Comment
progression in the placebo group. The absence of a *Erik S G Stroes, Diederik F van Wijk
beneficial effect on parameters of the aortic vessel wall
might be due to the heterogeneity of anti-atherosclerotic
effects or the small sample size. A similar study with
anacetrapib, a more potent CETP inhibitor, could resolve
this issue, although the simultaneous decrease of LDL-C
by anacetrapib complicates interpretation of the exact
role of HDL-C.11
In addition to MRI, patients in Fayad and colleagues’
study were also assessed with ¹⁸FDG-PET/CT. FDG
uptake indicates inflammation of the arterial wall,
which is most probably attributable to accumulation
within plaque macrophages.12 Whether CETP-mediated
increase in HDL would lead to pro-inflammatory HDL
particles has long been debated. The decrease in carotid
FDG uptake observed in the dalcetrapib group implies
an anti-inflammatory effect of the HDL-C particle,
which is supported by the inverse correlation between
HDL-C increase and FDG uptake in the present study.
Counterintuitively, markers of systemic inflammation
did not decrease in the dalcetrapib group, underscoring
the poor correlation between systemic and vessel wall
inflammation. These findings indicate that the time
has come to assess the effect of selective, potent anti-
inflammatory drugs on vessel wall inflammation and
cardiovascular outcome. This effect is currently being
tested in the CANTOS study with an antagonist of
the interleukin 1β receptor in patients with cardio-
vascular disease.13
As we await the final verdict on dalcetrapib in 2013,
when the DAL-OUTCOME study will provide data on
cardiovascular endpoints in 15 600 patients, the findings
of Fayad and colleagues bring us one step higher on the
ladder of CETP research, after its free fall since 2006.
Management of low back pain in primary care: a new approach
Published Online In The Lancet, Jonathan Hill and colleagues1 present
September 29, 2011
DOI:10.1016/S0140-
a new and promising approach for the management
6736(11)61033-7 of low back pain in primary care. UK national clinical
See Articles page 1560 guidelines recommend triage for patients who present
with low back pain in primary care. Patients are divided
into those with specific low back pain (a small group)
and non-specific low back pain (a large group).2 Finding
optimum treatments for the large group with non-
specific low back pain is a challenge for clinicians and
1530
Department of Vascular Medicine, Academisch Medisch
Centrum, Meibergdreef, 1105 AZ Amsterdam, Netherlands
e.s.stroes@amc.uva.nl
We declare that we have no conflicts of interest.
1 Camont L, Chapman MJ, Kontush A. Biological activities of HDL
subpopulations and their relevance to cardiovascular disease.
Trends Mol Med 2011; published online Aug 11. DOI:10.1016/
j.molmed.2011.05.013.
2 Barter PJ, Caulfield M, Eriksson M, et al, for the ILLUMINATE Investigators.
Effects of torcetrapib in patients at high risk for coronary events.
N Engl J Med 2007; 357: 2109–22.
3 Rader DJ. Illuminating HDL—is it still a viable therapeutic target?
N Engl J Med 2007; 357: 2180–83.
4 Fayad ZA, Mani V, Woodward M, et al, for the dal-PLAQUE Investigators.
Safety and efficacy of dalcetrapib on atherosclerotic disease using novel
non-invasive multimodality imaging (dal-PLAQUE): a randomised
clinical trial. Lancet 2011; published online Sept 12. DOI:10.1016/S0140-
6736(11)61383-4.
5 Hu X, Dietz JD, Xia C, et al. Torcetrapib induces aldosterone and cortisol
production by an intracellular calcium-mediated mechanism
independently of cholesteryl ester transfer protein inhibition.
Endocrinology 2009; 150: 2211–19.
6 Stroes ES, Kastelein JJ, Benardeau A, et al. Dalcetrapib: no off-target toxicity
on blood pressure or on genes related to the renin-angiotensin-aldosterone
system in rats. Br J Pharmacol 2009; 158: 1763–70.
7 Sofat R, Hingorani AD, Smeeth L, et al. Separating the mechanism-based
and off-target actions of cholesteryl ester transfer protein inhibitors with
CETP gene polymorphisms. Circulation 2010; 121: 52–62.
8 Vergeer M, Bots ML, van Leuven SI, et al. Cholesteryl ester transfer protein
inhibitor torcetrapib and off-target toxicity: a pooled analysis of the Rating
Atherosclerotic Disease Change by Imaging With a New CETP Inhibitor
(RADIANCE) trials. Circulation 2008; 118: 2515–22.
9 Stein EA, Stroes ES, Steiner G, et al. Safety and tolerability of dalcetrapib.
Am J Cardiol 2009; 104: 82–91.
10 Kastelein JJ, van Leuven SI, Burgess L, et al. Effect of torcetrapib on carotid
atherosclerosis in familial hypercholesterolemia. N Engl J Med 2007;
356: 1620–30.
11 Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with
or at high risk for coronary heart disease. N Engl J Med 2010; 363: 2406–15.
12 Rudd JH, Hyafil F, Fayad ZA. Inflammation imaging in atherosclerosis.
Arterioscler Thromb Vasc Biol 2009; 29: 1009–16.
13 Libby P, Ridker PM, Hansson GK. Progress and challenges in translating
the biology of atherosclerosis. Nature 2011; 473: 317–25.
researchers. The group with non-specific low back
pain is probably heterogeneous in terms of patients’
clinical characteristics, prognosis, and susceptibility to
treatments. For patients with non-specific low back
pain, a wide range of interventions are available within
primary care (eg, advice and education, pain medication,
physical treatments, and psychosocial interventions),
but there are few clues available for best matching of
individuals to the treatment options.
www.thelancet.com Vol 378 October 29, 2011

Treatment results for patients with low back pain
in general are moderate, as shown by the outcomes
of systematic reviews.3–6 These results have led to
many attempts to identify relevant subgroups so that
patients can be matched to specific interventions with
increased accuracy. Reliable and valid classification
of patients could lead to tailored treatments and
improved outcomes. Until now, not many attempts
have met these qualifications, although there is much
work in progress.7–9
The STarT Back1 trial shows promising results in
terms of the assessment of stratified primary care
management. Hill and colleagues assessed a two-step
model. First, 851 patients with low back pain were
stratified according to their risk of persistent disability.
On the basis of a simple screening questionnaire,
patients were grouped according to low, medium, and
high risk. Second, treatment pathways were matched
to the three risk groups. The low-risk group was given
a minimum intervention of one (baseline) session
only, the medium-risk group a referral for standardised
physiotherapy, and the high-risk group a referral for
psychologically informed physiotherapy. In the STarT
Back trial, this new approach was directly compared
with a control group that was given non-stratified
best practice, including (physiotherapy) treatment at
the discretion of the physiotherapist involved in the
baseline session.
The STarT Back trial was well designed and executed.
Besides assessment of the overall clinical and economic
outcomes of the new stratified management
approach, the trial was sufficiently powered to assess
outcomes in the three risk groups separately. For
low-risk patients the aim was to assess non-inferiority
of the minimum intervention, and for the medium-risk
and high-risk groups superiority compared with the
control intervention.
The most important finding is that stratified
primary care management did show better clinical
and economic outcomes than did non-stratified
conventional care in the UK. In terms of disability,
the primary outcome, the reduction was larger in the
intervention group than in the control group after
4 months (between-group difference in adjusted
mean change in score on the Roland Morris Disability
Questionnaire 1·81 [95%CI 1·06–2·57]). Similar results
were noted for a range of relevant secondary outcome
www.thelancet.com Vol 378 October 29, 2011
Comment
Science Photo Library
measures, including pain intensity, global change,
and psychological measures. The outcomes in the
low-risk groups showed non-inferiority. Thus, for this
subgroup, the minimum intervention did not lead to
worse outcomes than did current best practice. In the
medium-risk and high-risk groups, the differences as
compared with the control intervention in reduction
of disability were largest at 4 months of follow-up. At
12 months of follow-up, differences were still apparent
but no longer significant in the high-risk group.
Should this new intervention now be widely
implemented? These results are indeed very promising.
The within-group treatment effects of the stratified
approach are substantial, although it is noteworthy
that the magnitude of the between-group treatment
effects of the stratified approach are not large. The
largest between-group difference on the Roland Morris
Disability Questionnaire was 2·53 (95% CI 0·90–4·16) in
the high-risk group after 4 months of follow-up. This is
a small effect and the effects were even smaller at other
timepoints and in the medium-risk group. However, in
the absence of better alternatives we should welcome
small improvements. Additionally, the economic
assessment showed that the new approach was cost
effective so there is no financial reason not to implement
the new intervention. When using the new approach, we
need to acknowledge that patients generally improve
with time. However, 38% of patients in the intervention
group and 43% in the control group reported that they
had not recovered after 12 months of follow-up. In the
high-risk group, higher percentages of patients reported
1531
 Comment
that they had not recovered. So, further improvements
are desirable. Hill and colleagues are to be applauded
for showing that improvements in the management of
low back pain in primary care are feasible. Clinicians and
researchers now face the challenge of implementing and
further optimising the new approach.
Bart Koes
Department of General Practice, Erasmus University Medical
Centre, 3000 CA Rotterdam, Netherlands
b.koes@erasmusmc.nl
I declare that I have no conflicts of interest.
1 Hill JC, Whitehurst DGT, Lewis M, et al. Comparison of stratified primary
care management for low back pain with current best practice (STarT
Back): a randomised controlled trial. Lancet 2011; published online Sept 29.
DOI:10.1016/S0140-6736(11)60937-9.
2 Koes BW, van Tulder M, Lin CW, Macedo LG, McAuley J, Maher C.
An updated overview of clinical guidelines for the management of
non-specific low back pain in primary care. Eur Spine J 2010; 16: 2075–94.
The point of point-of-care testing
See Articles page 1572 Ilesh Jani and colleagues’ study1 of point-of-care (POC)
CD4 cell testing in The Lancet provides an example of
effective operational research with routinely collected
clinical data in a resource-limited setting. New
durable, simple, and affordable cytometric CD4 testing
devices aim to decrease the time to antiretroviral
therapy initiation and loss to follow-up.2–4 Rapid
testing with microfluidics meets the criteria for true
POC testing, providing immediate results without
needing laboratory personnel or infrastructure.5,6 These
Reuters
Patients await treatment at an AIDS clinic outside Maputo, Mozambique
1532
3 van Tulder MW, Koes B, Malmivaara A. Outcome of non-invasive treatment
modalities on back pain—an evidence-based review. Eur Spine J 2006;
15 (suppl 1): S64–S81.
4 Kuijpers T, van Middelkoop M, Rubinstein SM, et al. A systematic review on
the effectiveness of pharmacological interventions for chronic non-specific
low-back pain. Eur Spine J 2011; 20: 40–50.
5 van Middelkoop M, Rubinstein SM, Kuijpers T, et al. A systematic review on
the effectiveness of physical and rehabilitation interventions for chronic
non-specific low back pain. Eur Spine J 2011; 20: 19–39.
6 Rubinstein SM, van Middelkoop M, Kuijpers T, et al. A systematic review on
the effectiveness of complementary and alternative medicine for chronic
non-specific low-back pain. Eur Spine J 2010; 19: 1213–28.
7 Foster NE, Hill JC, Hay EM. Subgrouping patients with low back pain in
primary care: are we getting any better at it? Man Ther 2011; 16: 3–8.
8 Kamper SJ, Maher CG, Hancock MJ, Koes BW, Croft PR, Hay E.
Treatment-based subgroups of low back pain: a guide to appraisal
of research studies and a summary of current evidence.
Best Pract Res Clin Rheumatol 2010; 24: 181–91.
9 Stanton TR, Hancock MJ, Maher CG, Koes BW. Critical appraisal of clinical
prediction rules that aim to optimize treatment selection for
musculoskeletal conditions. Phys Ther 2010; 90: 843–54.
tests will conserve diagnostic resources and provide
convenience and savings for patients. Whether the
availability of such technology will help to overcome
the many obstacles to successful delivery and scale-up
of antiretroviral therapy in resource-limited settings is
still to be shown.
CD4 staging establishes eligibility for antiretroviral
therapy after HIV diagnosis. To obtain a CD4 cell
count in resource-limited settings presents many
challenges, and the scale of these challenges is often
underestimated.1 The required two minimum clinic
visits often span a month or longer, and associated
transport costs can deter access to care. Pre-analysis
infrastructure includes blood collection apparatus,
a trained phlebotomist, and quick, reliable, and
accountable transport and tracking of samples.
Laboratories need functioning and calibrated instru-
ments, trained and disciplined personnel, and quality
assurance programmes.7 Finally, the return of CD4
results to a distant clinic is fraught with the difficulties
of handwritten medical records and unique identifiers.
POC testing offers a solution to many of these
difficulties by dispensing with these multiple steps
without compromising the accuracy of the result.
The clinical settings in which POC CD4 testing might
be most effective in treatment and retention have not
been identified. Based on an observational study carried
www.thelancet.com Vol 378 October 29, 2011