Clinical Health Updates

Basal insulin less effective, better tolerated than biphasic and prandial

Clinical Question:
Which is preferred — biphasic, prandial, or basal insulin — for patients with poorly controlled Type 2 diabetes mellitus?

Bottom Line:
Patients choosing biphasic or prandial insulin regiments should be prepared to gain approximately 10 pounds to 12 pounds and expect 4 to 8 moderate or severe episodes of hypoglycemia per year. Basal insulin was a bit less effective as measured by the change in glycated hemoglobin (Hb A1C), but resulted in less weight gain and much less hypoglycemia. Of course, we don’t know whether any of these regiments improve long-term clinical outcomes in these patients. If you are going to add insulin for a patient with poorly controlled Type 2 diabetes, it makes sense to start with a single dose of basal insulin for most patients, and to focus primarily on those patients with an initial Hb A1C of more than 8.5%.

Reference:
Holman RR, Thorne KI, Farmer AJ, et al, for the 4-T Study Group. Addition of biphasic, prandial or basal insulin to oral therapy in Type 2 diabetes. N Engl J Med 2007;357(17):1716-1730.

Study Design:
Randomized controlled trial (nonblinded)

Synopsis:
Adding insulin to oral therapy in type 2 diabetes mellitus is customary when glycemic control is suboptimal, though evidence supporting specific insulin regimens is limited. In an open-label, controlled, multicenter trial, we randomly assigned 708 patients with a suboptimal glycated hemoglobin level (7.0 to 10.0%) who were receiving maximally tolerated doses of metformin and sulfonylurea to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Outcome measures at 1 year were the mean glycated hemoglobin level, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain. At 1 year, mean glycated hemoglobin levels were similar in the biphasic group (7.3%) and the prandial group (7.2%) (P=0.08) but higher in the basal group (7.6%, P<0.001 for both comparisons). The respective proportions of patients with a glycated hemoglobin level of 6.5% or less were 17.0%, 23.9%, and 8.1%; respective mean numbers of hypoglycemic events per patient per year were 5.7, 12.0, and 2.3; and respective mean weight gains were 4.7 kg, 5.7 kg, and 1.9 kg. Rates of adverse events were similar among the three groups.

Antibiotics for URIs reduce complications (but not enough to matter)

Clinical Question:
Does antibiotic treatment of common respiratory infections decrease the risk of serious complications?

Bottom Line:
Antibiotics are not justified to reduce the risk of serious complications for upper respiratory tract infection, sore throat, or otitis media. Antibiotics substantially reduce the risk of pneumonia after chest infection, particularly in elderly people in whom the risk is highest.

Reference:
Petersen I, Johnson AM, Islam A, Duckworth G, Livermore DM, Hayward AC. Protective effect of antibiotics against serious complications of common respiratory tract infections: retrospective cohort study with the UK General Practice Research Database. BMJ 2007;335(76-27):982-987.

Study Design:
Cohort (prospective)

Synopsis:
The authors determined the extent to which antibiotics reduce the risk of serious complications after common respiratory tract infections. They did a Retrospective cohort study. They used UK primary care practices contributing to the general practice research database 3.36 million episodes of respiratory tract infection. The investigators study the risk of serious complications in treated and untreated patients in the month after diagnosis: mastoiditis after otitis media, quinsy after sore throat, and pneumonia after upper respiratory tract infection and chest infection. Number of patients needed to treat to prevent one complication. Serious complications were rare after upper respiratory tract infections, sore throat, and otitis media, and the number needed to treat was over 4000. The risk of pneumonia after chest infection was high, particularly in elderly people, and was substantially reduced by antibiotic use, with a number needed to treat of 39 for those aged > or =65 and 96-119 in younger age groups.

Pneumonia in patients aged 16 years to 64 years decreased from 6.73 to 5.4 per 10,000 URIs with the use of antibiotics. Though statistically significant, 4407 patients (of all ages) have to be treated with an antibiotic to prevent 1 episode of pneumonia (number needed to treat (NNT) = 4407 for all ages; NNTs were not provided for individual age groups). Results were similar for peritonsillar abscess following sore throat and mastoiditis associated with ear infection: antibiotics decreased complications but had NNTs greater than 4000. The only exception was the incidence of pneumonia after bronchitis: The NNTs varied by age from 119 in patients aged 16 years to 64 years to 39 for patients older than 65 years.

Angled insulin insertion with 6-mm needle best for children with Type 1 Diabetes Mellitus

Clinical Question:
What needle length and injection technique most reliably delivers insulin into subcutaneous fat in children with diabetes?

Bottom Line:
A pinched technique with angled insertion using 6-mm needles most reliably results in the appropriately placed subcutaneous injection of insulin in children with diabetes. This same needle-size used in the abdominal site also resulted in the least amount of injection pain.

Reference:
Hofman PL, Lawton SA, Peart JM, et al. An angled insertion technique using 6-mm needles markedly reduces the risk of intramuscular injections in children and adolescents. Diabetic Medicine 2007;74(12):1400-1405.

Study Design:
Non-randomized controlled trial

Synopsis:
The authors aims of this study were
(i) to establish which children with Type 1 diabetes are at risk of intramuscular or intradermal insulin injections
(ii) to determine a needle length and technique that reliably administers insulin into subcutaneous fat.
Seventy-two healthy diabetic children (age 6.3-14.3 years, body mass index standard deviation score 1.0 +/- 1.4) were recruited for study 1 and 37 of this cohort participated in study 2. In study 1, 200 microl air was injected into the abdomen and anterior thigh by a pinched skin-fold technique using either a perpendicular insertion of NovoFine(R) 31G 6-mm or an angled insertion of NovoFine(R) 30G 8-mm needles. In study 2, subjects received injections into abdomen and anterior thigh via angled 6-mm needles with either an unpinched or pinched technique. The site of air injection was visualized by ultrasound scan and measurements taken of subcutaneous fat thickness. In study 1, intramuscular injections were detected in 32% of subjects, and in a further 22% air was visualized at the muscle fascia. In study 2, intramuscular injections occurred in 3% of subjects and a further 11% had muscle fascia air detected. No intramuscular injections occurred in subjects injecting with a 6-mm needle and an angled pinched skin-fold technique. Pinching abdomen and thigh skin folds increased the subcutaneous fat thickness by 192 +/- 16% and 22 +/- 6%, respectively. In very lean subjects, pinching thighs actually reduced subcutaneous fat thickness.

Reducing homocysteine not beneficial in advanced chronic kidney disease

Clinical Question:
Does reducing homocysteine levels with supplemental folic acid and B vitamins reduce mortality or morbidity in patients with chronic kidney disease?

Bottom Line:
Supplemental folic acid and B vitamins in patients with chronic kidney disease does not reduce mortality or the incidence of cardiovascular events.

Reference:
Jamison RL, Hartigan P, Kaufman JS, et al, for the Veterans Affairs Site Investigators. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease. A randomized controlled trial. JAMA 2007;298(10):1163-1170.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Supplemental folic acid and B vitamins is not beneficial in high-risk cardiovascular patients. Whether this is also true for patients with chronic renal disease is unknown. These investigators identified 2056 adults, 21 years or older, with advanced or end-stage chronic kidney disease and elevated homocysteine levels (>= 15 umol/L). Patients randomly received, in double-blind fashion (concealed allocation assignment), a once-daily capsule containing folic acid (40 mg), pyridoxine (100 mg), and cyanocobalamin (2mg), or an identical placebo. Individuals assessing outcomes remained masked to treatment group assignment. Complete follow-up occurred for more than 96% of patients for a median length of 3.2 years. Analyses were by intention to treat. Although plasma homocysteine levels were significantly lower in the intervention group, treatment had no effect on all-cause mortality or the incidence of any secondary outcomes, including myocardial infarction, stroke, or amputation. The study was 80% powered to detect a 17% relative risk reduction in mortality in the intervention group compared with the placebo group.

Acupuncture may have value in treating GERD

Clinical Question:
Is adding acupuncture more effective than doubling the dose of proton pump inhibitor in patients with heartburn symptoms despite treatment?

Bottom Line:
In this small, short-term study, adding twice weekly acupuncture to standard-dose proton pump inhibitor (PPI) treatment was more effective in controlling symptoms than doubling the PPI dose. Acupuncture may be useful for some patients, but the long-term benefits, if any, have not been established.

Reference:
Dickman R, Schiff E, Holland A, et al. Clinical trial: acupuncture vs. doubling the proton pump inhibitor dose in refractory heartburn. Aliment Pharmacol Ther 2007;26(10):1333-1344.

Study Design:
Randomized controlled trial (nonblinded)

Synopsis:
The authors enrolled 30 adult patients with a 3-month history of symptoms related to gastroesophageal reflux disease despite taking a standard-dose PPI (omeprazole 20 mg daily). These patients were also willing to undergo endoscopy (and did so). To minimize the variability of the 2 groups because of the small sample size, the researchers matched participants by age, sex, and body mass index. The patients were randomized, allocation concealment unknown, to receive either a double dose of omeprazole or 10 acupuncture sessions over 4 weeks while continuing the standard-dose PPI. Acupuncture consisted of 5 points selected to “calm” or “regulate” the stomach (CV 12, 17, Per.6, Sp.9, and St.36). Although acupuncturists were instructed to minimize interaction with patients, 10 sessions so closely spaced are likely to exert a significant placebo effect and the study would have been much better had it employed a double-dummy approach using sham acupuncture and placebo omeprazole in the opposite groups. Another issue: The investigators used statistical tests that typically are not believed to be valid for small numbers of patients.

In this short-term study, the addition of acupuncture to standard dose PPI therapy significantly decreased symptoms of daytime and nighttime heartburn, acid regurgitation, dysphagia, and chest pain, whereas there was no change with double-dose PPI. Quality of life, assessed at the end of the study using the SF-36 general health scale was significantly improved in the acupuncture group as compared with the increased dose group.

7 days of tx good for H. pylori

Clinical Question:
What is the optimum duration of treatment for Helicobacter pylori eradication?

Bottom Line:
Seven days of treatment with triple therapy — a proton pump inibitor (PPI) + clarithromycin (Biaxin) + amoxicillin or metronidazole — produces rates of eradication that are nearly as good as 10 days to 14 days of treatment, and are equally good if only high-quality research is considered.

Reference:
Fuccio L, Minardi ME, Zagari RM, Grilli D, Magrini N, Bazzoli F. Meta-analysis: Duration of first-line proton-pump inhibitor-based triple therapy for Helicobacter pylori eradication. Ann Intern Med 2007;147(8):553-562.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
Researchers conducting this meta-analysis searched 3 databases to find research comparing different durations of triple therapy for H. pylori eradication. They also searched conference proceedings, but limited all of their choices to articles in English. Two researchers independently abstracted the data and assessed study quality via the commonly used Jadad criteria. Their search yielded 21 studies comparing 7, 10, and 14 days of treatment using regimens of a PPI with clarithromycin and amoxicillin or a PPI with clarithromycin and metronidazole. Most of the studies evaluated patients with peptic ulcer disease (n = 15). Only 4 of the studies had a quality score of 4 or 5 of a possible 5, with only 3 studies clearly described concealed allocation and only 4 studies were double blinded.

The 11 studies comparing 7 days with 10 days of treatment collectively showed a slightly higher cure rate with 10 days of therapy, though the difference is not likely clinically relevant (77% vs 81% cure; relative risk = 1.05). Differences between 7 days and 14 days of treatment were similar in 13 studies: 73% versus 78%; relative risk = 1.07. There was heterogeneity among the study results that could be explained by the use of antibiotic. The difference in outcome between durations of therapy were present in studies using amoxicillin but not in studies using metronidazole. The outcomes were not different based on duration of therapy when only the high-quality studies were analyzed.

Prophylactic dialysis reduces long-term dialysis in pts with renal failure after coronary angiography

Clinical Question:
In patients with advanced renal failure, does prophylactic hemodialysis after coronary angiography reduce the need for long-term dialysis?

Bottom Line:
Prophylactic hemodialysis after coronary angiography in patients with renal failure reduces the need for long-term dialysis without causing complications.

Reference:
Lee P, Chou K, Liu C, et al. Renal protection for coronary angiography in advanced renal failure patients by prophylactic hemodialysis. A randomized controlled trial. J Am Coll Cardiol 2007;50(11):1015-1020.

Study Design:
Randomized controlled trial (nonblind)

Synopsis:
Patients requiring coronary angiography who had a serum creatinine concentration greater than 3.5 mg/dL (and had been stable for 1 month) were randomized to receive hemodialysis or no hemodialysis following angiography. Acetylcysteine and mannitol were not permitted during the study. Angiography was done with nonionic contrast. The primary end point was the change in creatinine clearance (CrCl) between baseline and day 4 following angiography.
Ninety patients were randomized, and 8 of them were excluded because of insufficient follow up, taking drugs not permitted by protocol, or having a second contrast procedure within 28 hours. Intention-to-treat analysis was not used. Patients were matched for baseline characteristics. Half the patients required percutaneous coronary intervention. At day 4, patients receiving prophylactic dialysis had less decline in CrCl (-0.4 vs -2.2 ml/min/1.73m2). Temporary dialysis was required in 2% of the dialysis group versus 14% of the control group, and maintenance dialysis following discharge was required in 13% of the control patients but none of the dialysis patients [number needed to treat = 8; 95% CI, 4 – 64]. Prophylactic dialysis resulted in shorter hospital stays (6 days vs 13 days; P = .017). No major complications occurred as a result of dialysis.

Pneumonia can be treated with 3 to 5 days of antibiotics

Clinical Question:
Can community-acquired pneumonia be treated with 3 days to 5 days of antibiotic therapy?

Bottom Line:
Ten to 14 days of antibiotics are no more effective in patients with community-acquired pneumonia than 3 to 5 days of treatment. Clinical failures and mortality were similar regardless of treatment length. The equivalent effectiveness was demonstrated with 3 to 5 days of oral or parenteral azithromycin, levofloxacin for 5 days, cefuroxime for 7 days, and intravenous ceftriaxone for 5 days.

Reference:
Li JZ, Winston LG, Moore DH, Bent S. Efficacy of short-course antibiotic regimens for community-acquired pneumonia: a meta-analysis. Am J Med 2007;120(9):783-790.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
There is little consensus on the most appropriate duration of antibiotic treatment for community-acquired pneumonia. The authors systematically reviewed randomized controlled trials comparing short-course and extended-course antibiotic regimens for community-acquired pneumonia. They searched MEDLINE, Embase, and CENTRAL, and reviewed reference lists from 1980 through June 2006. Studies were included if they were randomized controlled trials that compared short-course (7 days or less) versus extended-course (>7 days) antibiotic monotherapy for community-acquired pneumonia in adults. The primary outcome measure was failure to achieve clinical improvement. They found 15 randomized controlled trials matching our inclusion and exclusion criteria comprising 2796 total subjects. Short-course regimens primarily studied the use of azithromycin (n=10), but trials examining beta-lactams (n=2), fluoroquinolones (n=2), and ketolides (n=1) were found as well. Of the extended-course regimens, 3 studies utilized the same antibiotic, whereas 9 involved an antibiotic of the same class. Overall, there was no difference in the risk of clinical failure between the short-course and extended-course regimens (0.89, 95% confidence interval [CI], 0.78-1.02). In addition, there were no differences in the risk of mortality (0.81, 95% CI, 0.46-1.43) or bacteriologic eradication (1.11, 95% CI, 0.76-1.62). In subgroup analyses, there was a trend toward favorable clinical efficacy for the short-course regimens in all antibiotic classes (range of relative risk, 0.88-0.94).

ADVANCE Trial

Clinical Question:
Is perindopril plus indapamide effective in decreasing bad outcomes in patients with type 2 diabetes and existing macrovascular disease?

Bottom Line:
Perindopril (Aceon) plus indapamide (Lozol) is better than placebo in decreasing clinically relevant events in patients with type 2 diabetes who are at high risk of cardiovascular complications. Whether the combination is better than other medications — like aspirin — isn’t addressed by this study.

Reference:
Patel A, et al, and the ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007;370(9590):829-840.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
This study included more than 11,000 patients older than 55 years who had type 2 diabetes and either a prior cardiovascular event (eg, myocardial infarction, stroke, amputation) or at least one other risk factor for cardiovascular disease, including microvascular complications, tobacco use, an elevated cholesterol level, a low HDL cholesterol level, microalbuminuria, more than 10 years of diabetes, or more than 65 years of age. After completing a 6-week run-in period the “surviving” patients were randomly assigned to perindopril 2 mg plus indapamide 0.625 mg daily or matching placebo. Since the authors weeded out patients who didn’t comply or who were unable to tolerate the side effects, any data about drop-outs after randomization are unlikely to reflect tolerability in the real world. After 3 months of treatment, the doses were doubled. The authors were interested in a composite outcome that included cause-specific mortality, cardiovascular events, new or worsening nephropathy, retinopathy, and so forth. I dislike composite end points like this; some outcomes don’t make sense to combine. When there is no difference in the occurrence of a more frequent and devastating outcome (like death), but an improvement in some less important outcomes (like the number of photocoagulations as opposed to loss of vision), and the results all get lumped together, the devastating outcome suddenly looks good. For a more cogent example, all one has to do is look at all the bastardizations of the UKPDS trial (BMJ 2000;320:1720-23.).

After an average of 4.3 years, the researchers found that 15.5% of the treatment group had a bad outcome compared with 16.8% of the placebo group (number needed to treat [NNT] = 77; 95% CI, 37 – 10,257). All-cause mortality was also lower in the treatment group (7.3% vs 8.5%; NNT = 84; 95% CI, 47 – 790) as was the total number of coronary events (8.4% vs 9.6%; NNT = 84; 95% CI, 45 – 734). Only 15 patients were lost to follow-up after randomization. During the follow-up sessions, the randomized treatment was continued in 83% of the treatment group and 87% of the placebo group.

Only 1 in every 3 children with eczema will develop asthma

Clinical Question:
What is the risk that children with atopic eczema during the first 4 years of life will develop asthma later?

Bottom Line:
Approximately 1 in 3 young children with atopic eczema in the first 4 years of life will develop asthma at age 6 years or older.

Reference:
van der Hulst AE, Klip H, Brand PL. Risk of developing asthma in young children with atopic eczema: A systematic review. J Allergy Clin Immunol 2007;120(3):565-569.

Study Design:
Cohort (prospective)

Synopsis:
It is commonly believed that the majority of infants and young children with early atopic eczema will develop asthma in later childhood. This belief is mainly based on cross-sectional population studies. Recent evidence suggests a more complex relationship between early eczema and asthma. This systematic review was conducted to assess the risk of developing asthma in children with atopic eczema during the first 4 years of life. A sensitive search was performed to identify all prospective cohort studies on the topic. By pooling the eligible reports, we calculated the risk of developing asthma at 6 years of age or older in children with atopic eczema in the first 4 years of life. Thirteen prospective cohort studies were included, with 4 representing birth cohort studies and 9 representing eczema cohort studies. The pooled odds ratio for the risk of asthma after eczema, compared with children without eczema, in birth cohort studies was 2.14 (95% CI, 1.67-2.75). The prevalence of asthma at the age of 6 years in eczema cohort studies was 35.8% (95% CI, 32.2% to 39.9%) for inpatients and 29.5% (95% CI, 28.2% to 32.7%) for a combined group of inpatients and outpatients. CONCLUSION: Although there is an increased risk of developing asthma after eczema in early childhood, only 1 in every 3 children with eczema develops asthma during later childhood. This is lower than previously assumed.