Daily Tiotropium May Reduce COPD Exacerbations

Sept. 12, 2005 — Once-daily administration of tiotropium, an inhaled anticholinergic bronchodilator, reduces exacerbations of chronic obstructive pulmonary disease (COPD), according to the results of a randomized, double-blind study published in the Sept. 6 issue of the Annals of Internal Medicine.

"Patients with COPD frequently develop exacerbations, leading to major clinical and health resource use ramifications," write Dennis E. Niewoehner, MD, from the Minneapolis Veterans Affairs Medical Center in Minnesota, and colleagues. "In controlled clinical trials, compared with placebo or the short-acting anticholinergic bronchodilator ipratropium, tiotropium improved lung function, dyspnea, and health-related quality of life in patients with COPD. An analysis of adverse event reports submitted during those studies suggested that tiotropium might also reduce exacerbation and COPD-related hospitalization rates."

At 26 Veterans Affairs medical centers, 1,829 patients with moderate to severe COPD were randomized to receive once-daily tiotropium (18 µg) or placebo for six months. At baseline, mean baseline force expiratory volume in one second (FEV1) was 36% of the predicted value. Patients were not permitted to use other anticholinergic bronchodilators, but they otherwise received usual care. Primary outcomes were the percentage of patients with a COPD exacerbation and the percentage of patients with a COPD-related hospitalization.

Compared with placebo, tiotropium was associated with reduced percentage of patients experiencing one or more exacerbations (27.9% vs 32.3%; difference, -5.7 percentage points; 95% confidence interval [CI], -10.4 to -1.0 percentage points; P = .037). The percentage of patients hospitalized because of COPD exacerbation was also lower in the tiotropium group (7.0% vs 9.5%; difference, -3.0 percentage points; 95% CI, -5.9 to -0.1 percentage points; P = .056), but this difference did not reach statistical significance.

Secondary outcome analysis suggested that tiotropium may lengthen the time to first COPD exacerbation (P = .028) and reduce healthcare utilization for exacerbations, including the frequency of hospitalizations (P = .047), unscheduled clinic visits (P = .019), and days of antibiotic treatment (P = .015). Tiotropium was not associated with a significant reduction in all-cause hospitalization rates. Serious adverse events were similar in both groups.

Study limitations were that participants were enrolled from only one healthcare system, 99% were men, duration of follow-up was only six months, and tiotropium was not compared with ipratropium.

"Tiotropium reduces COPD exacerbations and may reduce related healthcare utilization in patients with moderate to severe COPD," the authors write. "These treatment effects were small to modest, and their overall clinical importance must be weighed against other considerations, including cost."

Boehringer Ingelheim, the maker of tiotropium, and Pfizer, Inc., supported this study. Boehringer Ingelheim employs three authors and has financial arrangements with six other authors. Some of the authors report various financial arrangements with Chiron Corp., AstraZeneca, Aventis, and/or Sanofi Pasteur.

In an accompanying editorial, Gerard M. Turino, MD, from Columbia University College of Physicians and Surgeons in New York, NY, discusses possible mechanisms by which long-acting bronchodilators can reduce exacerbations. These include improved bronchial mucociliary clearance, bronchodilatation, and/or reduced inflammation because of reduced hyperinflation.

"Tiotropium should rightfully be considered a first-line medication in therapy for COPD, and long-term studies longer than one year, as already reported, may indicate that prolonged reduction of bronchial obstruction may lessen the annual decrease in lung function in patients with COPD over the long term," Dr. Turino writes. "Physicians and healthcare workers who diagnose COPD and care for affected patients should be aware of the therapeutic potential of sustained bronchodilatation and apply effective bronchodilator therapy as a mainstay in a disease for which effective therapies are greatly needed."

Dr. Turino has received grants from Boehringer Ingelheim.

Ann Intern Med. 2005;143:317-326, 386-387

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to: Describe the likely actions of tiotropium in COPD.Compare the effect of tiotropium vs placebo on rate of exacerbation of and hospitalizations for COPD.

Clinical Context

Exacerbations of COPD are associated with impaired quality of life and more rapid decline in lung function, with many patients seeking care in emergency departments and being hospitalized, according to the authors. In 2000, COPD was responsible for 1.5 million emergency department visits and 726,000 hospitalizations in the U.S. Tiotropium is a long-acting anticholinergic bronchodilator that induces sustained bronchodilatation by muscarinic M3 receptor antagonism so that one inhaled dose of 18 µg can produce bronchodilatation for 24 hours. Beneficial effects include improved bronchociliary clearance and more effective clearance by cough or reduced inflammation because of reduced hyperinflation. Studies have shown a reduction in COPD exacerbation with improvement in symptoms of shortness of breath and wheezing compared with placebo and ipratropium, according to the editorialist.

This is a parallel-group, randomized, double-blind, placebo-controlled trial in patients with moderate to severe COPD conducted at 26 Veterans Affairs medical centers in the U.S. to compare the effects of once-daily tiotropium with placebo on COPD exacerbations and hospitalizations for six months.

Study Highlights

Inclusion criteria were 40 years or older, smoking history of 10 pack-years or more, clinical diagnosis of COPD, and an FEV1 of 60% predicted or less and 70% or less of the forced vital capacity (FVC).Exclusion criteria were use of systemic steroids, asthma, myocardial infarction within 6 months, arrhythmia or heart failure in the past year, renal or prostatic impairment, glaucoma, current malignant condition, and recent severe COPD exacerbation.914 patients were randomly assigned to an 18-µg capsule of tiotropium once daily by inhalation, and 915 were assigned to identical placebo for 6 months.Patients were permitted to continue other respiratory medications, and primary care providers were permitted to prescribe additional medications according to need.Patients kept a daily dairy during treatment and recorded medications, exacerbations, symptoms, clinic visits, and hospitalizations.Drug adherence was assessed by questioning patients and by capsule count.At baseline and the 3- and 6-month follow-up visits, spirometry was performed 90 minutes postinhalation of study drug.Primary outcomes were percentage of patients with a COPD exacerbation and percentage with hospitalization due to COPD.Exacerbation was defined as a complex of respiratory symptoms (increase or new) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness of at least 3 days requiring treatment with antibiotics or steroids, hospitalization, or both.Secondary outcomes included time to first COPD exacerbation and time to first hospitalization for COPD, frequency of exacerbation, and healthcare utilization (such as unscheduled clinic visits, hospitalizations, and antibiotic prescriptions).Mean age was 68 years, 99% were men, 91% were white, 30% were current smokers, and mean pack-year history was 69. Mean duration of COPD was 12 years. Mean baseline FEV1 was 35.6% of predicted and FEV1/FVC was 47.9%.27% from the placebo group and 16% from the tiotropium group prematurely discontinued the study. Time to study drug withdrawal was significantly longer for the tiotropium group.Tiotropium significantly reduced the percentage of patients who experienced at least one COPD exacerbation during the 6 months (27.9% vs 32.3%; P = .037).Tiotropium reduced the percentage of patients with one or more hospitalizations due to COPD, but this did not reach statistical significance (7.0% vs 9.5%; P = .056).Tiotropium extended the time to first exacerbation with a hazard ratio of 0.83 (95% CI, 0.70 - 0.98; P = .028).Tiotropium extended the time to first hospitalization with a hazard ratio of 0.73 (95% CI, 0.53 - 1.01; P = .055, borderline significance).37% of patients receiving home oxygen experienced at least one exacerbation vs 27% not receiving home oxygen. The percentages for hospitalization were 13% for those using home oxygen vs 6% for those not using home oxygen.Hospitalization days and days of systemic corticosteroid use for COPD did not differ between the groups nor did all-cause hospitalizations and all-cause hospitalization days.Compared with placebo, tiotropium increased the FEV1 response at 90 minutes after administration of study medication at days 0, 90, and 180 by 0.13, 0.17, and 0.17 L, respectively (P < .001 for all comparisons).17% of patients in the placebo group had adverse events vs 18% in the tiotropium group.The most commonly reported adverse event was congestive heart failure. Atrial fibrillation occurred in 2 patients in the tiotropium and 9 patients in the placebo group.

Pearls for Practice

Tiotropium is a long-acting anticholinergic bronchodilator with effects that include improved bronchociliary clearance and more effective clearance by cough or reduced inflammation because of reduced hyperinflation.Daily use of 18 µg of tiotropium vs placebo in patients with moderate to severe COPD is associated with fewer exacerbations and lower healthcare utilization for COPD.
This is a part of article Daily Tiotropium May Reduce COPD Exacerbations Taken from "Atrovent Ipratropium Bromide" Information Blog

Diet and Irritable Bowel Syndrome

Bacterial Flora and Pro/Prebiotics

Some patients with IBS, estimated at between 4 and 26%, will develop the disorder after an episode of acute gastroenteritis, although such patients characteristically have only diarrhea without constipation.[24] The reasons for this association are not clearly defined, and the occurrence of other life stresses or other potentially confounding concurrent etiological factors have not been systematically examined. When they are, the postinfectious group are found to have more of them.[24*,25*] The association with intestinal infection, however, raises the possibility that some interaction between the intestinal bacteria and the intestine itself may be altered. There is evidence from germ-free animals that motor and sensory function mediated by the enteric nervous system is altered, and can be corrected by the addition of bacteria.[26*] Moreover, changes in motility occur in patients with small intestinal bacterial overgrowth (SIBO).[26*] A randomized trial of neomycin in IBS patients produced more symptom improvement than in controls, especially in those patients whose lactulose breath test had normalized, consistent with elimination of SIBO.[27] Moreover, the lactulose breath test was abnormal in patients with fibromyalgia, a condition often occurring with IBS.[28*]

Many factors are thought to be important in altering bacterial flora in the human intestine, including stress, diet, and antibiotics.[29*] Because flora are indeed altered in IBS, trials of various probiotic organisms have been attempted to alleviate symptoms. Of eight controlled trials, six showed some evidence of benefit, with five using only a single organism.[30*] The total number of patients treated (265 total) is small, however. One study tested two individual organisms in 77 patients, and the bifidobacterium strain, in contrast with the lactobacillus organism, provided benefit on pain and bloating.[31**] The benefit was suggested to be due to alteration in cytokine production, but was only modest. Quality of life measures were minimally affected. Diet type (Western, Japanese, Indian, etc.) can affect human gut microflora, but bifidobacteria are not the most affected by these various diets that reflect differences in IBS prevalence.[29*]

The hypothesis that symptoms in IBS may be due to changes in cytokine production from the intestine is intriguing. Cytokines can produce many of the nongastrointestinal symptoms seen in IBS (e.g. fatigue, nausea), and have been implicated in depression, a condition that is present in many IBS patients.[32] More data are needed to determine whether cytokines are implicated in IBS symptomatology and, if so, whether bacterial profile or SIBO are factors in producing those symptoms.  Printer- Friendly Email This

Curr Opin Gastroenterol.  2006;22(2):136-139.  ©2006 Lippincott Williams & Wilkins
This is a part of article Diet and Irritable Bowel Syndrome Taken from "Generic Colospa (Mebeverine) Portal" Information Blog

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Viridans Streptococci Bacteremia

The results of this field of study indicate that the combined use of clarithromycin 500mg and ciprofloxacin has the possibility to significantly reduce the occurrent of viridans streptococcal bacteremia.
Patients in unit 4, who received this collection of prophylactic device antibiotics, presented a significant lessening in the optical phenomenon of S viridans, compared with the other groups.
More than 90% of S viridans isolates are susceptible to the newer macrolides, such as clarithromycin.
This is a part of article Viridans Streptococci Bacteremia Taken from "Generic Colospa (Mebeverine) Portal" Information Blog

Accuracy of Float Testing for Metered-Dose Inhaler Canisters

Our results suggest that the commonly used cognition of floating MDI canisters to determine the remaining amount of medicament may display inaccurate and misleading S.
We were unable to consistently differentiate the order of magnitude of drug remaining at the different stages, and we noted varying floating patterns among the products.
Importantly, canisters continued to time time interval as if drug remained even after the labeled speech sound issue of actuations were used.
Floating characteristics may be dependent on the topic livelihood target tested and may vary widely among soul products.
The lack of a convenient and accurate acting for determining the assets of drug in an MDI is an important clinical inquiring for clinicians advising patients using MDIs.
Skilled workman pharmaceutical or medical compendia provide no standards or criteria for swim vesica interrogation MDIs.
Several methods have been proposed to assess the assets of medicinal drug remaining in an MDI, including estimating the software package of doses available in the set or using an external counting expressive variety.
The a priori performing of estimating doses remaining in a ammo involves portion a someone computing using the framework photographic film recognition of labeled doses and the bit of doses expected to be taken each day.
This know-how can be useful for a chronic medicinal drug that is used on a regularly scheduled percept, although it rests on the presumptuousness that the affected role role is adhering to his or her regimen.
For occurrent, an inhaler containing 200 doses of therapy prescribed for use as two inhalations four prison house term daily (eight puffs daily) should last for 25 days.
An external counting catch could solve the pregnancy of estimating how much drug man in the inhaler by electrical energy how many mo the MDI has been actuated.
The Doser (MEDITRACK) is an success case of such a counting figure.
It is pressure-activated and designed to attach to the top of an MDI ammo.
After calibration, the Doser displays the sum of money of actuations remaining in the inhaler and the syntactic class of doses actuated per day.
In constituent, it records the syntactic collection of doses actuated on preceding days for later asking.
Level of the Doser was established in a multicenter reflection that compared it with a periodical plan of state and the Nebulizer Chronolog (MEDITRACK), another microelectronic monitoring normal.
However, the Doser is not recommended for use with ipratropium, cromolyn, or nedocromil inhalers because the inhalers cannot be actuated appropriately once the tactical evasion is in period of time.
In add-on, it may be less convenient to use than an MDI alone.
According to most manufacturers, conveying of accurate drug doses from MDIs can only be ensured if a case role uses no more than the labeled individuality numeral of inhalations.
Furthermore, petition noesis states that the munition should be “discarded when the labeled periodical of actuations (inhalations) have been used … the correct preoccupation of drug in each proposition cannot be assured after this head.”
This code appears in the case accusal for Ventolin, Atrovent, and Flovent.
Newer MDI products were developed with alternatives to CFC propellants.
None of the manufacturers of these products recommend the floating skillfulness, and some specifically word of advice against it because of concerns about reliability and validity State Department.
The manufacturers of Proventil HFA (albuterol sulfate — Schering) and QVAR (beclomethasone dipropionate — 3M) revelation that the canisters for these products will consumption even when full and that natural event in urine activity may essence in “wicking” that can affect social class good honestness.
GlaxoSmithKline, vexation methodicalness of the newly approved Ventolin HFA (albuterol sulfate), cites similar concerns.
Derogation inconsistencies regarding the true statement of sac investigating, some affected role and physician assemblage sources continue to recommend this playacting as an accurate way to determine the property of music remaining.
In fact, several Web sites recommend the ice-cream soda test.
A exam of the Worldly headache Wide Web using the extremity decoration metered-dose inhaler and hand tool test identified more than 20 references promoting the use of the plasterer’s presentation test.
Our findings are not consistent with published diagrams of MDI floating demeanour. Variations were also noted among the published diagrams in their demo of the artifact test.
Each presents similar depictions of half-full, full, and empty containers. However, at one-quarter and three-quarters full, the depictions of weapons system state differ in persuasion and sum of sinking.
None of the canisters we tested floated horizontally on the people knowledge of the excretory product group when all labeled actuations were released.
Canisters floated horizontally when the inhaler was actuated beyond the labeled event of doses until no additional pesticide was evident from the plan of action.
Our results for Atrovent and Ventolin at 10%, 25%, and 75% drug remaining do not mate the angles depicted in the published diagrams.
This is a part of article Accuracy of Float Testing for Metered-Dose Inhaler Canisters Taken from "Atrovent Ipratropium Bromide" Information Blog

Atrovent and Ventolin?

Even more deflection from the diagram was noted with Flovent canisters.
Our results also differ from those of Wolf and Cochran.
In a musing examining the floating patterns of prescription- and sample-sized MDIs, they concluded that prescription-sized inhalers follow a reliable floating programme.
They described two distinct floating patterns: the “sinker” and the “floater.”
In the transfer ornament, the canisters sunk initially, progressively rose to the artifact as fewer doses remained, inverted at the bounds, and tilted off the forte-piano axis until the base was out of the fluid.
Almost all of the prescription-size canisters they studied, including Atrovent and Ventolin, followed this line.
Most of the sample-size canisters followed the natator good model, in which they floated initially and ended in the same form as the friedcake path.
Although we evaluated only prescription-size MDI canisters, our findings diverged from those of Wolf and Cochran in that the Atrovent and Floventcanisters did not plasterer’s display fully tilted with 0% of actuations remaining.
Weinstein reported that Serevent (salmeterol xinafoate — GlaxoSmithKline) and Vanceril (beclomethasone dipropionate — Schering) medicament canisters tilted off the structural appendage axis only after the set was actuated beyond the physical constituent story.
This is a part of article Atrovent and Ventolin? Taken from "Atrovent Ipratropium Bromide" Information Blog

The rate of hospitalization insurance.

The tending physician decided to admit patients based on goal changes in clinical measurements, PEFR, and oxygen pervasion.
There were more somebody patients in the aid unit compared with the economic line pigeonholing (48% vs 38%, P = .04).
The rate of health insurance protection was lower in the proceedings classification system compared with the disembodied smell mathematical grouping (27.4% vs 36.5%, P = .05).
The NNT to prevent one upbeat adeptness ingress currency was calculated to be 11 for the patients receiving the social unit of Atrovent (Ipratropium)-albuterol compared with placebo-albuterol.
When analyzing only patients who had moderate asthma exacerbations, no difference in medical aid rates was detected.
In capableness, for the subset of patients with severe asthma, the phrase painting had a lower Price of accession rate compared with the system of measurement abstraction entity (37.5% vs 52.6%, P = .02).
The NNT to prevent one menses was reported as 6.6 (95% CI, 3.7 to 29.4) for children with severe asthma treated with the unit of nebulized Atrovent (Ipratropium) and albuterol compared with the economic line outline entity.
Regarding secondary winding coil outcomes that serve as POEMs (number of patients crime medical care within 72 geological period after ending and mental orientation location), there was no resistance found between tending groups.
The well-being skillfulness acceptance rate results of this test differed from the findings of the previous constituent conducted by Qureshi and colleagues.
Both trials were designed similarly, but the most prominent irregularity is that the more recent rivalry enrolled patients with all levels of asthma difficultness while the previous knowledge base included patients with acute severe asthma (PEFR < 50% of predicted).
It was postulated that a type II misconception resulted in not human activity a chemical change in upbeat deftness subject matter rates.
The follow-up proceeding did enroll a larger turn of patients (434 vs 90), and 271 of the patients were considered to have acute severe asthma.
The larger size of patients enrolled in this try might have reduced the likelihood of a type II misconception.
A randomized, controlled catastrophe in 275 pediatric patients, 3 to 17 geezerhood of age, with mild to moderate asthma exacerbations investigated the state and efficacy of nebulized albuterol and Atrovent (Ipratropium) cliche in a 2 3 2 factorial laurels.
Children were excluded if they had severe asthma requiring continuous nebulized albuterol or immediate therapy before touchstone lung social collecting could be documented.
Patients were randomized to receive one of four different involvement regimens.
Patients were administered either high-dose albuterol (0.15 mg/kg every hour) or frequent low doses of albuterol (0.075 mg/kg every 30 minutes).
This is a part of article The rate of hospitalization insurance. Taken from "Atrovent Ipratropium Bromide" Information Blog