viernes, 30 de noviembre de 2012

HDL Cholesterol: Why Higher Levels No Longer Equal Lower Risk

A large genetic analysis reported in the May 17, 2012, issue of the Lancet1showed no association between naturally high levels of HDL cholesterol (HDL-C) and a reduced risk of heart disease, raising even more questions about available HDL-raising strategies and the pharmaceutical research and development programs focused on bringing new agents to market.

The results are the third data set in the past several years to cast doubt on the widely held HDL-C hypothesis: HDL protects against atherosclerosis. The AIM-HIGH study2 was stopped early when there was no clinical benefit seen from the addition of niacin to statin therapy in patients with established cardiovascular disease, despite significant improvement in levels of HDL-C.3 More recently, a Phase 3 clinical trial of the cholesteryl ester transfer protein inhibitor dalcetrapib (dal-OUTCOMES)4 also was stopped for lack of efficacy.5

• Do the disappointing results of the genetic analysis constitute a third strike and effectively “bench” HDL-raising as a means to help reduce cardiovascular risk?
• What important questions do these studies raise about the cardioprotective mechanisms of HDL-C?
• What should primary care physicians tell patients who ask about current HDL-raising strategies?
• Should those strategies be modified while scientists re-think the HDL hypothesis and re-focus investigation?

To answer these questions and put the issue into clinical perspective for primary care physicians, here are Drs Christopher Cannon and Payal Kohli. Dr Cannon, a senior investigator with the TIMI Study Group, is Editor-in-Chief of Cardiosource Science and Quality. He is also Professor of Medicine at Harvard Medical School and Associate Physician in the Cardiovascular Division of Brigham and Womens’ Hospital in Boston. Dr Kohli graduated from Harvard Medical School, completed her internal medicine training in Boston, and is currently a fellow in cardiovascular medicine at the University of California San Francisco.

Take-Home Points 1. The results of the genetic study challenge a number of established views about HDL-C: first is the concept that raising plasma HDL-C levels should translate into reduction in risk of MI and, second is the belief that HDL-C is an appropriate surrogate measure for risk of MI in intervention trials.
2. The genetic data do not place into question the value of using low HDL-C levels as a marker of risk for MI. Continue to check HDL-C levels, and for now, management of patients with low values should reinforce lifestyle change (eg, improved diet, regular exercise, weight loss, smoking cessation when relevant) and focus on meeting LDL-C targets.
3. Research is still ongoing for new drugs that raise HDL-C levels.


jueves, 8 de noviembre de 2012

Long-Acting Insulins Win FDA Panel Support

SILVER SPRING, Md. -- An FDA advisory committee voted 8-4 Thursday in favor of approval of a new ultra-long-acting insulin for type 1 and type 2 diabetes.
But the Endocrinologic and Metabolic Drugs Advisory Committee also voted unanimously (12-0) in support of a cardiovascular outcomes trial for the product's two formulations, insulin degludec (Tresiba) and insulin degludec/aspart, (Ryzodeg), due to a potential signal in a meta-analysis of major trials conducted thus far.
The majority of panelists who voted in favor of approving the drug said such a trial could be done post marketing.
"I think this agent has advantages over what's currently available," said panelist Ellen Seely, MD, of Harvard University in Boston. "Both insulin glargine (Lantus) and insulin detemir (Levemir) were supposed to be 24-hour insulins but fell short of that. We've spent a long time searching for an insulin that would last 24 hours."
Thomas Weber, MD, of Duke University Medical Center, said he was impressed by the pharmacokinetics and that a true ability to dose just once a day, at any time, would help improve adherence among patients.
Yet some panelists said that the benefits of the drug were not overwhelming and expressed strong concerns over cardiovascular risks that may not outweigh any advantages.
Brendan Everett, MD, MPH, a cardiologist at Brigham & Women's Hospital in Boston, voted against approval, noting that diabetics already have a substantial burden of heart disease tied to high morbidity and mortality.
He cited current "experience with other anti-diabetic medications that have adverse cardiovascular risk profile but are widely used. As a result, we've put patients at risk for adverse outcomes."
"I don't know that what we've seen [in terms of a cardiovascular signal] is real," he added, "but I have enough concerns about it that I would want to know the answer before a large number of patients with diabetes take this medication."
Erica Brittain, PhD, of the National Institute of Allergy and Infectious Diseases in Bethesda, Md., who also cast a "No" vote, said she doesn't "feel comfortable exposing millions of patients to a drug when there is this much concern about the cardiovascular risks."
Robert Smith, MD, of Brown University in East Providence, R.I., and Marvin Konstam, MD, of Tufts Medical Center in Boston, cast the other dissenting votes.
In a separate vote on whether a cardiovascular outcomes trial is necessary, Brittain said her "Yes" vote was the "easiest vote I've had since I've been on this committee."
William Hiatt, MD, of the University of Colorado in Aurora, said he voted in favor of such a trial because the mechanism linking the insulin to heart problems "is completely unclear."
"Understanding what might be at play may be important in addition to simply counting events," Hiatt said.
Panelists' interpretations as to whether the insulin was associated with a lower risk of hypoglycemia compared with other insulins were varied. Many felt the risk of hypoglycemia was comparable to other therapies, though some believed there was indeed a signal for reduced hypoglycemic events with both versions of insulin degludec.
In its review of 16 trials, FDA found a suggestion of an excess risk of cardiovascular events with degludec compared with other insulins. The agency has continued to delay a decision on the company's new drug application, submitted last September.
The FDA was initially supposed to deliver its decision in October. The agency isn't obligated to follow the advice of its advisory committees, but often does.
European regulators gave the product a thumbs up last month.


jueves, 1 de noviembre de 2012

Is Total Testosterone Measurement an Accurate Method of Predicting Hypogonadism in Men ?

Total testosterone measurement to predict male hypogonadism
Clinical question
How accurate is the measurement of total testosterone for predicting hypogonadism in men?
Bottom line
A total testosterone level of 280 ng/dL or higher is fairly accurate in ruling out hypogonadism in men, with a false negative rate of only 2.1%. A low total testosterone level (< 280 ng/dL) is only moderately useful in predicting hypogonadism (false positive rate = nearly 62%). (LOE = 1b)
Anawalt BD, Hotaling JM, Walsh TJ, Matsumoto AM. Performance of total testosterone measurement to predict free testosterone for the biochemical evaluation of male hypogonadism. J Urol 2012;187(4):1369-1373. [PubMed® abstract]
Study design: Cohort (retrospective)

Funding source: Foundation

Setting: Outpatient (specialty)

Male hypogonadism affects an estimated 5% to 10% of men older than 30 years. The measurement of free testosterone level, considered the reference standard for the biochemical diagnosis of hypogonadism (< 34 pg/mL), is costly and time consuming and so it's not often used in clinical practice. These investigators reviewed the medical records of all 3672 men, aged 20 years to 90 years, who were evaluated for possible hypogonadism at a Veterans Administration health system from 1997 through 2007. All patients were tested for total testosterone (TT), sex hormone-binding globulin (SHBG), albumin, and calculated free testosterone (cFT). Approximately one third of the men had diabetes mellitus and nearly half were obese (BMI > 30 kg/m2). One individual abstracted and recorded all data. The prevalence of low cFT was 15.2%. The sensitivity of TT (lower limit of normal = 280 ng/dL) to identify a low cFT was 91% and the specificity was 73.7%. The positive predictive value (the likelihood that a positive result, meaning abnormally low TT, is truly positive) was 38.3% (false positive rate = nearly 62%). The negative predictive value (the likelihood that a negative result, meaning a TT > 280 ng/dL, is truly negative) was 97.9% (false negative rate = 2.1%). The positive likelihood ratio for hypogonadism, defined as a low cFT, was greater than 10 (which is considered moderately to strongly clinically useful) only when the TT level was less than 200 ng/dL. The negative likelihood ratio of a TT level 280 ng/dL or greater was 0.12, which is considered moderately useful. A more useful clinical decision rule which will calculate posttest prevalence for individual levels of TT will be available later this summer in Essential Evidence Plus.
David Slawson, MD
Vice Chair, Department of Family Medicine
University of Virginia
Charlottesville, VA

Probiotics protect against diarrhoea associated with antibiotics

JAMA 2012;307:1959-69 [PubMed® abstract]

More evidence that probiotics can help prevent diarrhoea associated with antibiotics has emerged from a meta-analysis of randomised trials. The authors found 82 trials after a systematic search but only 63 reported how many people took the probiotics, how many took the control treatment, and how many developed diarrhoea. Across these 63 trials, probiotics were associated with a 42% reduction in the risk of diarrhoea (relative risk 0.58, 95% CI 0.50 to 0.68; number needed to treat 13, 10.3 to 19.1).
Most trials tested probiotic preparations containing lactobacilli, alone or in mixed cultures. The effect looked consistent in multiple different analyses, including two confined to high quality trials and another that looked specifically at adults taking antibiotics for Helicobacter pylori infections (the most commonly reported indication). The authors are confident their results are as robust as they can be given the generally poor quality of the evidence base.
Most trials were underpowered and badly reported. It is still hard to know the precise mix of micro-organisms that is likely to work best and the characteristics of patients most likely to benefit. Details of the antibiotics being taken were missing from many trials, as were reliable assessments of side effects. Still, we have enough encouraging evidence to justify further research to fine tune these results, say the authors. Diarrhoea associated with antibiotics is common and can be life threatening.

2012 ACC/AHA Unstable Angina and NSTEMI Guideline Update: 10 Points to Remember

Title: 2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction (Updating the 2007 Guideline and Replacing the 2011 Focused Update): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines
Date Posted: July 16, 2012
Authors: Jneid H, Anderson JL, Wright RS, et al.
Citation: J Am Coll Cardiol 2012;Jul 16:[Link to free full-text JACC article PDF]
The following are 10 points to remember about this guideline update:
  1. Aspirin should be administered to unstable angina (UA)/non–ST-segment elevation myocardial infarction (NSTEMI) patients as soon as possible after hospital presentation and continued indefinitely in patients who tolerate it.
  2. A loading dose of P2Y12 receptor inhibitor therapy is recommended for UA/NSTEMI patients for whom percutaneous coronary intervention (PCI) is planned.
  3. Prasugrel should not be administered routinely to patients with UA/NSTEMI before angiography, such as in an emergency department, or used in patients with UA/NSTEMI who have not undergone PCI.
  4. Physicians and patients should be cautioned against early discontinuation of P2Y12 receptor inhibitors for elective noncardiac procedures.
  5. In patients taking a P2Y12 receptor inhibitor in whom coronary artery bypass grafting (CABG) is planned and can be delayed, it is recommended that the drug be discontinued to allow for dissipation of the antiplatelet effect. The period of withdrawal should be at least 5 days in patients receiving clopidogrel or ticagrelor and at least 7 days in patients receiving prasugrel unless the need for revascularization and/or the net benefit of the P2Y12 receptor inhibitor therapy outweighs the potential risks of excess bleeding.
  6. An early invasive strategy (i.e., diagnostic angiography with intent to perform revascularization) is indicated in UA/NSTEMI patients who have refractory angina or hemodynamic or electrical instability (without serious comorbidities or contraindications to such procedures).
  7. For UA/NSTEMI patients in whom an initial conservative strategy is selected, if recurrent symptoms/ischemia, heart failure, or serious arrhythmias subsequently appear, then diagnostic angiography should be performed.
  8. Use of warfarin in conjunction with aspirin and/or P2Y12 receptor inhibitor therapy is associated with an increased risk of bleeding, and patients and clinicians should watch for bleeding, especially gastrointestinal, and seek medical evaluation for evidence of bleeding.
  9. Creatinine clearance should be estimated in UA/NSTEMI patients and the doses of renally cleared medications should be adjusted according to the pharmacokinetic data for specific medications.
  10. The development of regional systems of UA/NSTEMI care is a matter of utmost importance. This includes encouraging the participation of key stakeholders in collaborative efforts to evaluate care using standardized performance and quality-improvement measures, such as those endorsed by the American College of Cardiology and the American Heart Association for UA/NSTEMI.
Debabrata Mukherjee, M.D., F.A.C.C. (Disclosure)