist. Selective blockade of this receptor has been shown to lead to decreased appetite and food intake in animal models. Clinical studies have shown that rimonabant 20 mg once daily produces significant decreases in weight and waist circumference in obese human subjects and improves the lipid profile and glucose control. The frequency of metabolic syndrome also decreased significantly with rimonabant 20 mg daily. Limited data are available regarding the pharmacokinetics and pharmacodynamics of rimonabant. Preclinical data have demonstrated a long duration of action. As of yet, no drug–drug, drug–food, or drug– disease interactions have been identified with rimonabant. Adverse reactions occurred rarely, with nausea, dizziness, diarrhea, arthralgia, and back pain being the most common. Psychiatric disorders, including depression and anxiety, were the most common reasons for subjects to withdraw from rimonabant studies. Rimonabant has been shown to be safe for up to two years of treatment. Further research will clarify currently unknown areas, including pharmacokinetics, drug interactions, and the drug’s role in standard therapy.
Conclusion. Rimonabant, a selective CB1 antagonist, is a novel treatment option for obese and overweight individuals. Significant weight loss, decrease in waist circumference, and improvements in lipid profile and glucose control have been shown in clinical trials of rimonabant.
American Journal of Health-System Pharmacy, Vol. 64, Issue 5, 481-489
PRITI N. PATEL, PHARM.D., BCPS, is Assistant Clinical Professor, College of Pharmacy and Allied Health Professions, and Director, Drug Information Center, St. John’s University, Queens, NY. ROLEE PATHAK, PHARM.D., BCPS, is Clinical Assistant Professor, Ernest Mario College of Pharmacy, Rutgers University, Piscataway, NJ, and Clinical Coordinator, Englewood Hospital and Medical Center, Englewood, NJ.
Purpose. The pharmacology, pharmacokinetics, clinical efficacy, safety, drug interactions, and dosage and administration of rimonabant in the treatment of obesity and related metabolic factors are reviewed.
Summary. Discovery of the cannabinoid receptors has led to the development of rimonabant, a cannabinoid-1 (CB1) antagonist. Selective blockade of this receptor has been shown to lead to decreased appetite and food intake in animal models. Clinical studies have shown that rimonabant 20 mg once daily produces significant decreases in weight and waist circumference in obese human subjects and improves the lipid profile and glucose control. The frequency of metabolic syndrome also decreased significantly with rimonabant 20 mg daily. Limited data are available regarding the pharmacokinetics and pharmacodynamics of rimonabant. Preclinical data have demonstrated a long duration of action. As of yet, no drug–drug, drug–food, or drug– disease interactions have been identified with rimonabant. Adverse reactions occurred rarely, with nausea, dizziness, diarrhea, arthralgia, and back pain being the most common. Psychiatric disorders, including depression and anxiety, were the most common reasons for subjects to withdraw from rimonabant studies. Rimonabant has been shown to be safe for up to two years of treatment. Further research will clarify currently unknown areas, including pharmacokinetics, drug interactions, and the drug’s role in standard therapy.
Conclusion. Rimonabant, a selective CB1 antagonist, is a novel treatment option for obese and overweight individuals. Significant weight loss, decrease in waist circumference, and improvements in lipid profile and glucose control have been shown in clinical trials of rimonabant.
Thursday, May 17, 2007
ALISKIREN - Doubts about the effectiveness
Hypertension rebels voice doubts about ALISKIREN
New York, NY - Doubts about the effectiveness of the new renin inhibitor antihypertensive aliskiren (Tektura, Novartis) have been voiced in a somewhat controversial review article in the May 2007 issue of the American Journal of Hypertension [1].
The authors, Dr John Laragh (editor of the journal) and his wife and fellow hypertension researcher Dr Jean Sealey (New York Hospital/Cornell University Medical Center, New York), say that aliskiren is no more effective than current antihypertensives and suggest that its ability to lower blood pressure may be limited by reactive renin secretion, an effect that may actually increase blood pressure in certain patient groups.
In an interview with heartwire, Laragh said: "We don't have an urgent need for a new drug like this. It is not a breakthrough. It is a weak antihypertensive drug. It is no better than what we already have, and it will be much more expensive. In addition, aliskiren causes a greater reactive rise in renin production than any other antihypertensive, which could be dangerous for patients with the most highly reactive renin systems."
Laragh and Sealey are no strangers to controversy, having been at the center of a bitter row with the American Society of Hypertension (ASH), which resulted in the American Journal of Hypertension no longer being the official journal of ASH and the end of Laragh's and Sealey's involvement with ASH.
New York, NY - Doubts about the effectiveness of the new renin inhibitor antihypertensive aliskiren (Tektura, Novartis) have been voiced in a somewhat controversial review article in the May 2007 issue of the American Journal of Hypertension [1].
The authors, Dr John Laragh (editor of the journal) and his wife and fellow hypertension researcher Dr Jean Sealey (New York Hospital/Cornell University Medical Center, New York), say that aliskiren is no more effective than current antihypertensives and suggest that its ability to lower blood pressure may be limited by reactive renin secretion, an effect that may actually increase blood pressure in certain patient groups.
In an interview with heartwire, Laragh said: "We don't have an urgent need for a new drug like this. It is not a breakthrough. It is a weak antihypertensive drug. It is no better than what we already have, and it will be much more expensive. In addition, aliskiren causes a greater reactive rise in renin production than any other antihypertensive, which could be dangerous for patients with the most highly reactive renin systems."
Laragh and Sealey are no strangers to controversy, having been at the center of a bitter row with the American Society of Hypertension (ASH), which resulted in the American Journal of Hypertension no longer being the official journal of ASH and the end of Laragh's and Sealey's involvement with ASH.
Friday, May 11, 2007
Reviewers Question First In-Class Rennin Inhibitor for Hypertension
Abstract:
Aliskiren, the First Renin Inhibitor for Treating Hypertension: Reactive Renin Secretion May Limit Its Effectiveness
American Journal of Hypertension, Volume 20, Issue 5, May 2007, Pages 587-597
Jean E. Sealey and John H. Laragh Jean E. Sealey and John H. LaraghDepartment of Cardiothoracic Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, New York.
A review of six clinical trials of aliskiren involving >5,000 patients with mild to moderate hypertension indicated that this first of a new class of orally active antihypertensive drugs is no more effective than angiotensin-converting enzyme inhibitors (CEIs), angiotensin receptor blockers (ARBs), or diuretics for lowering blood pressure. The starting dose is 150 mg; 300 mg is usually more effective, but 600 mg is no better than 300 mg. Aliskiren in combination with a diuretic appeared to lower blood pressure more than an aliskiren-ARB combination, but still failed to control blood pressure (<140/90) in 50% of the patients. Although aliskiren suppresses plasma renin activity, it causes much greater reactive rises in plasma renin concentration than does any other antihypertensive class tested.
Because aliskiren, like CEIs and ARBs, only blocks 90% to 95% of plasma renin, the pressor consequences of its greater reactive increases in plasma renin concentration appear to offset its net ability to lower blood pressure, especially with higher doses.
Patients with hyperreactive renin systems (renovascular, advanced, and malignant hypertension) were excluded from all of the trials.
Until the possibility is eliminated of inducing increases in blood pressure with aliskiren in patients with highly reactive renin levels, it seems safe and simple to stick to the less expensive, equally effective and widely available generic CEI drugs for treating the renin factor in hypertension.
Aliskiren, the First Renin Inhibitor for Treating Hypertension: Reactive Renin Secretion May Limit Its Effectiveness
American Journal of Hypertension, Volume 20, Issue 5, May 2007, Pages 587-597
Jean E. Sealey and John H. Laragh Jean E. Sealey and John H. LaraghDepartment of Cardiothoracic Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, New York.
A review of six clinical trials of aliskiren involving >5,000 patients with mild to moderate hypertension indicated that this first of a new class of orally active antihypertensive drugs is no more effective than angiotensin-converting enzyme inhibitors (CEIs), angiotensin receptor blockers (ARBs), or diuretics for lowering blood pressure. The starting dose is 150 mg; 300 mg is usually more effective, but 600 mg is no better than 300 mg. Aliskiren in combination with a diuretic appeared to lower blood pressure more than an aliskiren-ARB combination, but still failed to control blood pressure (<140/90) in 50% of the patients. Although aliskiren suppresses plasma renin activity, it causes much greater reactive rises in plasma renin concentration than does any other antihypertensive class tested.
Because aliskiren, like CEIs and ARBs, only blocks 90% to 95% of plasma renin, the pressor consequences of its greater reactive increases in plasma renin concentration appear to offset its net ability to lower blood pressure, especially with higher doses.
Patients with hyperreactive renin systems (renovascular, advanced, and malignant hypertension) were excluded from all of the trials.
Until the possibility is eliminated of inducing increases in blood pressure with aliskiren in patients with highly reactive renin levels, it seems safe and simple to stick to the less expensive, equally effective and widely available generic CEI drugs for treating the renin factor in hypertension.
Thursday, May 10, 2007
Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults. 2007 Update.
Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults. 2007 Update. A Guideline From the American Heart Association, American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group
Joseph Broderick MD, FAHA, Chair; Sander Connolly MD, FAHA, Vice-Chair; Edward Feldmann MD, FAHA; Daniel Hanley MD, FAHA; Carlos Kase MD, FAHA; Derk Krieger MD; Marc Mayberg MD, FAHA; Lewis Morgenstern MD, FAHA; Christopher S. Ogilvy MD; Paul Vespa MD; and Mario Zuccarello MD
Purpose--The aim of this statement is to present current and comprehensive recommendations for the diagnosis and treatment of acute spontaneous intracerebral hemorrhage.
Methods--A formal literature search of Medline was performed through the end date of August 2006. The results of this search were complemented by additional articles on related issues known to the writing committee. Data were synthesized with the use of evidence tables. The American Heart Association Stroke Council’s Levels of Evidence grading algorithm was used to grade each recommendation. Prerelease review of the draft guideline was performed by 5 expert peer reviewers and by the members of the Stroke Council Leadership Committee. It is intended that this guideline be fully updated in 3 years’ time.
Results--Evidence-based guidelines are presented for the diagnosis of intracerebral hemorrhage, the management of increased arterial blood pressure and intracranial pressure, the treatment of medical complications of intracerebral hemorrhage, and the prevention of recurrent intracerebral hemorrhage. Recent trials of recombinant factor VII to slow initial bleeding are discussed. Recommendations for various surgical approaches for treatment of spontaneous intracerebral hemorrhage are presented. Finally, withdrawal-of-care and end-of-life issues in patients with intracerebral hemorrhage are examined.
The guidelines, published in the June issue of Stroke, Journal of the American Heart Association
COMMENTARIES:
Intracerebral hemorrhage, which causes 10% to 15% of first-ever strokes, has a 30-day mortality rate of 35% to 52%
The guidelines suggest that the hemorrhage should be removed as soon as possible if:
It's greater than 3 cm.
The patient is deteriorating neurologically.
The patient has brain stem compression, hydrocephalus from ventricular obstruction, or both.
There is some evidence that using recombinant activated factor VII within four hours of the stroke limits bleeding and may reduce the risk of death.
The guidelines also recommend that:
Appropriate antiepileptic therapy should always be used for treatment of seizures.
Sources of fever should be treated and antipyretic medications should be given as needed.
Early mobilization and rehabilitation are recommended in patients who are clinically stable.
A new aspect of the guidelines is discussion of withdrawal of care and end-of-life issues. The guidelines recommend that do-not-resuscitate orders not be initiated during the first 24 hours after the onset of stroke because they are associated with "an overall lack of aggressiveness of care."
Joseph Broderick MD, FAHA, Chair; Sander Connolly MD, FAHA, Vice-Chair; Edward Feldmann MD, FAHA; Daniel Hanley MD, FAHA; Carlos Kase MD, FAHA; Derk Krieger MD; Marc Mayberg MD, FAHA; Lewis Morgenstern MD, FAHA; Christopher S. Ogilvy MD; Paul Vespa MD; and Mario Zuccarello MD
Purpose--The aim of this statement is to present current and comprehensive recommendations for the diagnosis and treatment of acute spontaneous intracerebral hemorrhage.
Methods--A formal literature search of Medline was performed through the end date of August 2006. The results of this search were complemented by additional articles on related issues known to the writing committee. Data were synthesized with the use of evidence tables. The American Heart Association Stroke Council’s Levels of Evidence grading algorithm was used to grade each recommendation. Prerelease review of the draft guideline was performed by 5 expert peer reviewers and by the members of the Stroke Council Leadership Committee. It is intended that this guideline be fully updated in 3 years’ time.
Results--Evidence-based guidelines are presented for the diagnosis of intracerebral hemorrhage, the management of increased arterial blood pressure and intracranial pressure, the treatment of medical complications of intracerebral hemorrhage, and the prevention of recurrent intracerebral hemorrhage. Recent trials of recombinant factor VII to slow initial bleeding are discussed. Recommendations for various surgical approaches for treatment of spontaneous intracerebral hemorrhage are presented. Finally, withdrawal-of-care and end-of-life issues in patients with intracerebral hemorrhage are examined.
The guidelines, published in the June issue of Stroke, Journal of the American Heart Association
COMMENTARIES:
Intracerebral hemorrhage, which causes 10% to 15% of first-ever strokes, has a 30-day mortality rate of 35% to 52%
The guidelines suggest that the hemorrhage should be removed as soon as possible if:
It's greater than 3 cm.
The patient is deteriorating neurologically.
The patient has brain stem compression, hydrocephalus from ventricular obstruction, or both.
There is some evidence that using recombinant activated factor VII within four hours of the stroke limits bleeding and may reduce the risk of death.
The guidelines also recommend that:
Appropriate antiepileptic therapy should always be used for treatment of seizures.
Sources of fever should be treated and antipyretic medications should be given as needed.
Early mobilization and rehabilitation are recommended in patients who are clinically stable.
A new aspect of the guidelines is discussion of withdrawal of care and end-of-life issues. The guidelines recommend that do-not-resuscitate orders not be initiated during the first 24 hours after the onset of stroke because they are associated with "an overall lack of aggressiveness of care."
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