Long-acting Beta2-Agonist Monotherapy vs. Continued Therapy with Inhaled Corticosteroids

Source: Lazarus SC, et al. JAMA. 2001;285:2583-2593.

Current consensus documents recommend that for patients suffering persistent asthma, anti-inflammatory controller medication be instituted as first-line therapy, usually inhaled corticosteroids (ICSs). Long-acting beta agonists (LABA) show favorable effects on peak flow rates (PEF), asthma symptom scores, quality of life (QOL), and need for rescue short-acting beta agonists (SABA) in persons with persistent asthma. This 28-week study evaluated the effect of substitution of salmeterol for ICSs in patients with well-controlled asthma (n = 164).

Outcomes measurement—including PEF, asthma symptom scores, need for rescue SABA, and QOL—was not significantly different between asthmatics who were maintained on ICS and those substituted with LABA. On the other hand, LABA patients were 4 times as likely to experience treatment failure, and almost 3 times as likely to have exacerbations.

Asthma is acknowledged to be an inflammatory disease, with potential for detrimental airway remodeling. Lazarus and colleagues measured a variety of markers of inflammation in asthma, including sputum eosinophils, eosinophil cationic protein, and tryptase, each of which was less favorably impacted by LABA than ICSs. Lazarus et al conclude that for patients who are well controlled on ICSs, a switch to LABA may result in loss of asthmatic control, as well as relative augmentation of inflammatory markers.

Relation of Impaired Fasting and Postload Glucose with Incident Type 2 Diabetes

Source: de Vegt F, et al. JAMA. 2001;285:2109-2113.

The burgeoning population of type 2 diabetes (DM2) patients in the United States is a matter of great concern to clinicians. Prevention of DM2 at this time rests upon identification of at-risk individuals. To this end, impaired glucose tolerance (IGT) is a helpful predictor: 23-62% of IGT patients progress to DM2 over long- term follow-up. We have less information about the predictive value of impaired fasting glucose (IFG). Much of the epidemiologic information in reference to progression from IGT to DM2 comes from populations with a disproportionate incidence of DM2, such as Pima Indians in the United States.

The current study investigated a large Caucasian population (n = 2484) age 50-75 years in the Netherlands who underwent both fasting and 2-hour post glucose load (75 g oral glucose) measurement on 2 occasions, 4-7 years apart.

Over the study period, almost two-thirds of persons with both IFG and IGT progressed to DM2. Using only IFG or IGT alone, subsequent progression to DM2 was 35.5-40.8%, respectively. Both IFG and IGT are significant predictors of progression to DM2, but the combination is superior still.

NSAIDs and Selective COX-2 Inhibitors: Competition Between Gastroprotection and Cardioprotection

Source: Boers M. Lancet. 2001;

The special promise of cox-2 specific agents (ie, celecoxib, rofecoxib) was the hope that since they did not, within the therapeutic range, impair COX-1, they might be free of gastrointestinal (GI) risk, specifically GI bleeding. Some data on the COX-2 agents support the premise that GI bleeding in association with these drugs is similar to that of placebo-not zero, since numerous other paths than COX inhibition may lead to GI bleeding (eg, alcohol, bleeding diathesis, helicobacter disease). An additional potential benefit of COX-2 agents is that platelet inhibition is a COX-1 event, so that COX-2 agents do not impair platelet function.

Boers points out that in 2 of the largest COX-2 trials reported there appear to be tradeoffs related to cardioprotection and gastroprotection. In the VIGOR trial (n = 8000, rofecoxib vs naproxen), despite a substantial 60% reduction in GI bleed, Boers points out an unanticipated 4-fold increase in myocardial infarction in the rofecoxib group (0.4% vs 0.1%); in the CLASS trial (n = 8000, celecoxib vs ibuprofen or diclofenac), though no increase in MI was seen, there was not a demonstration of risk reduction in GI toxicity between celecoxib and traditional NSAIDs that reached statistical significance. Boers suggests that the issues of competing risks will need to be weighed in the decision process of when and how to use COX-2 agents.

Smoking Cessation in Patients with Chronic Obstructive Pulmonary Disease

Source: Tashkin D, et al. Lancet. 2001;357:1571-1575.

Smoking cessation for patients with COPD is the most important single step for reducing risk of disease progression. Although there are numerous reports of smoking cessation that use a variety of tools and techniques, none has specifically addressed the efficacy of buproprion SR (BUP) for patients with existing COPD. This report provides specific focus on a population (n = 404) of mild-to-moderate COPD patients treated with traditional dosing BUP in a placebo-controlled trial for 12 weeks. In addition to BUP (or placebo), all participants received counseling about smoking cessation.

The most common adverse drug effects were insomnia, headache, anxiety, and dry mouth. The discontinuation rate for BUP was not different from placebo, and there were no serious adverse events.

At 7 weeks, 28% of subjects remained smoking abstinent (placebo = 16%). This number decreased to 16% (placebo = 9%) 14 weeks after cessation of pharmacotherapy.

Though these rates are a bit less than those demonstrated in some previous trials, the potential for success in even a small subgroup of COPD patients has important individual and public health implications.

Is the Placebo Powerless?

Source: Hrobjartsson A, Gotzsche PC. N Engl J Med. 2001;344:

The word placebo in medical usage is derived from the Latin word which means "to please." The intent of current parlance is that a placebo is any concrete intervention that possesses no demonstrable inherent therapeutic effect. Hence, any effect occurring in placebo recipients, favorable or untoward, is attributed to other secondary effects, such as the personal belief system of the patient, positive thinking, etc. Your reviewer prefers to think of placebo as the channel of forces that can be marshaled (for positive or negative outcomes) in persons given appropriate stimuli. For instance, mothers confronted with their child trapped beneath a heavy vehicle call upon untapped strength to free their child, yet when strength-tested under less stimulating situations, are unable to repeat such acts.

Quantification of the effect of placebo has perhaps been overestimated, since most trials compare placebo with an active therapy. During such a trial, regression to the mean and natural history of the disease over time might be misinterpreted as favorable placebo effects. Hence, the best comparison trial for placebo effect would be placebo vs. no treatment. To this end, Hrobjartsson and Gotzsche performed a meta-analysis on 114 trials (n = 3795).

Hrobjartsson and Gotzsche comment that there were no significant placebo effects on objective outcomes. Subjective outcomes and pain demonstrated some small possible benefit, but since their review also shows that increasing sample size was associated with lesser magnitude of effect, the possibility of bias related to trial size is evident. Hrobjartsson and Gotzsche posit, based upon this review, that use of placebos is unjustified outside the setting of clinical trials.

Understanding the Experience of Pain in Terminally Ill Patients

Source: Weiss SC, et al. Lancet. 2001;357:1311-1315.

At least 20% of terminal
patients experience moderate to severe pain, and the proportion may be as high as 75%, specifically among seriously ill cancer patients. Because of concerns about the veracity of data referable to pain in terminally ill patients, Weiss and colleagues surveyed by personal interview almost 1000 terminally ill patients. The line of inquiry was specifically: 1) In the past 4 weeks, did you desire more pain medicine than you received from your PCP/pain specialist? 2) Why did you not want more?

Half of these patients reported moderate-to-severe pain in the previous 4 weeks, the majority of whom had seen their PCP during this period. Most PCP patients (62%) were satisfied with their level of analgesia, but almost one-third did desire increased analgesia, and 9% wanted a decrease or cessation of analgesia.

Patients who did not desire more analgesia mentioned fear of addiction, adverse drug effects, and desire to avoid medication as their rationale.

Since the demographics of this report include a diversity of US communities and ethnicities, it may well be representative of clinical practice in a variety of settings. It is encouraging that the background level of moderate-severe pain in this group is not as high as previously described in some studies, yet the 30% of individuals reporting a desire for increased analgesia highlights the need for continued vigilance to analgesic adequacy.