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

Original heart hope of Viagra realised

By Michelle Roberts BBC News, health reporter

The drug works on blood vessels

Say the name Viagra and most people will automatically think of a drug to treat impotence.

But doctors are finding it is good at boosting parts of the body other than the penis, such as the blood vessels of the heart and lungs - as has been seen in the case of premature baby Lewis Goodfellow.

This is not altogether surprising given that Viagra was originally designed to lower blood pressure and treat angina.

Chance finding

It was during early testing that its developers noticed the drug aided the male erection - a curious and, as it turned out, very lucrative side effect.

Pfizer therefore decided to market it for erectile dysfunction, rather than as a heart drug, and after more safety tests Viagra was finally licensed as an impotence treatment in 1998.

It was originally looked at as a heart drug Vicky Styman of the British Heart Foundation

Years later Viagra is turning full circle and doctors are re-exploring its use for treating circulatory problems involving the heart and lungs.

The drug, also known as sildenafil, does not directly give a man an erection. It works by boosting blood flow to the penis.

It does this by specifically blocking a particular enzyme called phosphodiesterase type 5 (PDE 5).

This action means the drug is also good at improving blood flow elsewhere in the body.

Vicky Styman of the British Heart Foundation explained: "It is a potent vasodilator, opening up the blood vessels and it was originally looked at as a heart drug."

But there have been concerns about whether it is safe for men with heart disease on particular medications that work in the same way.

I suspect we will see a generation of drugs coming out from the sildenafil group which are actually designed for working on the heart Ian Banks of the Men's Health Forum

Doctors are told not to prescribe Viagra along with these angina drugs called nitrates as the mix could lower blood pressure to dangerous levels.

It appears to be safe in other heart patients, but Ms Styman added: "If you have a heart condition you should check with your doctor before taking Viagra."

As erectile dysfunction and cardiovascular diseases have common risk factors, many of the patients who might benefit from Viagra also have cardiovascular diseases.

Ian Banks of the Men's Health Forum said: "It was a very attractive drug for cardiac conditions and lowering blood pressure.

"Indeed, I've noticed that when I prescribe Viagra to patients with a heart condition it actually improves their heart condition as well as their erectile dysfunction.

"It does what it originally said on the tin. But Pfizer knew they were on to a winner with the erectile dysfunction line.

"But people are still interested in using it for other conditions and I suspect we will see a generation of drugs coming out from the sildenafil group which are actually designed for working on the heart because it is so effective."

Other uses

Studies suggest the drug could treat a variety of conditions other than erectile dysfunction.

Scientists have shown it can help thicken up the lining of the womb in women experiencing fertility problems and reduce the risk of a complication of pregnancy called pre-eclampsia.

The best evidence so far of an alternative use is for treating high blood pressure in the vessels of the lungs, known as pulmonary hypertension.

There have been reports of cases where doctors have used Viagra to save the lives of babies with this potentially fatal condition.

Dr Alan Fenton, consultant neonatologist Newcastle's Royal Victoria Infirmary, has first hand experience of this.

He explains: "The problem we see in premature babies with breathing difficulties is although we can blow oxygen into their lungs to help them, there isn't enough blood supply to various areas of the lungs to take the oxygen around the rest of the body.

"What sildenafil does is open up the blood vessels so they can capture the oxygen and take it around the body."

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