Abstract and Introduction

Abstract

Helicobacter pylori infection is the main known cause of gastritis, gastroduodenal ulcer disease and gastric cancer. After more than 20 years of experience in H. pylori treatment, however, the ideal regimen to treat this infection has still to be found. Nowadays, apart from having to know well first-line eradication regimens, we must also be prepared to face treatment failures. Therefore, in designing a treatment strategy we should not focus on the results of primary therapy alone, but also on the final (overall) eradication rate. The choice of a 'rescue' treatment depends on which treatment is used initially. If a first-line clarithromycin-based regimen was used, a second-line metronidazole-based treatment (quadruple therapy) may be used afterwards, and then a levofloxacin-based combination would be a third-line 'rescue' option. Alternatively, it has recently been suggested that levofloxacin-based 'rescue' therapy constitutes an encouraging second-line strategy, representing an alternative to quadruple therapy in patients with previous PPI-clarithromycin-amoxicillin failure, with the advantage of efficacy, simplicity and safety. In this case, quadruple regimen may be reserved as a third-line 'rescue' option. Finally, rifabutin-based 'rescue' therapy constitutes an encouraging empirical fourth-line strategy after multiple previous eradication failures with key antibiotics such as amoxicillin, clarithromycin, metronidazole, tetracycline, and levofloxacin. Even after two consecutive failures, several studies have demonstrated that H. pylori eradication can finally be achieved in almost all patients if several 'rescue' therapies are consecutively given. Therefore, the attitude in H. pylori eradication therapy failure, even after two or more unsuccessful attempts, should be to fight and not to surrender.

Introduction

Helicobacter pylori infection is the main known cause of gastritis, gastroduodenal ulcer disease and gastric cancer. After more than 20 years of experience in H. pylori treatment, however, the ideal regimen to treat this infection has still to be found [Vakil, 2009]. Consensus conferences have recommended therapeutic regimens that achieve H. pylori cure rates higher than 80% on an intention-to-treat basis [Malfertheiner et al. 2007, 2002; Howden et al. 1998]. However, several large clinical trials and meta-analyses have shown that the most commonly used first-line therapies – including proton-pump inhibitors (PPIs) plus two antibiotics – may fail in up to 20% of patients [Gisbert et al. 2007d, 2000b], and in the clinical routine setting, the treatment failure rate might be even higher. Moreover, during the last few years, the efficacy of PPI-based regimens seems to be decreasing, and several studies have reported intention-to-treat eradication rates lower than 75% [Paoluzi et al. 2006; Calvet et al. 2005; Gisbert et al. 2005b; Vakil et al. 2004; Hawkey et al. 2003; Veldhuyzen Van Zanten et al. 2003; Laine et al. 2000, 1998] and even lower than 50% [Altintas et al. 2004; Gumurdulu et al. 2004; Della Monica et al. 2002]. Antibiotic resistance to clarithromycin has been identified as one of the major factors affecting our ability to cure H. pylori infection, and the rate of resistance to this antibiotic seems to be increasing in many geographical areas [Egan et al. 2008; Megraud, 2004; Vakil et al. 1998].

Papers dealing with retreatment of H. pylori after failure are difficult to analyze due to several reasons [Axon, 2000]. Firstly, patients who fail with their first treatment probably include a higher percentage of individuals who are unreliable tablet takers, others who have resistant organisms and also the 'constitutional' group, where failure will be inevitable. On the other hand, some patients submitted for 'rescue' therapy have already had more than one previous treatment for H. pylori, and this circumstance is not always clarified in the protocols. Furthermore, the original primary treatments vary among the different studies, not only with respect to the antibiotic type, but also in respect to the dose and duration of the regimen. Finally, only a few studies have directly compared, in the same protocol, two or more second-line therapies [Gisbert, 2008; Gisbert and Pajares, 2002, 2005].

Several 'rescue' therapies have been recommended, but they still fail to eradicate H. pylori in more than 20% of the cases [Gisbert and Pajares, 2002], and these patients constitute a therapeutic dilemma [Gisbert, 2008; Gisbert and Pajares, 2005]. Patients who are not cured with two consecutive treatments including clarithromycin and metronidazole will have at least single, and usually double, resistance [Romano et al. 2008; Megraud, 2004]. Furthermore, bismuth salts are not available worldwide anymore and, therefore, management of first-line eradication failures is becoming challenging. Currently, a standard third-line therapy is lacking, and European guidelines recommend culture in these patients to select a third-line treatment according to microbial sensitivity to antibiotics [Malfertheiner et al. 2007, 2002]. However, cultures are often carried out only in research centers, and the use of this procedure as 'routine practice' in patients who failed several treatments seems not to be feasible [Gisbert, 2008; Gisbert and Pajares, 2005; Zullo et al. 2003b; Gisbert and Pajares, 2002]. Therefore, the evaluation of drugs without cross-resistance to nitroimidazole or macrolides as components of retreatment combination therapies would be worthwhile [Graham, 2009].

Probiotics have been proposed as a useful adjunct. Some studies prescribing probiotics with H. pylori eradication therapy had no effect on the side-effect profile but did increase the rates of eradication [Kim et al. 2008]. However, other studies on concurrent probiotic administration suggested the inverse with better side-effect profiles but no increase in eradication or rates of compliance with therapy [Cremonini et al. 2002]. All these issues are important at the present time, but they will be even more relevant in a near future, as therapy for H. pylori infection is becoming more and more frequently prescribed. Therefore, the evaluation of second or third 'rescue' regimens for these problematic cases seems to be worthwhile. In designing a treatment strategy we should not focus on the results of primary therapy alone; an adequate strategy for treating this infection should use several therapies which, if consecutively prescribed, come as close to the 100% cure rate as possible [Calvet et al. 2001; De Boer and Tytgat, 2000; Gisbert, 2008; Gisbert et al. 2005a; Gisbert and Pajares, 2002].

The aim of the present manuscript will be to review the experience dealing with 'nonresponders' to H. pylori eradication therapy. As, at present, the current most prescribed first-line regimens include a combination of PPI plus two antibiotics, the present review will focus only in 'rescue' regimen when these triple combinations fail. Bibliographical searches were performed in the PubMed (Internet) database including studies available until July 2009, looking for the following words (all fields): pylori AND (retreatment OR re-treatment OR rescue OR failure OR salvage OR second-line OR third-line OR fourth-line). References of reviews on H. pylori eradication treatment, and from the articles selected for the study, were also examined in search of articles meeting inclusion criteria (i.e. dealing with H. pylori 'rescue' therapies).

Abstract and Introduction

Abstract

Hypertension remains the most prevalent chronic disease in the world, and its adequate treatment results in predictable reductions in cardiovascular morbidity and mortality. However, most hypertensive subjects do not achieve goal blood pressure despite availability of multiple antihypertensive agents with various pharmacological mechanisms of action and relatively few side effects. We review the reasons for low hypertension control rates, including factors that affect patients' adherence to therapy, number of agents required to achieve goal blood pressure, pathophysiology-based selection of therapy and diagnosis of resistant hypertension. Within this framework, we discuss the possible impact of a single-pill, triple-therapy combination with an antagonist of the renin–angiotensin system, a calcium-channel blocker and a diuretic. We focus on possible differential diagnostic implications in terms of refractoriness to treatment, and therapeutic implications in terms of successful blood pressure control. We conclude that a single-pill, triple-therapy combination may improve control of hypertension by enhancing compliance, by achieving blood pressure goal rapidly and by reducing physician inertia in prescribing adequate antihypertensive therapy. We also suggest that such a combination may lead to improved accuracy in diagnosing resistant hypertension in general practice, avoiding unnecessary further workup and referrals to hypertension specialists.

Introduction

Six decades of epidemiological and clinical research have provided unequivocal evidence for the role of hypertension as a cardiovascular and renal risk factor and for the benefit of antihypertensive therapy. Concomitantly, pharmaceutical research has resulted in the development of a large armamentarium of antihypertensive drugs with a variety of mechanisms of action that address the diverse pathophysiologies of essential hypertension. Despite this extraordinary progress, control rates of hypertension, although somewhat improved, remain dismal, even in developed, wealthy societies. The sobering disparity between the science and its clinical application has resulted in the understanding that future developments in the field must address strategies to bridge the gap between them.

Epidemiology has established hypertension as a risk factor for cardiovascular disease in studies of large and diverse populations, and has quantified such risk with extreme accuracy. A meta-analysis containing data on 12.7 million patient-years of follow up documented that minor differences in blood pressure (2mmHg) have a major impact on ischemic heart disease or stroke mortality (7% and 10% decreases, respectively) [Lewington et al. 2002].

The demonstration, in 1959, by Kincaid-Smith that blood pressure reduction dramatically increased survival in subjects with malignant hypertension [Harington et al. 1959] began the journey of investigation that documented analogous results in subjects with progressively lower levels of diastolic blood pressure [VA and NIH-sponsored trials: Neaton et al. 1993; Hypertension Detection and Follow-up Program Cooperative Group, 1982; Veterans Administration Cooperative Study Group on Antihypertensive Agents 1970, 1967] in those with isolated systolic hypertension (SHEP [Cooperative Research Group 1991] and Syst-Eur [Tuomilehto et al. 1999]) and most recently, in the 'superelderly' (HYVET [Beckett et al. 2008]). The most striking observation of these studies is that pharmacological reduction of blood pressure removes the risks of stroke and ischemic heart disease by a magnitude almost equal to that predicted by epidemiology, a feature that is perhaps unique to the treatment of hypertension. This emphasizes the need to translate scientific knowledge to the health of the population.

Control rates of blood pressure among all hypertensive subjects in the US are 33% [Ong et al. 2007], worse in Europe [Chamontin et al. 2001], and even worse in developing countries [Gu et al. 2002]. They are calculated according to target blood pressure goals derived from clinical trials (<>et al. 2008].

Reasons for low hypertension control rates are multiple (Table 1), and much has been written about methods to improve them. This review will focus on the rationale for combining three antihypertensive agents in a single pill, a conceivable pharmaceutical development in the near future, to improve control rates of hypertension.

Clopidogrel-PPI interaction impact on clinical outcomes further explored

14 December 2009

MedWire News: Results of an observational study indicate there is no significant reduction in the clinical efficacy of clopidogrel through concomitant use of a proton-pump inhibitor (PPI).

How Virulent Is the 2009 Influenza A H1N1 (Swine Flu) Virus?

We might have better T cell responses against H1N1 than we thought.

New pandemic strains of influenza virus typically are more virulent than those that have been circulating longer, presumably because they present novel antigens to hosts. In this new study, researchers showed that 2009 influenza A H1N1 virus does not contain many surface antigens that have been presented to B cells by other viral strains. This conclusion is consistent with previous findings that few people who were born after 1957 have neutralizing antibodies to 2009 H1N1 and that H1N1 infection has been more problematic among younger people. Neutralizing antibodies typically recognize viral surface antigens.

However, the current pandemic H1N1 virus thus far has not proved to be as virulent as was feared initially. The researchers found that, compared with B cells, T cells (particularly CD8⁺ cells) are much more likely to recognize 2009 H1N1 virus — especially nonsurface antigens. Whereas the surface antigens of 2009 H1N1 are quite novel, the internal antigens are less novel. Although T cell responses to influenza virus might not affect transmissibility of the virus, they likely will affect virulence.

Comment: 2009 H1N1 virus is more virulent than seasonal flu viruses in laboratory animals with no previous influenza immunity. This report suggests, however, that internal antigens of 2009 H1N1 are less novel than its surface antigens and elicit a vigorous T cell response that diminishes severity of infection. Alternatively, the H1N1 pandemic, which began in March 2009, might have been relatively benign until now simply because temperatures have been relatively warm. Flu viruses love cold dry air, and winter weather will be here soon.

— Anthony L. Komaroff, MD

Published in Journal Watch General Medicine December 15, 2009

(CNN) -- One of the five manufacturers supplying H1N1 vaccine to the United States is recalling hundreds of thousands of flu shots because they aren't as potent as they should be.

The French manufacturer Sanofi Pasteur is voluntarily recalling about 800,000 doses of vaccine meant for children between the ages of 6 months and 35 months.

The company and the Centers for Disease Control and Prevention emphasized that the recall was not prompted by safety concerns, and that even though the vaccine isn't quite as potent as it's supposed to be, children who received it don't have to be immunized again against H1N1.

The CDC emphasized that there is no danger for any child who received this type of vaccine.

When asked what parents should do, CDC spokesman Tom Skinner said, "absolutely nothing." He said if children receive this vaccine, they will be fine.

Read more from the CDC

Sanofi Pasteur spokesman Len Lavenda said that the company's test results found the recalled vaccine's potency was 12 percent below the point where it should have been. He added that the company has done studies in the past that showed "vaccine containing as little as half of the recommended dosage" still created the necessary immune response in children.

Lavenda said Sanofi Pasteur has never had this happen with a flu vaccine before, and the company is having all of its experts investigate the cause of this loss in potency.

Lavenda told CNN that it takes about three to four months to produce flu vaccine. He said 85 percent of that time is spent on testing.

Learn more about H1N1

"In order for vaccine to move to next phase of production it [the vaccine] has to pass all tests and at the end, it has to pass another battery of tests before it can be shipped out," Lavenda said. The company also keeps samples of each batch of vaccine "to periodically test them to see if they stay within specification until expiration date."

Four batches -- or lots -- of H1N1 vaccine in question were shipped in early November. Lavenda said all four lots passed every test before they left the factory. However, on December 7, the company learned that all "four lots we tested failed," according to the spokesman.

That's when the company notified the CDC and the Food and Drug Administration, which asked them to retest the samples. Results from the subsequent sample came in on Monday, according to Lavenda, who said it takes about a week to complete these tests.

According to Sanofi Pasteur, it is unclear how many doses of this particular vaccine are still in circulation. This particular vaccine was targeted for infants and toddlers between the ages of 6 months and 35 months -- children who need to get two shots several weeks apart, but only get half of a regular dose each time.

The vaccine was shipped in 0.25-milliliter pre-filled syringes, which contain half a dose of vaccine in each shot. Children 3 years old and older would have been given a shot with a full dose.

According to the CDC's vaccine recommendations, children younger than 9 years need to have two flu shots to be fully protected against the H1N1 virus.

The CDC's Skinner said there is scientific evidence that when there's a slight drop in vaccine potency, the immune response is still sufficient.

"We're very confident that children who received this vaccine are properly protected, provided that they get the second dose that is recommended," Skinner said.

According to the CDC, this vaccine was distributed throughout the United States. Doctors and providers are urged to check their vaccines and return any to Sanofi Pasteur if they come from the following lots:

• 0.25 mL pre-filled syringes, 10-packs (NDC . 49281-650-25, sometimes coded as 49281-0650-25): UT023DA, UT028DA, UT028CB.

• 0.25 mL pre-filled syringes, 25-packs (NDC . 49281-650-70, sometimes coded as 49281-0650-70): UT030CA.

The vaccine was manufactured in Sanofi Pasteur's Swiftwater, Pennsylvania, factory.

Additional antithrombotics increase bleeding risk in MI patients

11 December 2009

MedWire News: The risk for bleeding associated with antithrombotic treatment among myocardial infarction (MI) patients increases in proportion to the number of antithrombotic drugs used, report researchers in The Lancet.

Their analysis of data for over 40,000 patients hospitalized with MI in Demark showed that the relative risk for hospitalization for fatal and non-fatal bleeding increased with all drug combinations and with each additional drug used, although dual therapy with clopidogrel and a vitamin K antagonist was nearly as hazardous as triple therapy.

Rikke Sørensen and colleagues from Copenhagen University Hospital Gentofte, Denmark, and colleagues recommend triple therapy or dual therapy with clopidogrel and a vitamin K antagonist should only be prescribed after thorough individual patient risk assessment.

The researchers identified 40,812 patients aged 30 years or older who had been admitted to hospital with a first-time MI between 2000 and 2005. Claimed prescriptions starting at hospital discharge were analyzed to categorize patients according to use of aspirin, clopidogrel, or a vitamin K antagonist as monotherapy, or combinations of these drugs in dual or triple therapy.

During a mean follow-up of 476.5 days, 1852 (4.5%) patients were admitted to hospital with nonfatal bleeding, and 115 (0.3%) died from a bleeding event.

The unadjusted yearly incidence of non-fatal and fatal bleeding was 2.6% among patients who took aspirin only, 4.6% among those on clopidogrel, 4.3% for vitamin K antagonist monotherapy users, 3.7% for those taking the combination of aspirin and clopidogrel, 5.1% with aspirin plus vitamin K antagonist, 12.3% with clopidogrel plus vitamin K antagonist, and 12.0% with triple therapy.

Compared with aspirin monotherapy, all antithrombotic exposures except vitamin K antagonist monotherapy were associated with increased adjusted hazards for fatal and nonfatal bleeding.

“Increased risk was proportional to the number of drugs used,” the authors note.

The hazard ratios were 1.33 for clopidogrel, 1.23 for vitamin K antagonist, 1.47 for aspirin plus clopidogrel, 1.84 for aspirin plus vitamin K antagonist, 3.52 for clopidogrel plus vitamin K antagonist, and 4.05 for triple therapy.

Of note, non-fatal bleeding was associated with a significant three-fold increased hazard for MI or death (p<0.0001).

Erik Grove (Aarhus University Hospital, Denmark) and Robert Storey (University of Sheffield, UK) noted in an accompanying commentary that conclusions cannot be drawn as to whether this is a causal association, but that it ties in what has been seen in studies such as OASIS-5, in which a reduction in bleeding led to improved outcomes in terms of death, MI, and stroke.

The bleeding hazards associated with double and triple antithrombotic therapy are an increasingly important issue with the aging population, Grove and Storey said.

While new technologies, stents, and drugs and possibly individually tailored therapy based on platelet reactivity may help to reduce the risk for bleeding in the future, they added, “balancing the risks and benefits of antiplatelet and anticoagulant treatment… will remain a difficult clinical task.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2009

Lancet 2009; 374: 1967–1974

Eur Heart J. 2007 Jul;28(14):1717-22. Epub 2007 Jun 11.

Combining warfarin and antiplatelet therapy after coronary stenting in the Global Registry of Acute Coronary Events: is it safe and effective to use just one antiplatelet agent?

Nguyen MC, Lim YL, Walton A, Lefkovits J, Agnelli G, Goodman SG, Budaj A, Gulba DC, Allegrone J, Brieger D; GRACE Investigators.

Centre for Cardiovascular Therapeutics, Western Hospital, Melbourne, Australia. mcnguyen@bidmc.harvard.edu

PMID: 17562671 [PubMed - indexed for MEDLINE]

Medscape gastroenterology 12-12-09

Aspirin plus clopidogrel treatment has not been found to be beneficial in patients with recent ischemic stroke or atrial fibrillation.^[9,10] In the MATCH trial, a nonsignificant reduction in major vascular events was observed when clopidogrel was added to aspirin (15.7%) versus clopidogrel alone (16.7%), with absolute risk reduction of 1% (95% CI –0.6 to 2.7) in patients with ischemic stroke or transient ischemic attack.^[9] Conversely, the risk of major bleeding was increased in the dual antiplatelet group versus clopidogrel alone when administered for a mean of 18 months (2% vs 1%; p <>[10] The study was stopped on the recommendation of the Data Safety and Monitoring Board before the planned follow-up was completed because of the clear evidence of superiority of oral anticoagulation. A significant reduction in the number of a first occurrence of stroke, non–central nervous system systemic embolus, MI, or vascular death with warfarin compared with dual antiplatelet therapy was observed (annual risk 3.93% vs 5.60%, respectively; RR 1.44 [95% CI 1.18 to 1.76]). However, the risk of major hemorrhage was not significantly different between the groups (aspirin plus clopidogrel 2.42% vs warfarin 2.21%; RR 1.10 [95% CI 0.83 to 1.5]). Warfarin demonstrated superiority to dual antiplatelet therapy in clinical outcomes without an increased risk of major bleeding.

• American College of Neuropsychopharmacology (ACNP) 48th Annual Meeting

This coverage is not sanctioned by, nor a part of, the American College of Neuropsychopharmacology.

December 7, 2009 — A new randomized trial--albeit a small one--suggests that continuing aspirin in patients with cardiovascular disease who develop peptic-ulcer bleeding will, not surprisingly, double their risk of bleeding but may also radically reduce their risk of all-cause mortality [1]. The increased bleeding was seen despite all patients receiving a 72-hour infusion of the proton-pump inhibitor (PPI) pantoprazole, followed by oral pantoprazole, after undergoing endoscopic therapy.

The paper, by Dr Joseph JY Sung and colleagues, is published online December 1, 2009 in the Annals of Internal Medicine and concludes that "early resumption" of low-dose aspirin "should be considered" in patients with bleeding ulcers to minimize the mortality risk of stopping aspirin.

To heartwire , Sung emphasized that the study was not powered to detect a difference in mortality: "Therefore, the possibility that the difference in all-cause mortality is merely [due to] chance cannot be excluded. However, cardiologists and gastroenterologists should be aware that there is a likelihood of increasing risk of cardiovascular death if aspirin is withheld for a prolonged period. A balance of risk and benefit of restarting aspirin should be considered."

To Stop or Not Stop

The study enrolled 156 patients already taking aspirin for secondary prevention of cardiovascular or cerebrovascular events who developed peptic-ulcer bleeding; after diagnosis and treatment (hemostasis achieved) of a bleeding ulcer, patients were randomized to receive low-dose aspirin or placebo for eight weeks. (Of note, patients taking clopidogrel were included in the study, but clopidogrel was stopped until the ulcer was completely healed.) Three patients withdrew during the course of the study.

In an intention-to-treat analysis, recurrent ulcer bleeding at 30 days--the study's primary end point--was nearly twice as high in the aspirin group as the placebo group. For the secondary end point of all-cause mortality, placebo-treated patients had a more than 10-fold increase in events, a statistically significant difference. Aspirin-treated patients also had lower rates of mortality due to cardiovascular, cerebrovascular, or gastrointestinal events.

Bleeding and Mortality Outcomes

Event	Aspirin (%)	Placebo (%)
Recurrent ulcer bleeding, 30 d	10.3	5.4
All-cause mortality, 8 wk	1.3	12.9
Death due to cardiovascular, cerebrovascular, or gastrointestinal complications, 8 wk	1.3	10.3

"Among low-dose-aspirin recipients who had peptic-ulcer bleeding, continuous aspirin therapy may increase the risk for recurrent bleeding but potentially reduces mortality rates," the authors cautiously conclude. "Larger trials are needed to confirm these findings."

Commenting on the findings for heartwire , Dr Dominick Angiolillo (University of Florida, Jacksonville) emphasized the small size of the study, pointing out that, typically, much larger randomized controlled trials have had "difficulty" showing differences in mortality; as such, the mortality differences seen by Sung et al "need to be taken with a grain of salt."

"Especially since this [mortality finding] is a secondary end point, this needs to be considered with caution," Angiolillo warned. "The other thing to keep in mind is that the study outcomes were evaluated out to eight weeks, and we do know that with bleeding, there can be potential clinical implications even long-term, beyond the eight weeks, which obviously are not reported in this study."

Long-term effects of bleeding include future ischemic events and CV mortality, he added.

"I would not make any definitive statements on what should be done [on the basis of this study]," Angiolillo told heartwire . "What we clearly know is that if you continue patients on aspirin, the patient is likely going to bleed, and the PPI, even given under infusion, is not going to prevent that."

What the study underscores is the need to evaluate patients on a case-by-case basis, he continued. Some patients on antiplatelet medication who develop bleeding may have good indications for continuing on aspirin.

"One indication may be a patient with a recent MI, who got a DES placed in the proximal LAD a week ago." he said. "That's very different from another patient who is on aspirin for a CV event [that took place] two years ago."

An editorial accompanying the study also urges caution in interpreting the study results, pointing to a number of methodological issues with the study [2]. But Drs Alan N Barkun (Montreal General Hospital, QC) and Marc Bardou (Centre Hospitalier Universitaire de Dijon, France) also urge physicians to "reconsider the all-too-common paradigm" of focusing on the gut at the expense of the heart.

"On the basis of all available data, international consensus recommendations (including the results from Sung and colleagues) concluded that patients with upper gastrointestinal bleeding who require secondary cardiovascular prophylaxis should resume low-dose aspirin therapy as soon as the cardiovascular risks outweigh the gastrointestinal risks (usually within seven days)," they note. "Until additional data become available to better guide management, clinicians will need to rely on limited evidence and appropriate use of common sense that considers the patient as a whole without focusing on a specific organ system to the detriment of another."

Author disclosures are listed in the article.

References

1. Sung JJY, Lau JYW, Ching JYL, et al. Continuation of low-dose aspirin in peptic ulcer bleeding. Ann Intern Med 2009; available at: http://www.annals.org.
2. Barkun AN and Bardou M. Aspirin withdrawal in acute peptic ulcer bleeding: Are we harming patients? Ann Intern Med 2009; available at: http://www.annals.org.

Clinical Context

Study Highlights

• The study was completed at 1 university medical center in Hong Kong and included consecutive patients evaluated for overt gastrointestinal bleeding between 2003 and 2006.
• Patients eligible for the current study protocol had evidence of acute peptic ulcer bleeding and also had indications for continuous therapy with aspirin at a dose of 325 mg daily or less. Patients who used aspirin for primary prophylaxis of cardiovascular disease were not eligible for randomization, nor were those with ulcer perforation or who were receiving concomitant therapy with corticosteroids or other nonsteroidal anti-inflammatory drugs.
• After endoscopy, all study patients received pantoprazole, 80 mg intravenously, followed by an infusion of pantoprazole, 8 mg per hour, for 72 hours. They then were given oral pantoprazole 40 mg daily for 8 weeks.
• Participants were randomly assigned to receive aspirin 80 mg daily or placebo for the 8-week trial period.
• The primary endpoint of the study was recurrent symptomatic peptic ulcer bleeding within 30 days of endoscopic treatment. Researchers also observed all-cause mortality and requirements for blood transfusion and hospital stay.
• 3412 patients received a diagnosis of upper gastrointestinal bleeding, and 156 patients underwent randomization in the current trial. The mean age was 74 years, and 62% of participants were men. None of the study subjects was receiving antiplatelet therapy other than aspirin at baseline.
• Continuing aspirin therapy was associated with a higher 30-day risk for recurrent ulcer bleeding vs placebo (incidence of 10.3% vs 5.4%, respectively). The site of recurrent bleeding was the same as the original bleeding site in all cases.
• However, the total amount of blood transfused was similar between the 2 randomized groups, indicating that recurrent peptic ulcer bleeding may have not been severe. The rate of hospital stay during the first 30 days was also similar between groups.
• All-cause mortality rate at 8 weeks was higher in the placebo group (12.9%) vs the aspirin group (1.3%). Mortality rate from cardiovascular, cerebrovascular, or gastrointestinal causes specifically was also lower in the aspirin group vs the placebo group.
• 4 nonfatal ischemic events occurred in the placebo group vs only 2 in the aspirin group. Other adverse events were disparate in nature and were more common in the aspirin group vs the placebo group.

Clinical Implications

• Aspirin therapy is associated with a 2- to 3-fold increase in the risk for peptic ulcer bleeding, and this risk is even higher among older patients with H pylori infection. Aspirin-induced peptic ulcers are associated with lower rates of dyspepsia, and there appears to be no tolerance with time to the gastropathic effects of aspirin.
• In the current study of older adults with peptic ulcer bleeding treated with proton-pump inhibitors, the use of aspirin after the bleeding event was associated with a higher risk for recurrent ulcer bleeding but a lower risk for overall mortalit

December 5, 2009 - Serious reactions after receiving the H1N1 swine flu vaccine are rare and not significantly higher than those seen from the seasonal flu vaccine, according to a briefing at the CDC today.

Director Thomas Frieden, MD, MPH, presented preliminary safety data and confidence that the H1N1 vaccine will not be dogged by Guillain-Barre syndrome, the neurological disorder that was associated with the 1976 swine flu vaccine.

"The likelihood that we'll have a 1976-like problem with this year's H1N1 influenza vaccine is vanishingly remote," said Frieden.

H1N1 flu cases fell off somewhat during the Thanksgiving week, with widespread activity reported in 25 states, a drop from 32 states in the previous week. Still, 17 children died last week of laboratory-confirmed H1N1 flu, bringing the number of child deaths to 210. That's three times the number of flu deaths expected in children at this point in a normal flu season.

"This virus is a much worse virus for younger people. The number of people, not just children, but young adults under age 50 who will get severely ill or die from this virus is much higher than it is from seasonal flu," said Frieden.

Tamiflu Shortage Coming to an End

Liquid forms of the antiviral drug Tamiflu should be easily available now, according to CDC. The agency distributed the drug from the strategic national stockpile until manufacturers could catch up with demand.

Frieden says the agency is seeing a dramatic improvement in the treatment of children who are severely ill with influenza, due to the use antivirals like Tamiflu. In most years, only one in five sick children arriving at a hospital have been started on an antiviral. This year, 80% are getting early treatment, which helps prevent severe illness.

The vaccine supply is increasing as well, with 73 million doses of the H1N1 swine flu vaccine available this week and another 10 million coming next week. Top priority for getting the shot should still go to people in the high-risk groups.

"Vaccination is the single best thing you can do to protect yourself and your family against the flu," Frieden said.

SOURCES:

CDC news conference.

Thomas Frieden, MD, MPH, director, CDC.