Gastroesophageal Reflux Disease

eMedicine Specialties > Gastroenterology > Esophagus

Author: Piero Marco Fisichella, MD, Assistant Professor of Surgery, Stritch School of Medicine, Loyola University; Director, Esophageal Motility Center, Loyola University Medical Center
Coauthor(s): Marco G Patti, MD, Professor of Surgery, Director, Center for Esophageal Diseases, University of Chicago Pritzker School of Medicine
Contributor Information and Disclosures

Updated: Apr 28, 2009

Background

Gastroesophageal reflux is a normal physiologic phenomenon experienced intermittently by most people, particularly after a meal. Gastroesophageal reflux disease (GERD) occurs when the amount of gastric juice that refluxes into the esophagus exceeds the normal limit, causing symptoms with or without associated esophageal mucosal injury (ie, esophagitis).

For excellent patient education resources, visit eMedicine's Heartburn/GERD/Reflux Center and Esophagus, Stomach, and Intestine Center. Also, see eMedicine's patient education articles Gastroesophageal Reflux Disease (GERD), Heartburn, and Heartburn/GERD Medications.

Pathophysiology

The physiologic and anatomic factors that prevent the reflux of gastric juice from the stomach into the esophagus include the following:

• The lower esophageal sphincter (LES) must have a normal length and pressure and a normal number of episodes of transient relaxation (relaxation in the absence of swallowing).
• The gastroesophageal junction must be located in the abdomen so that the diaphragmatic crura can assist the action of the LES, thus functioning as an extrinsic sphincter. The presence of a hiatal hernia disrupts this synergistic action and can promote reflux (see Image 3 or below).
  

  

  Barium swallow indicating hiatal hernia.

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  Barium swallow indicating hiatal hernia.

• Esophageal clearance must be able to neutralize the acid refluxed through the LES. (Mechanical clearance is achieved with esophageal peristalsis. Chemical clearance is achieved with saliva.)
• The stomach must empty properly.

Abnormal gastroesophageal reflux is caused by the abnormalities of one or more of the following protective mechanisms:

• A functional (frequent transient LES relaxation) or mechanical (hypotensive LES) problem of the LES is the most common cause of gastroesophageal reflux disease (GERD).
• Certain foods (eg, coffee, alcohol), medications (eg, calcium channel blockers, nitrates, beta-blockers), or hormones (eg, progesterone) can decrease the pressure of the LES.
• Obesity is a contributing factor in gastroesophageal reflux disease (GERD), probably because of the increased intra-abdominal pressure.

From a therapeutic point of view, informing patients that gastric refluxate is made up not only of acid but also of duodenal contents (eg, bile, pancreatic secretions) is important.

Frequency

United States

Heartburn is a common problem in the United States and in the Western world. Approximately 7% of the population experience symptoms of heartburn daily. An abnormal esophageal exposure to gastric juice is probably present in 20-40% of this population, meaning 20-40% of the people who experience heartburn do indeed have gastroesophageal reflux disease (GERD). In the remaining population, heartburn is probably due to other causes. Because many individuals control symptoms with over-the-counter (OTC) medications and without consulting a medical professional, the condition is likely underreported.

Mortality/Morbidity

• In addition to the typical symptoms of gastroesophageal reflux disease (GERD) (eg, heartburn, regurgitation, dysphagia), abnormal reflux can cause atypical symptoms, such as coughing, chest pain, and wheezing. Additional atypical symptoms from abnormal reflux include damage to the lungs (eg, pneumonia, asthma, idiopathic pulmonary fibrosis), vocal cords (eg, laryngitis, cancer), ear (eg, otitis media), and teeth (eg, enamel decay).
• Approximately 50% of patients with gastric reflux develop esophagitis (see Image 6 or below).
  

  

  Peptic esophagitis. A rapid urease test (RUT) is performed on the esophageal biopsy sample. The result is positive for esophagitis.

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  Peptic esophagitis. A rapid urease test (RUT) is performed on the esophageal biopsy sample. The result is positive for esophagitis.

  
  {{mediacaption:1674250_0}}Esophagitis is classified into the following 4 grades based on its severity:
  • Grade I – Erythema
  • Grade II – Linear nonconfluent erosions
  • Grade III – Circular confluent erosions
  • Grade IV – Stricture or Barrett esophagus. Barrett esophagus is thought to be caused by the chronic reflux of gastric juice into the esophagus. Barrett esophagus occurs when the squamous epithelium of the esophagus is replaced by the intestinal columnar epithelium (see Image 1 or below).
    

    

    Esophagogastroduodenoscopy indicating Barrett esophagus.

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    Esophagogastroduodenoscopy indicating Barrett esophagus.

    
    {{mediacaption:176678_1}}Barrett esophagus is present in 8-15% of patients with gastroesophageal reflux disease (GERD) and may progress to adenocarcinoma (see Images 2 and 7 or below).
    

    

    Gastroesophageal reflux disease (GERD)/Barrett esophagus/adenocarcinoma sequence.

    Gastroesophageal reflux disease (GERD)/Barrett esophagus/adenocarcinoma sequence.

    
    

    

    Endoscopy demonstrating intraluminal esophageal cancer.

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    Endoscopy demonstrating intraluminal esophageal cancer.

    
    {{mediacaption:1674255_3}}See Esophageal Cancer.

Race

• White males are at a greater risk for Barrett esophagus and adenocarcinoma than other populations.

Sex

• No sexual predilection exists. Gastroesophageal reflux disease (GERD) is as common in men as in women.
• The male-to-female incidence ratio for esophagitis is 2:1-3:1. The male-to-female incidence ratio for Barrett esophagus is 10:1.

Age

• Gastroesophageal reflux disease (GERD) occurs in all age groups.
• The prevalence of gastroesophageal reflux disease (GERD) increases in people older than 40 years.

Clinical

History

Gastroesophageal reflux disease (GERD) can cause typical (esophageal) symptoms or atypical (extraesophageal) symptoms. However, a diagnosis of gastroesophageal reflux disease (GERD) based on the presence of typical symptoms is correct in only 70% of patients.

• Typical (esophageal) symptoms include the following:
  • Heartburn is the most common typical symptom of gastroesophageal reflux disease (GERD). Heartburn is felt as a retrosternal sensation of burning or discomfort that usually occurs after eating or when lying down or bending over.
  • Regurgitation is an effortless return of gastric and/or esophageal contents into the pharynx. Regurgitation can induce respiratory complications if gastric contents spill into the tracheobronchial tree.
  • Dysphagia occurs in approximately one third of patients because of a mechanical stricture or a functional problem (eg, nonobstructive dysphagia secondary to abnormal esophageal peristalsis). Patients with dysphagia experience a sensation that food is stuck, particularly in the retrosternal area.
• Atypical (extraesophageal) symptoms include the following:
  • Coughing and/or wheezing are respiratory symptoms resulting from the aspiration of gastric contents into the tracheobronchial tree or from the vagal reflex arc producing bronchoconstriction. Approximately 50% of patients who have GERD-induced asthma do not experience heartburn.
  • Hoarseness results from irritation of the vocal cords by gastric refluxate and is often experienced by patients in the morning.
  • Reflux is the most common cause of noncardiac chest pain, accounting for approximately 50% of cases. Patients can present to the emergency department with pain resembling a myocardial infarction. Reflux should be ruled out (using esophageal manometry and 24-h pH testing if necessary) once a cardiac cause for the chest pain has been excluded. Alternatively, a therapeutic trial of a high-dose proton pump inhibitor (PPI) can be tried.
    

    

    Ambulatory pH monitoring indicating episodes of reflux correlating with the heartburn experienced by the patient.

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    Ambulatory pH monitoring indicating episodes of reflux correlating with the heartburn experienced by the patient.

Physical

The physical examination is noncontributory.

References

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What Should Patients Do With Unused Narcotics?

From Medscape Pharmacists > Ask the Experts

Jeffrey Fudin, PharmD

Question

Clinicians often tell patients to save their remaining narcotics for "next time." Is that sound advice?

Response from Jeffrey Fudin, PharmD Adjunct Associate Professor, Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York; Clinical Pharmacy Specialist, Stratten Veterans Affairs Medical Center, Albany, New York

Safety and environmental considerations have been widely overlooked in the disposal of medications. Customarily, patients were advised to flush medications down the toilet or pour them down the sink. Subsequently, trace amounts of medicinal byproducts have been found in the water supply. Although short-term studies fail to demonstrate harm to humans and animals, long-term effects, including endocrine disturbances, growth inhibition, and mutagenicity, still remain unclear.^[1,2]

The US Food and Drug Administration (FDA) published guidelines in 2007 with instructions on how to properly discard all prescription and nonprescription medications.^[1] In addition, the US Fish and Wildlife Service, the American Pharmacists Association, and the Pharmaceutical Research and Manufacturers of America have collaborated to promote environmentally safe discarding of medications in a program called "SMARxT Disposal."^[3] SMARxT Disposal recommendations include:

• Before any medication disposal, patients should read the product instructions or label carefully. If it states to flush the unused product down the toilet, the patient should follow those directions. Medications that carry such instructions are scheduled drugs with high abuse potential.
• Unless specified otherwise, medications should be crushed or dissolved with water and mixed with an undesirable material (eg, coffee grounds, saw dust, kitty litter) in a plastic baggie. The bag should then be sealed and discarded in the trash. Doing this reduces the appeal to children and animals.
• All medications should be taken out of original containers before recycling or disposal. Labels should be removed and personal information scratched off or destroyed to ensure patient confidentiality.

Approved state and local collection programs may be available to assist patients with medication disposal.

Narcotics may require special disposal procedures. According to the FDA guidelines, "about a dozen drugs, such as powerful narcotic pain relievers and other controlled substances, carry instructions for flushing to reduce the danger of unintentional use or overdose and illegal abuse."^[1] For example, a fentanyl transdermal patch contains active medication within the glue or ethyl cellulose matrices even after removal from the skin. Thus, the patch should be folded so the adhesive side adheres to itself and then flushed in the toilet immediately after removal.^[4] Disposal in this manner reduces the accessibility to children and pets.

Healthcare providers and pharmacists should stress the following general points to their patients:

• Do not keep leftover or expired medications for "later use" because storage of these medications may lead to abuse or accidental ingestion by other persons in the household. If a medical provider discontinues a medication and the patient has a remaining supply, he or she should be advised not to keep the medication in anticipation of returning symptoms.
• Taking medications after discontinuation by the prescriber could be dangerous. Discontinued medications could interact with newer prescriptions or medical conditions, contributing to life-threatening adverse reactions. In addition, degraded medications may contain a toxic byproduct. For example, use of degraded tetracycline has been associated with development of lactic acidosis and Fanconi's syndrome.^[5]

Failing to instruct patients on how to dispose of narcotics and other medications is a missed opportunity for important patient counseling.

The author wishes to acknowledge the assistance of Marissa Jean Cavaretta, student pharmacist, Albany College of Pharmacy & Health Sciences, Albany, New York

References

1. How to dispose of unused medicines. US Food and Drug Administration. Available at: www.fda.gov/ForConsumers/ConsumerUpdates/ucm101653.htm Accessed August 20, 2009.
2. Touraud E, Roig B, for ARMINES - Ecole des Mines d'Alès. KNAPPE: Knowledge and need assessment on pharmaceutical products in environmental waters. Available at: http://environmentalhealthcollaborative.org/images/KNAPPE_REPORT_FINAL.pdf Accessed September 8, 2009.
3. A prescription for a healthy planet. SMARxT Disposal. Available at: www.smarxtdisposal.net Accessed August 20, 2009.
4. Institute for Safe Medication Practices. ISMP Safe Medication Alert! New fentanyl warnings: more needed to protect patients. Available at: http://www.ismp.org/Newsletters/acutecare/articles/20050811.asp Accessed August 26, 2009.
5. 5. Montoliu J, Carrera M, Darnell A, Revert L. Lactic acidosis and Fanconi's syndrome due to degraded tetracycline. Br Med J (Clin Res Ed). 1981;283:1576-1577

MY ACTIVITIES IN NOVEMBER 2009

1. WORKSHOP ON TRAINING ROADMAP FOR ALLIED HEALTH PROFESSIONALS
(TRAINING ROADMAP - FUNCTIONAL & TASK SPECIFIC)

DATE: 12 - 13th NOV 2009

PLACE : NATIONAL HEALTH MANAGEMENT INSTITUTE, BANGSAR, KUALA LUMPUR.

ORGANISER : MOH TRAINING DIVISION & AHP DIVISION, MOH.


2. ASSISTANT PHARMACIST TECHNICAL MEETING WITH DIRECTOR OF PHARMACY SERVICES DIVISION, MINISTRY OF HEALTH

DATE : 16th NOVEMBER 2009

PLACE : HQ PHARMACY SERVICES DIVISION, MOH, PETALING JAYA


3. MALAYSIAN ASSISTANT PHARMACIST ASSOCIATION COMMITTEE MEMBER MEETING

DATE: 21st NOV 2009

PLACE : BRISDALE HOTEL, KUALA LUMPUR

FDA Watching 19 Drugs for Safety Risks

This is an article that very important for everyone to know, especially medical personels.

PLEASE READ THIS !

From Medscape Pharmacists

Susan J. Bliss, RPh, MBA

Published: 10/08/2009

Although prescription drugs undergo clinical trials before they hit the market, unexpected adverse events may still occur in the general patient population. As a result, the Food and Drug Administration (FDA) collects adverse event reports and looks for potential trends. In its latest surveillance report, the agency has identified 19 drugs that are associated with adverse events and, therefore, are undergoing close evaluation.

A centerpiece of the FDA's safety surveillance efforts is the Adverse Drug Event Reporting System. This computerized database is used to collect and analyze safety reports on all approved drug and therapeutic biological products. If a potential safety concern occurs, further epidemiologic studies may be performed, and, eventually, regulatory actions may be taken such as changing a drug's labeling, restricting its use, warning the public, or even removing the drug from the market.^[1]

The most recent FDA report based on Adverse Drug Event Reporting System data collected in the fourth quarter of 2008 provides a list of drugs that represents "potential signals of serious risks" or that has new safety information (Table).^[2] These potential safety issues were identified in reports filed by clinicians and patients via the agency's MedWatch program.

Table. Drugs With Potentially Serious Risks or New Safety Information

Active Ingredient (Trade Name) or Product Class	Potential Safety Risk or New Safety Information
Apomorphine (APOKYN®)	Psychiatric events
Choriogonadotropin alfa (Ovidrel®)	Anaphylactic reactions
Clomiphene citrate (Clomid®)	Visual disorders
Clozapine orally disintegrating tablet (FazaClo®)	Deaths
Darifenacin (ENABLEX®) and solifenacin (VESIcare®)	Angioedema and other allergic reactions
Drospirenone/ethinyl estradiol (Yasmin®)	Pancreatitis
Efavirenz (Sustiva®)	Birth defects involving the eye and face
Fibrin sealant, human (Evicel™)	Air embolism
Hydrochlorothiazide in combination products	Skin reactions
Imiquimod cream (Aldara™)	Dysuria due to severe local reactions during use in the genital area
Modafinil (Provigil®) and armodafinil (Nuvigil®)	Serious skin reactions
Orlistat (XENICAL®, alli-®)	Hepatotoxicity
Polyethylene glycol oral laxative (various trade names)	Neuropsychiatric events
Raltegravir (ISENTRESS®)	Psychiatric events
Selegiline (EMSAM®)	Hypertension
Sumatriptan/naproxen (TREXIMET®)	Myocardial infarction
Testosterone gel (AndroGel®, Testim®)	Adverse events from accidental exposure
Tolterodine tartrate (Detrol®)	Stevens-Johnson syndrome
Varenicline (CHANTIX®)	Angioedema, serious skin reactions, visual impairment, accidental injury

From US Department of Health & Human Services, US Food and Drug Administration. Available at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/
ucm161063.htm Accessed October 1, 2009.^[2]

FDA evaluation of these drugs continues, and officials stress that until a potential relationship between the drug and the risk is fully evaluated, it is not clear what causes the association.^[2] The adverse event(s) may be precipitated by concurrent disease states, coadministration of other drugs, change in patient health status, previous drug therapy, or other causes. Clinicians do not need to stop using these drugs, but they should be aware of the potential risks.

Already, the FDA has taken action on several of the drugs on the list. For example:

• Sumatriptan/naproxen. The FDA reviewed the existing boxed warning on the product label addressing myocardial infarction and concluded it was adequate^[2];
• Testosterone gel. A May 2009 news release announced the addition of a new boxed warning that addresses potential adverse events in children and women who are accidentally exposed to testosterone gel^[3]; and
• Varenicline, bupropion. The FDA distributed a Safety Alert and Public Health Advisory concerning these smoking cessation agents. The FDA now requires that medication guides highlighting the risk of neuropsychiatric symptoms be provided to patients receiving these medications. Information for healthcare professionals, patients, family members, and caregivers is included.^[4]

The FDA recently redesigned its Website (www.fda.gov) to make drug safety information more accessible for patients and providers. There are 3 ways to search for topics on this site: an A-to-Z index, a topic index, and a search box.

In addition, the federal agency provides several other tools that are useful for clinicians:

• MedWatch Website. MedWatch is the agency's reporting program, and the site provides the latest updates on adverse drug event reports. You can use the 1-page MedWatch form to report your own adverse drug events.
• Drug Safety Newsletter. Designed to complement FDA product labeling, Public Health Advisories, and Alerts for Healthcare Professionals, the Newsletter is available by electronic subscription and is posted on the FDA Website.
• MedWatch E-list. This free email subscription service allows for rapid dissemination of new safety information regarding drugs and devices. Subscribe here.
• FDA Transparency Blog. This is a place where you can have a "conversation" with the FDA -- ask questions, respond to their questions, and provide general feedback on the agency's efforts. Regular updates are scheduled to appear through November 2009.

Much of the drug safety information available on the FDA Website can be distributed via RSS feed and text messages sent directly to cell phones. Podcasts, videos, and other newsletters are also available on the Website.

Seasonal Flu Vaccine May Help Protect Against H1N1

Laurie Barclay, MD

October 7, 2009 — Seasonal influenza vaccine may help protect against novel pandemic influenza A (H1N1), according to the results of a frequency-matched, case-control study in Mexico City reported online October 6 in the British Medical Journal. However, the investigators and authors of an accompanying editorial urge that a specific vaccine against H1N1 flu is still needed.

"The viral genomic sequence for several of the novel A/H1N1 strains, including a Mexican isolate, has been made publicly available," write Lourdes Garcia-Garcia, from Instituto Nacional de Salud Pública in Cuernavaca, Mor, Mexico, and colleagues. "Given the new reassortant nature of this virus — that is, unusual mixing of swine, avian, and human influenza genetic sequences — the available evidence, although incomplete, suggests that seasonal vaccines will confer little or no protection against influenza A/H1N1. Mexican guidelines recommend vaccination with trivalent inactivated influenza vaccine (virus strains A/Brisbane/59/2007 (H1N1)-like, A/Brisbane/10/2007 (H3N2)-like, and B/Florida/4/2006-like antigen) for children aged 6-35 months, all adults aged more than 60, and individuals older than 35 months with conditions conferring a higher risk of influenza related complications."

The goal of this study was to examine the association of 2008–2009 seasonal trivalent inactivated vaccine with cases of influenza A/H1N1 during the epidemic in Mexico. From March to May 2009 at a specialty hospital in Mexico City, 60 patients with laboratory-confirmed influenza A/H1N1 were compared with 180 control patients matched for age and socioeconomic status. Control subjects had diseases other than influenza-like illness or pneumonia and were living in Mexico City or the state of Mexico. The primary study endpoints were odds ratio (OR) and effectiveness of trivalent inactivated vaccine against influenza A/H1N1.

Compared with control patients, patients with laboratory-confirmed influenza A (H1N1) had higher rates of hospitalization, invasive mechanical ventilation, and death. However, control patients were more likely than patients with laboratory-confirmed influenza A (H1N1) to have chronic conditions associated with a higher risk for influenza-related complications. H1N1 influenza was independently associated with receipt of trivalent inactivated vaccine (OR, 0.27; 95% confidence interval [CI], 0.11 – 0.66) and with underlying conditions (OR, 0.15; 95% CI, 0.08 – 0.30), based on the multivariate model. Trivalent inactivated vaccine effectiveness against H1N1 influenza was 73% (95% CI, 34% – 89%), and none of the 8 vaccinated patients with laboratory-confirmed influenza A (H1N1) died.

"Preliminary evidence suggests some protection from the 2008-9 trivalent inactivated vaccine against pandemic influenza A/H1N1 2009, particularly severe forms of the disease, diagnosed in a specialty hospital during the influenza epidemic in Mexico City," the study authors write. "These results are to be considered cautiously and in no way indicate that seasonal vaccine should replace vaccination against pandemic influenza A/H1N1 2009. Our data support the hypothesis that partial protection provided by the seasonal vaccine may be explained by the boosting of existing antibodies that were elicited by previous exposure, through either infection or vaccination, to an influenza A/H1N1 virus genetically and antigenically more closely related to the novel influenza virus than contemporary seasonal H1N1 strains."

Limitations of this study include its retrospective design, small sample size, self-reported vaccine status, and lack of blinding of interviewers to the status of patients with laboratory-confirmed influenza A (H1N1) and control patients.

"The estimates for vaccine effectiveness could be inflated owing to a high prevalence of chronic conditions and vaccination in our control population," the study authors conclude. "Similar studies in other settings are needed to confirm or refute our results."

In an accompanying editorial, Menno D. de Jong, from the Academic Medical Centre of the University of Amsterdam, the Netherlands, and Rogier W. Sanders, from Weill Medical College of Cornell University, New York City, also warn that a specific vaccine against influenza A (H1N1) is still needed. Even in countries that have arranged for vaccine production in sufficient quantities, vaccines may not be available in time.

"Antibodies that recognise multiple influenza strains are rare, which explains the frequent lack of cross protection between vaccines and natural infection," Dr. De Jong and Dr. Sanders write. "However, antibodies have been identified that may open possibilities of developing a 'universal flu vaccine.' Traditional flu vaccines have a good track record in terms of efficacy and safety, so it will take years to replace them, but the new techniques and vaccines at various stages of testing are both necessary and promising."

The Mexican Ministry of Health supported this study. Two of the study authors are employed by Laboratorios de Biológicos y Reactivos de México. Dr. De Jong and Dr. Sanders have disclosed no relevant financial relationships.

BMJ. Published online October 6, 2009.

HOW SHOULD WE MANAGE DRUG INTERACTIONS BETWEEN CLOPIDOGREL AND PROTON-PUMP INHIBITORS?

AN ARTICLE FROM MEDSCAPE

Question

What is the best practice intervention for patients on both clopidogrel and proton-pump inhibitors (PPIs)?

Response from Jenny A. Van Amburgh, PharmD, CDE Associate Clinical Professor, School of Pharmacy, Northeastern University, Boston, Massachusetts; Director of the Clinical Pharmacy Team and Residency Director, Harbor Health Services, Inc., Boston, Massachusetts

According to a 2007 survey, clopidogrel is the sixth most commonly dispensed medication in the United States. Indicated to reduce the rates of antithrombotic events in patients with a recent cardiovascular event, clopidogrel plays an integral role in the care of patients after myocardial infarction, stroke, or acute coronary syndrome. To reduce the risk for gastrointestinal bleeding, which can be associated with this drug, clinicians often prescribe a concomitant proton-pump inhibitor (PPI) for high-risk patients. Because of its generic availability and over-the-counter (OTC) status, omeprazole (Prilosec^®, Prilosec OTC^®) is one of the most widely used and accessible PPIs today.

Recent evidence suggests that certain PPIs reduce the antiplatelet effects of clopidogrel. Clopidogrel, a prodrug, requires metabolism in the liver via cytochrome P450 (CYP) enzymes. Once activated, clopidogrel blocks platelet aggregation by inhibiting adenosine diphosphate at the P2Y12 receptor. PPIs, such as omeprazole and its S-enantiomer esomeprazole (Nexium^®), are thought to inhibit the CYP2C19 enzyme, thus negating the antithrombotic effects of clopidogrel. CYP2C19 also acts as the primary enzyme responsible for determining a patient’s pharmacodynamic response to clopidogrel. The question of how to best care for patients taking both PPIs and clopidogrel remains unanswered.

Gilard and colleagues conducted a randomized, double-blind, placebo-controlled study to assess the influence of omeprazole on clopidogrel efficacy. They randomly assigned 145 patients who were undergoing coronary artery stent implantation and receiving aspirin, 75 mg daily, and clopidogrel, 75 mg daily (after a 300-mg loading dose), into 2 groups. The treatment group received omeprazole, 20 mg daily for 7 days, and the control group received placebo for 7 days. Assessment of the platelet reactivity index (PRI) was the primary endpoint. A PRI less than 50% indicated a favorable response to clopidogrel.

The data from 124 patients were reviewed after the 7-day course of therapy. Before treatment, the PRI was 83.2% in the control group and 83.9% in the treatment group. At study end, the PRI was 39.8% in the control group and 51.4% in the treatment group (P < .001). Patients who received gastroprotection with omeprazole were 4.31 times more likely to respond poorly to clopidogrel. The long-term implications of this interaction are uncertain but may suggest reduced cardioprotective benefits of clopidogrel.

Although recent evidence indicates an interaction between PPIs and clopidogrel, further emphasis should be placed on the pharmacogenetic properties that influence clopidogrel metabolism. An estimated 30% of whites, 40% of blacks, and over 55% of East Asians have a CYP2C19 gene polymorphism that reduces the pharmacodynamic and pharmacokinetic response of clopidogrel. With clopidogrel metabolism reduced in these patients, concomitant PPI therapy can further reduce its metabolism, predisposing patients to such adverse events as cardiovascular events and death.

At the 2009 Society for Cardiovascular Angiography and Interventions meeting, investigators reported results of a retrospective cohort of over 16,700 patients who received clopidogrel (with or without PPI) after stenting. Patients who received PPIs had a more than 50% higher risk for 1-year cardiovascular events compared with patients who did not receive PPIs. The findings suggest that the increased risk for cardiovascular events may be a class effect of PPIs and may not just be the result of specific agents as once perceived.

For now, healthcare providers should exercise clinical judgment and recommend that only high risk-patients (those receiving dual antiplatelet therapy, those with a history of gastrointestinal bleeding or ulcers, or those receiving concomitant anticoagulant therapy) receive PPIs in conjunction with clopidogrel. The manufacturer of clopidogrel discourages its use with omeprazole on the basis of the new evidence.

If gastroprotection is deemed appropriate, consider using histamine-2 blockers such as ranitidine (Zantac^®) or famotidine (Pepcid^®) as first-line therapy. Clinicians should note that histamine-2 blockers may be less efficacious than PPIs for gastroprotection, but they have similar efficacy for heartburn and symptoms similar to those of gastroesophageal reflux disease.

APPROVAL OF NEW DIPLOMA TITLE

Good day to all Malaysian Assistant Pharmacist. Today another history was created in our profession. The long awaited to get recognised of our Diploma is finally succeeded. The Education Bureau from Health Ministry Training Division finally approved our diploma title change from "Diploma Pembantu Farmasi" to "DIPLOMA FARMASI". (Diploma in Assistant Pharmacist to Diploma in Pharmacy).

This is the most sweetest news after the change of our job title. At the meeting this morning, the bureau also approved our very first "POST BASIC" course since 50yrs of our profession in the Pharmacy Industry.

All the credit should be given to Pharmacy Services Division, National Pharmacy Assistant Association, our Union, staffs from Health Ministry training division, staffs from pharmacy college (KSKB Sg.Buloh)and those involved make this dream come true. GOD BLESS ALL.

Most thankfull to our new Pharmacy Services Division Director, Puan Eisah bt Abd Rahman who always supported our struggle, understand and who really care as a mother to fulfill the needs of a child.

GOD BLESS MOTHER EISAH AND EVERYONE INVOLVED.

THANK YOU

Pharmacist-Doctor Teams Help Keep Heart-Failure Patients Out of the Hospital

ARTICLE FROM MEDSCAPE, AUGUST 18TH

August 18, 2009 (Adelaide, Australia) — Collaboration between doctors and pharmacists can reduce medication-related problems and hospitalizations and improve health outcomes in patients with heart failure, Australian researchers report in a study published online before print August 18, 2009 in Circulation: Heart Failure [1].

A service wherein pharmacists visited heart-failure patients in their homes to review their medications and then reported the findings to the patients' doctors cut the rate of hospitalization for heart failure by 45% in its first year of operation, Dr Elizabeth E Roughead (University of South Australia, Adelaide) and colleagues write.

"Medication-related problems contribute to the problem of hospitalization for heart-failure patients, so educating these patients about drug use is important," Roughead told heartwire . "The home visit part of this program enables time for more thorough education. Clinicians should work with pharmacists to help their heart-failure patients."

A Synergistic Relationship

Dr Mauro Moscucci (University of Miami Miller School of Medicine, FL) agreed that the partnership between pharmacists and clinicians has important and positive implications for improving outcomes for heart-failure patients.

"It's the synergy that is impressive. Improved outcome is due not to pharmacists' visits alone but to the partnership between the two healthcare providers," Moscucci told heartwire .

Roughead and her colleagues sought to determine whether collaborative medication reviews, which have been shown to be successful in improving outcomes for patients with heart failure in randomized controlled trials, would also be successful in a "real-world" setting. Such reviews are nationally funded in Australia.

They retrospectively reviewed administrative claims data on veterans and war widows aged 65 years and older who were prescribed bisoprolol, carvedilol, or metoprolol succinate for heart failure and compared 273 patients who received general practitioner-pharmacist collaborative home medication review with 5444 controls who did not.

The average age of the patients in both groups was 81.6 years. The median number of comorbidities was eight in the group who received the collaborative reviews compared with seven in the group who did not (p<0.0001).>

"We chose to study a veteran population because they are elderly and an appropriate target population for home medicines review services," Roughead explained.

Review Delayed Hospitalization for Heart Failure

The time to hospitalization for heart failure was significantly delayed in the group that received a home medicines review, the investigators found. After adjustment for a variety of confounding variables, only 5.5% of the patients in the review group were hospitalized within a year, compared with 12% of the control group (hazard ratio [HR] 0.55, 95% CI 0.39–0.77; p<0.0001).

Pharmacist Dr Amy Seybert (University of Pittsburgh Medical Center, PA) told heartwire that pharmacists are particularly well-suited for counseling patients. "Definitely. It's what we are trained to do. We explain to patients why they should take their medications and stress the importance of compliance. We tell them how the drugs work. I really think that if patients understand why they are taking something and for what purpose, they are much more apt to be compliant."

Her colleague, Dr Joon Sun Lee (University of Pittsburgh Medical Center), agrees.

"The Australian study confirms much that is known. As treatment regimens, especially medication regimens for heart-failure patients, become more and more complex, the potential for patients to get confused becomes greater. So measures that confirm medication regimens and also check up on patients are effective at decreasing readmissions," he said.

It Works Well Down Under, But Will It Work in the US?

More and more institutions in the US are using pharmacists to help educate patients, usually as part of hospital discharge programs. But Sun Lee questions whether a partnership between pharmacist and clinician as the Australians have would be feasible in the US.

"One of the vulnerabilities and inefficiencies of the US healthcare system is that the collaborative medication review part of healthcare is not rewarded financially. It is an extra cost without reimbursement, whether you are talking about the hospital incurring the cost or the doctor's office. Right now, this is one of the cracks that exist in the delivery care system," he said

Diabetes May Soon Be Diagnosed by MRI

by, DIABETES PHARMACIST.COM
August 6, 2009 by Joel Shpigel R.Ph.

Using noninvasive imaging (Magnetic Resonance Imaging (MRI) ) for the first time in diabetes research, physicians at Massachusetts General Hospital and Harvard Medical School have discovered how it may aid in the early diagnosis, staging, and treatment of diabetes.

"With noninvasive MRI we have the ability to evaluate beta cell mass, a major factor of insulin secretion that is significantly reduced in type two diabetes and almost gone in type one,” said Anna Moore, MD, lead author of the study. “Knowing the number of functional beta cells left would allow physicians to develop the most appropriate treatment plans for their patients. It would also allow them to respond, change or manipulate those treatment plans at any time,” she said.

- Diabetes Pharmacist has been named one of the 100 Best Blogs for Pharmacy Students by Jill Gordon on Nursing Schools.Net., a nursing school network and directory.

Medication Reconciliation Performed by Pharmacy Technicians at the Time of Preoperative Screening

Abstract

Background: Medication errors occur regularly in surgical patients, especially due to transfer problems at the time of hospital admission. A method for decreasing the error rate is medication reconciliation by hospital pharmacists as part of a preoperative clinic. The role of pharmacy technicians in this process has not been studied.
Objective: To study the use of pharmacy technicians in medication reconciliation by measuring the effect of early reconciliation in the preoperative clinic on medication and allergy discrepancies and on inadvertent continuation of antithrombotics. A secondary objective was to study the effect of community pharmacist follow-up on recommendations to discontinue antithrombotic therapy.
Methods: During the preintervention measurement period, patients received usual care by anesthesiologists, who recorded the medication and documented allergies of the patient. The intervention consisted of the addition of a pharmacy technician to the preoperative screening clinic to perform the same tasks as anesthesiologists as related to medication reconciliation. If necessary, the patient was advised on stopping the antithrombotic. On the day that the patient was supposed to stop the antithrombotic, that person's community pharmacist contacted the patient to determine whether this had been done. The main outcome measures were the proportions of patients with one or more medication discrepancy, one or more allergy discrepancy, and one or more antithrombotic error.
Results: In the preintervention period, 204 patients were evaluated; 93 were included in the postintervention analysis. The proportion of patients with one or more medication discrepancy (RR 0.29; 95% CI 0.12 to 0.71) was statistically significantly reduced in the postintervention group. The proportions of patients with one or more allergy discrepancy (RR 0.76; 95% CI 0.35 to 1.64) and one or more antithrombotic errors (RR 0.18; 95% CI 0.02 to 1.33) were reduced, but not significantly. Follow-up by the community pharmacist did not identify any patients who had not followed the preoperative clinic's advice on temporarily withholding their antithrombotics.
Conclusions: The results of this study show that pharmacy technicians can be successfully assigned to a preoperative clinic, resulting in a statistically significant decrease in medication discrepancies.

INNOVATION AWARDS FOR PHARMACIST & PHARMACY TECHNICIAN

See how a good team work between Pharmacist and Pharmacy Technicians on a innovation project in USA which gives more room to Pharmacist to practice in clinical works.

We should follow this steps too in Malaysia. Read more belows from MEDSCAPE.

New York (MedscapeWire) Dec 13 — Five teams of pharmacists and certified pharmacy technicians were declared the winners of this year's Innovations in Pharmaceutical Care Award on December 4th at the American Society of Health-System Pharmacists (ASHP) Midyear Conference in Las Vegas, Nevada.

Winners included a team at Duke University Medical Center that reengineered pharmacy work functions to allow pharmacists more time to focus on patient care. Another winning team, from North Mississippi Medical Center - Department of Pharmacy Services, uses a certified pharmacy technician in the medication error tracking and reporting process, giving pharmacists and other health professionals more time to implement new patient care programs.

The award, founded in 1998 by the Pharmacy Technician Certification Board (PTCB), recognizes innovations in pharmaceutical care by teams of pharmacists and certified pharmacy technicians in any practice setting. Each of the five winning teams received a cash award of $1,000 to be shared equally by the pharmacist and certified pharmacy technician and a framed certificate to be displayed in their respective practice settings.

"We take great pride in the Innovations Award Program," said Melissa M. Murer, RPh, PTCB Executive Director. "Efforts to enhance patient care, reduce medication errors and manage patient's chronic diseases serve as best practices for the over 70,800 certified pharmacy technicians nationwide."

ARTICLE FROM MEDSCAPE

New CDC Recommendation: All Children Should Receive Annual Seasonal Flu Vaccines

July 27, 2009 — The US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, is changing its recommendation for annual seasonal influenza vaccination for children aged 6 months to 18 years to a "full recommendation," Anne Schuchat, MD, director of the CDC's National Center for Immunization and Respiratory Diseases, announced.

In addition, the CDC is advising a seasonal flu vaccine for anyone who feels they need one.

"While we are focusing a lot of attention on the 2009 H1N1 influenza virus, we do expect seasonal strains to emerge, and we are issuing updates of which strains to expect," Dr. Schuchat said. These include the A-H1N1, A-H3N2, and B strains, "which are available in this year's vaccine," she noted. "This past year's recommendations encouraged annual vaccination [of children].... This year, [the CDC] is no longer just advising vaccination whenever feasible but is [issuing] a full-out recommendation" of the seasonal flu vaccine.

Only about 40% of the US population received a flu vaccine last year. The CDC is recommending and emphasizing "an intensification of use" of the vaccine.

The CDC has specifically recommended that healthcare workers be immunized, as well as that campers at sleepover summer camps and attendees of military academies where there have been notable outbreaks of influenza receive the flu vaccine and antiviral agents, but only if appropriate.

"I don't think antiviral prophylaxis is a good idea," Dr. Schuchat said, noting that oseltamivir-resistant influenza strains have been reported.

Dr. Schuchat said that the latest laboratory-confirmed case count for the H1N1 influenza virus is 43,771 cases and 302 deaths, "but this is the last time we will be reporting cases in this way." Instead, the CDC will have a FluView Weekly Surveillance Report, updated every Friday, on its Web site.

The National Institutes of Health announced yesterday that clinical trials will begin as early as next week of 2 H1N1 influenza vaccine candidates in adults, either alone or in conjunction with the seasonal flu vaccine and, if safe, in children.

Sanofi Aventis and CSL Biotherapies, manufacturers of the 2 candidate vaccines, told a US Food and Drug Administration (FDA) advisory committee yesterday that they expect to have a vaccine available by October. Dr. Schuchat said that she is concerned that the flu season could be well underway by that time, because the school year begins within weeks in many areas.

The virus is unpredictable, she said, "skipping entire communities, while hitting others really hard." In addition, the virus can cause a wide spectrum of illness, from mild symptoms to respiratory arrest and neurological problems, including seizures. "That is why we are taking the virus so seriously." H1N1 often affects young, apparently healthy individuals, as well as those at high risk, and it could affect more than 40% of the population.

"We are preparing for the worst-case scenario of 60% of the population being affected," Dr. Schuchat said. "The value of worst-case scenario planning is that it allows for continuity planning."

The FDA's Advisory Committee on Immunization Practices is set to meet July 29 to propose H1N1 vaccine recommendations. Children aged 0 to 4 years will likely be the top priority, followed by school-age children, healthcare workers, pregnant women, and adults with chronic diseases.

Today, the FDA announced it had issued an emergency use authorization for a third diagnostic test for the 2009 H1N1 influenza virus because a public health emergency involving H1N1 was declared on April 26, 2009. It is the Focus Diagnostics Influenza H1N1 (2009) Real-Time Reverse Transcription Polymerase Chain Reaction diagnostic test.

The emergency use authorization allows Focus Diagnostics to distribute the test to laboratories certified under the Clinical Laboratory Improvement Amendments to perform high-complexity tests. This test is intended for use in the detection of the 2009 H1N1 influenza virus in patients with symptoms of respiratory infection.

The test does not indicate the stage of infection, nor does a negative result preclude influenza virus infection, FDA officials emphasize.

MMWR Morb Mortal Wkly Rep. Posted online July 24, 2009

From MedscapeCME Cardiology

Raising Awareness of Resistant Hypertension: Burden, Diagnosis, and Emerging Therapies

Michael A. Weber, MD

Published: 07/31/2009

Introduction

Resistant hypertension is defined as blood pressure that remains above target goals despite concurrent use of 3 antihypertensive medications of different classes, including a diuretic, all at optimal doses.[1-3] The exact prevalence of resistant hypertension is not well defined, and there is no current standard of care for its management. Overall, resistant hypertension remains understudied and additional knowledge is needed to better identify and treat patients with the condition. Clinical data on novel therapeutic options for the management of treatment-resistant hypertension were highlighted at this year's meeting of the European of Society of Hypertension (ESH), held June 12-16, 2009 in Milan, Italy. To provide a context for these results, Linda Brookes, MSc, on behalf of MedscapeCME Cardiology, spoke with Michael A. Weber, MD, Professor of Medicine, SUNY Downstate College of Medicine, Brooklyn, New York. In the following interview, Dr. Weber discusses the global burden of the condition, diagnosis, and current and emerging treatment options.
Burden of Resistant Hypertension

MedscapeCME: Hypertension management guidelines are consistent about the definition of resistant hypertension as failure to achieve blood pressure goal (<>

Michael A. Weber, MD: Resistant hypertension may occur in only about 10% to 15% of all cases of hypertension, but bearing in mind that there are over 70 million people with hypertension in the United States, this means that there are several million people with resistant hypertension.[4] So if this were a disease all by itself, it would be regarded as a relatively common condition.

MedscapeCME: Is this why resistant hypertension seems to have been the subject of so much attention recently?

Dr. Weber: In many places around the world, physicians are pressured to do a better job in treating common chronic conditions and to demonstrate that they are doing everything they possibly can to treat them. In hypertension, they must show either that they have the patient's blood pressure well controlled or at least that they have gone through all the steps to try and get it well controlled. Yet there will be a proportion of patients who will be difficult to treat, and I believe experts are focused on that problem now.
Challenges in Diagnosing and Managing Resistant Hypertension

MedscapeCME: What about the diagnosis of resistant hypertension? This seems to involve 3 questions: What makes hypertension truly "resistant?" How early can it be recognized? And is there a genotype or a typical phenotype associated with resistant hypertension?

Dr. Weber: For a start, there isn't a recognized genotype. And there really isn't an obvious predictive finding that tells you in advance that a particular patient is going to have treatment-resistant hypertension. Many people with treatment-resistant hypertension emerge with that classification only after several weeks or months of disappointments for the physician trying to manage the hypertension.

MedscapeCME: So how does a physician confirm that a patient has resistant hypertension?

Dr. Weber: First, it is important to ensure, as best you can, that the patients are actually taking their medications. This may involve a lot of detailed discussion with patients to satisfy doctors that the patients really are following their treatment. If they are, the next question is whether the treatment regimen is a logical one. For instance, does it include drugs that ought to be part of any hypertension treatment plan, such as a diuretic and a blocker of the renin-angiotensin system, and are the drugs being given at appropriate doses?

In terms of diuretics, I believe that our efforts in the past few years have sometimes been inadequate in that we have tended to often rely on low-dose hydrochlorothiazide (HCTZ). This works well in most hypertensive patients when it is paired with a drug such as an angiotensin-receptor blocker (ARB), an angiotensin-converting enzyme (ACE) inhibitor, or a calcium-channel blocker. However, in people with resistant hypertension, who often have diminished renal function, HCTZ at a dose of 12.5 or 25 mg may not be effective and chlorthalidone should be considered instead. Also, much of the clinical trial experience demonstrating prevention of major outcomes, such as stroke, has been with chlorthalidone rather than HCTZ.[5-9]

So if the right drugs are being prescribed in the right doses and the patient is taking their medications, is something happening to prevent these drugs from working effectively? One explanation may be that the patient has an underlying so-called "secondary cause'" for hypertension that does not respond to drugs -- for example, an adrenal cortex tumor, a pheochromocytoma, renal artery stenosis, or advanced kidney disease.[2] The other main cause of not responding adequately despite a good treatment regimen is that the patient is taking a medication that is raising blood pressure and interfering with the actions of the antihypertensive drugs.[2] Culprits include nonsteroidal anti-inflammatory drugs (NSAIDs), oral contraceptives, and some common cold remedies.

MedscapeCME: Wouldn't patients usually be warned about taking other medications at the start of their treatment?

Dr. Weber: Not necessarily. Some physicians overlook the fact that drugs such as NSAIDs might be a problem, and second, they may not always know that a patient is taking drugs like ibuprofen or naproxen because they are usually acquired over the counter and not reported to the doctor. So it is necessary to think proactively about drugs that could be interfering with blood pressure-lowering medications.

MedscapeCME: Presumably it is fairly straightforward to deal with those sorts of problems, but identifying or ruling out secondary causes is more complicated and time-consuming?

Dr. Weber: That is correct. The modern approach to looking for secondary causes typically involves some sort of imaging -- for example, an angiogram, computerized tomography scan, or magnetic resonance imaging. So it can be a fairly major commitment to consider a secondary cause of hypertension. It has to be on the list of possible causes to check, however. You have to decide that these conditions are unlikely before you can conclude that a patient truly has treatment-resistant hypertension.

MedscapeCME: At that point should a patient have been referred to a clinical hypertension specialist?

Dr. Weber: Yes. If you are really pursuing secondary hypertension, the patient is probably served best in the hands of a specialist who has experience in working up these kinds of conditions. In reality, these conditions are relatively uncommon and most physicians have probably not had much experience in the latest diagnostic methods for identifying underlying causes of hypertension. So the patient should be referred to a hypertension specialist, or if there isn't one readily available, then a nephrologist or other specialist who has experience with secondary hypertension.

MedscapeCME: What about primary aldosteronism -- is that a common secondary cause?

Dr. Weber: A fair number of people with resistant hypertension have high aldosterone levels, so the simplest, most effective approach might be to try an aldosterone-receptor blocker, such as spironolactone or eplerenone, for a few weeks and see whether it works. Experience suggests that this should produce a good result quite often,[10-14] especially in African American patients, although there have not been comprehensive studies to confirm this.

MedscapeCME: Even after trying an aldosterone-receptor blocker, there are a number of other classes of drugs that might be tried, such as beta-blockers and centrally acting alpha-agonists. How does a physician decide which one to add?

Dr. Weber: A beta-blocker, preferably one that does not carry the metabolic and symptomatic side effects of the more traditional beta-blockers, may be effective (ie, nebivolol or carvedilol). Then you can consider the centrally acting drugs, such as clonidine, which can be quite efficacious even though they may cause drowsiness in some patients.[1] It is possible to consider even older drugs like reserpine, although it has been shown that some patients experience negative emotional disturbances with the drug.[1] Hydralazine can be effective; it is a vasodilator, but it causes fluid retention, so you should ensure that the patient is getting a good diuretic. It can also accelerate the heart rate, so you usually need to give a beta-blocker as well. If you want to be more aggressive than hydralazine, you can give a stronger vasodilator, minoxidil, which can be effective in patients with complicated cases of refractory hypertension and concomitant kidney disease.[1] In short, some of these older drugs work, but they can be difficult to use.
Emerging Therapeutic Options

MedscapeCME: So it appears that even after exercising all of these options, there are some patients whose blood pressure remains uncontrolled. What is the future, as far as new drugs are concerned, with different mechanisms of action?

Dr. Weber: There are a number of investigational drugs and interventions in development for the management of resistant hypertension. The effects of endothelin antagonism, for example, were discussed at this year's ESH meeting.

We presented the results of the phase 3 clinical trial, DAR-311 (also known as DORADO), which evaluated the use of darusentan (Gilead Sciences; Foster City, California), an investigational oral, once-daily endothelin- receptor antagonist for the treatment of resistant hypertension.[15] As reported at the American Society of Hypertension (ASH) meeting in San Francisco[16] and at the ESH meeting,[17] the findings showed that compared with placebo, darusentan was associated with significant reductions in blood pressure in patients with resistant hypertension.

All patients enrolled in the DAR-311 trial were already taking at least 3 well-selected and well-dosed drugs -- in fact, 60% were taking 4 or more drugs -- so they were getting good treatment. With the addition of darusentan they achieved close to an additional 10-mm Hg decrease in systolic blood pressure compared with placebo. Previously in a phase 2 study, darusentan was seen to decrease mean systolic and diastolic blood pressure and was well tolerated compared with placebo in over 100 patients with resistant hypertension.[18]

MedscapeCME: Darusentan is a selective endothelin type A-receptor antagonist. Do these phase 3 data tell us more about the role of endogenous endothelin in hypertension?

Dr. Weber: We know theoretically that endothelin could have adverse vascular effects that might be associated with the major cardiovascular outcomes of hypertension. However, there are many endogenous factors that potentially could have adverse vascular effects, so we must be careful that we don't overinterpret our results. Although the findings with endothelin blockade are interesting, we should be cautious about using these data to speculate about underlying causes of resistant hypertension.

MedscapeCME: Can you comment on the cardiac side effects associated with darusentan that occurred in the phase 3 trial?

Dr. Weber: We reported a number of cardiac side effects, but it is important to understand that the treatment-resistant patients we studied were a high-risk group: 40% of them had diabetes, about one third had kidney disease, and about one third had a history of coronary disease. This group was at high cardiovascular risk and it shouldn't be a surprise that 2 patients taking darusentan had nonfatal myocardial infarctions and 1 patient on placebo had sudden cardiac death. There were also some patients who had the clinical findings of heart failure. One case was a patient known to have heart failure before the study began and should not have been enrolled in the trial. The other heart failure cases in patients receiving darusentan appeared to be related to fluid retention and manifested as pulmonary congestion. In fact, the patients with heart failure all had preserved left ventricular systolic function with normal ejection fractions. My personal belief is that these patients, who responded rapidly to appropriate diuretic therapy, most likely represented an unmasking of underlying left ventricular diastolic dysfunction in patients with long-standing severe hypertension. Bearing in mind that these events, with concomitant fluid retention, became apparent in the first few weeks of therapy, it seems unlikely that the drug affected heart function independently of its volume effects. This phenomenon has also been observed with other vasodilatory drugs used in hypertension.

We did learn a lesson, though, which was that in using vasodilatory drugs like darusentan, we cannot assume that the low doses of HCTZ typically prescribed in hypertension will be adequate. In patients who have diabetes or kidney disease or a history of coronary events, this type of diuretic therapy is not sufficient. I believe that we either need to use higher doses of HCTZ or, even better, work with a drug like chlorthalidone or consider a long-acting loop diuretic like torsemide (rather than furosemide, which is difficult to work with long-term in hypertensive patients).

MedscapeCME: Is there another phase 3 trial ongoing with darusentan?

Dr. Weber: A long-term extension of the recently completed trial and an additional phase 3 study (DAR-312 [also known as DORADO-AC]) comparing darusentan with active treatment rather than with placebo are being done.[19] I believe that the latter trial will be finished before the end of the year.

We have shown that darusentan is an effective strategy in treatment-resistant hypertension. Our next task is to devise clear information for physicians on its use -- in other words, how to choose the correct dose and how to optimize the other drugs that are taken with it. These are areas that we have an obligation to study.

MedscapeCME: What about the other investigational drugs in clinical development for resistant hypertension?

Dr. Weber: LCI699 (Novartis AG; Basel, Switzerland) is an aldosterone-synthase inhibitor in clinical trials for resistant hypertension.[20] This is an interesting drug, as it provides an alternative to aldosterone-receptor blockers but may be better tolerated than spironolactone. Another promising strategy for the future may be LCZ696 (Novartis Pharmaceuticals; East Hanover, New Jersey), a novel vasopeptidase inhibitor that acts as a dual ARB inhibitor plus neutral endopeptidase (NEP) inhibitor. Unlike omapatrilat, a dual ACE inhibitor plus NEP inhibitor that was effective but associated with severe angioedema, LCZ696 has been shown to be effective but apparently without major adverse effects.[21,22] I have also heard about a nicotinic-channel blocker, TC-5214 (Targacept, Inc; Winston-Salem, North Carolina), that is being looked at as a possible augmentation therapy for resistant hypertension.[23,24]

MedscapeCME: There are 2 interventional approaches that are being developed for patients with resistant hypertension: the Rheos® Hypertension Therapy system (CVRx, Inc; Minneapolis, Minnesota), an implantable device that has been shown in clinical trials to lower blood pressure through activation of carotid baroreceptors[25]; and renal sympathetic denervation, a catheter-based interventional procedure, which has been shown to be effective in a proof-of-concept study.[26]

Dr. Weber: These approaches have shown encouraging results, although they both involve significant interventions. They should be studied further because there are so many patients who are very hard to treat.

Perspective

MedscapeCME: Are you hopeful for the future treatment of resistant hypertension in general?

Dr. Weber: One of the good things about these recent developments is that they have drawn a lot of physicians' attention to resistant hypertension. These cases can draw nihilism after 3 or 4 drugs have been tried without success. This new focus on resistant hypertension will, I believe, energize many physicians to try a little longer and a little harder with their patients to find an answer to their hypertension problems.

This activity is supported by an independent educational grant from Gilead Sciences, Inc.