Comment
8 Cave DM, Gazmuri RJ, Otto CW, et al. Part 7: CPR techniques and devices. 12 Plaisance P, Lurie KG, Payen D. Inspiratory impedance during active
2010 American Heart Association guidelines for cardiopulmonary
resuscitation and emergency cardiovascular care. Circulation 2010;
122 (suppl 3): S720–28.
9 Deakin CD, Nolan JP, Soar J, et al. European Resuscitation Council
guidelines for resuscitation 2010 section 4: adult advanced life support.
Resuscitation 2010; 81: 1305–52.
10 Cabrini L, Beccaria P, Landoni G, et al. Impact of impedance threshold devices
on cardiopulmonary resuscitation: a systematic review and meta-analysis of
randomized controlled studies. Critical Care Med 2008; 36: 1625–32.
11 Aufderheide TP, Nichol G, Rea TD, et al. The Resuscitation Outcomes
Consortium (ROC) PRIMED impedance threshold device (ITD) cardiac arrest
trial: a prospective, randomized, double-blind, controlled clinical trial.
Circulation 2010; 122: 2215–26 (abstr).
Initial combination antihypertensives: let’s ACCELERATE
Published Online The increased incidence and prevalence of hypertension
January 13, 2011
DOI:10.1016/S0140-
in developed countries parallel those of obesity and have
6736(10)62270-2 been growing since the 1980s.1 In the USA, the Healthy
See Articles page 312 People 2000 health-objectives programme (launched
by the US Department of Health and Human Services)
set as a goal that half of those being treated for blood
pressure should reach less than 140/90 mm Hg, which
was achieved in 2008.2
Improvement of blood pressure control in the USA,
in the face of increasing obesity, is partly due to the
efforts of many groups and governmental agencies.
These groups have adopted the blood pressure goals
of the seventh report of the Joint National Committee
on Prevention,3 Detection, Evaluation, and Treatment
of High Blood Pressure, including the need for initial
antihypertensive combinations when blood pressure is
greater than 20/10 mm Hg above goal.4,5
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278
compression-decompression cardiopulmonary resuscitation: a randomized
evaluation in patients in cardiac arrest. Circulation 2000; 101: 989–94.
13 Plaisance P, Lurie KG, Vicaut E, et al. Evaluation of an impedance threshold
device in patients receiving active compression-decompression
cardiopulmonary resuscitation for out of hospital cardiac arrest.
Resuscitation 2004; 61: 265–71.
14 Wolcke BB, Mauer DK, Schoefmann MF, et al. Comparison of standard
cardiopulmonary resuscitation versus the combination of active
compression-decompression cardiopulmonary resuscitation and an
inspiratory impedance threshold device for out-of-hospital cardiac arrest.
Circulation 2003; 108: 2201–05.
Monotherapy has proven inadequate to control
blood pressure in most patients with hypertension. This
finding is shown by trials such as the Antihypertensive
and Lipid-Lowering Treatment to Prevent Heart Attack
Trial (ALLHAT), in which only a quarter of the 33 000 or
so participants achieved goal values.6 This failure of the
drug to lower blood pressure adequately without adding
medication, related to physicians’ inertia,7 is associated
with increased cardiovascular events in patients on
monotherapy.8 Many cardiovascular events occur early
in clinical trials of initial monotherapy because of large
differences in blood pressures between groups.9,10 Thus
more aggressive initial control of blood pressure could
further reduce the risk of cardiovascular events.
Combination antihypertensive therapy is not new. In
the mid-1960s a fixed-dose combination of reserpine,
hydrochlorothiazide, and hydralazine was available and
widely used.11 Since the 1980s there have been several
antihypertensive combinations of drug classes with
complementary pharmacological mechanisms, joined in
one pill or given independently, to help to achieve blood
pressure goals.5
Recent evidence supports the rationale for starting
combination antihypertensive therapy because of its
effect of reaching blood pressure goals with reduced
adverse outcomes. The Study of Hypertension and the
Efficacy of Lotrel in Diabetes (SHIELD) trial was one of the
first trials to show rapid achievement of blood pressure
control with few side-effects in patients with type 2
diabetes who had stage 2 hypertension.12 Here, the initial
fixed-dose combination of amlodipine plus benazepril
was compared with enalapril alone; both agents were
maximally titrated to achieve blood pressure less than
130/80 mm Hg. Even when a thiazide diuretic was added,
www.thelancet.com Vol 377 January 22, 2011

fewer patients in the enalapril group achieved this goal
than in the amlodipine plus benazepril group.
In The Lancet, the results of the ACCELERATE (Aliskiren
and the Calcium Channel Blocker Amlodipine Combination
as an Initial Treatment Strategy for Hypertension) trial13
confirm and expand the results of SHIELD. ACCELERATE
randomised almost six times more patients (n=1254) than
SHIELD did, had a longer follow-up (32 weeks), and was
representative of the general population. ACCELERATE
showed higher rates of blood pressure control after
8 and 16 weeks of treatment in patients initially treated
with a combination of aliskiren and amlodipine than in
those on the monotherapy components of the combi-
nation. More importantly, ACCELERATE extends SHIELD’s
findings by showing that starting combination therapy
helps patients to achieve blood pressure goals faster
than does initial monotherapy, even when an additional
antihypertensive agent is given to control blood pressure.
ACCELERATE defined goal blood pressures as less than
140/90 mm Hg or a reduction greater than 20 mm Hg
in systolic pressure from baseline. Logistical regression
showed clinically important differences in blood pressure
values between the combination and monotherapy
groups at 24 and 32 weeks, when all three groups were
titrated to maximum doses. At 32 weeks, 77·0% of
patients on initial combination therapy reached their
blood pressure goal compared with 73·7% of those
randomly assigned to aliskiren alone and 65·8% of those
receiving amlodipine alone. Differences of 2·5 mm Hg
or more can make a big difference to cardiovascular risk,
especially stroke risk when studying large groups of
people, as meta-analyses of large outcome trials show.14
ACCELERATE puts into proper context the importance
of starting with combination antihypertensives to lower
blood pressure towards guideline goals for the general
population. Monotherapy, even when maximally titrated
and with add-on agents, generally does not provide the
same level of control and risk reduction in people who
are 20/10 mm Hg above their goal.
A position paper by the American Society of Hyper-
tension reviewed all the evidence from clinical trials and
recommended combination antihypertensive therapy,
with a blocker of the renin–angiotensin system combined
with either a calcium-channel antagonist or long-acting
thiazide for initial therapy.5 A change in guidelines is
clearly necessary after the ACCELERATE report and that of
the Avoiding Cardiovascular events through COMbination
www.thelancet.com Vol 377 January 22, 2011
Comment
therapy in Patients LIving with Systolic Hypertension
(ACCOMPLISH) trial,15 the first cardiovascular outcome trial
to randomise and titrate fixed-dose antihypertensives in
people not at blood pressure goal on existing treatment.
On the basis of available data and results of ACCOMPLISH,
initial combination therapy should be advocated for
all those already implementing lifestyle changes who
are still above 150/90 mm Hg, as most people in
ACCELERATE were.
Ivana Lazich, *George Bakris
University of Chicago Hypertensive Diseases Unit, Department
of Medicine, University of Chicago Pritzker School of Medicine,
Chicago, IL 60637, USA
gbakris@medicine.bsd.uchicago.edu
IL declares that she has no conflicts of interest. GB has been a consultant for Merck,
Novartis, Walgreen’s, Daichi-Sankyo, Abbott, Takeda, Otsuka, and Fibrogen; and
has applied for grants from Novartis, Pepsico, NIH, Forest Labs, and
GlaskoSmithKline; and received payment for visiting professorships and university
grand-rounds lectures as well as lectures at national and international meetings.
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incidence in women and men. The NHANES I Epidemiologic Follow-up Study.
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2 Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment,
and control of hypertension, 1988–2008. JAMA 2010; 303: 2043–50.
3 Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National
Committee on prevention, detection, evaluation, and treatment of high
blood pressure. Hypertension 2003; 42: 1206–52.
4 Singer GM, Izhar M, Black HR. Goal-oriented hypertension management:
translating clinical trials to practice. Hypertension 2002; 40: 464–69.
5 Gradman AH, Basile JN, Carter BL, et al. Combination therapy in hypertension.
J Am Soc Hypertens 2010; 4: 90–98.
6 Cushman WC, Ford CE, Einhorn PT, et al, for the ALLHAT Collaborative
Research Group. Blood pressure control by drug group in the
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
(ALLHAT). J Clin Hypertens (Greenwich) 2008; 10: 751–60.
7 Faria C, Wenzel M, Lee KW, Coderre K, Nichols J, Belletti DA. A narrative review
of clinical inertia: focus on hypertension. J Am Soc Hypertens 2009; 3: 267–76.
8 Redón J, Coca A, Lázaro P, et al. Factors associated with therapeutic inertia in
hypertension: validation of a predictive model. J Hypertens 2010; 28: 1770–77.
9 Weber MA, Julius S, Kjeldsen SE, et al. Blood pressure dependent and
independent effects of antihypertensive treatment on clinical events
in the VALUE Trial. Lancet 2004; 363: 2049–51.
10 The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research
Group. Major outcomes in high-risk hypertensive patients randomized to
angiotensin-converting enzyme inhibitor or calcium channel blocker vs
diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent
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of fixed-dose combination therapy. Arch Intern Med 1996; 156: 1969–78.
12 Bakris GL, Weir MR, on behalf of the Study of Hypertension and the Efficacy of
Lotrel in Diabetes (SHIELD) Investigators. Achieving goal blood pressure in
patients with type 2 diabetes: conventional versus fixed-dose combination
approaches. J Clin Hypertens (Greenwich) 2003; 5: 202–09.
13 Brown MJ, McInnes GT, Cherif Papst C, Zhang J, MacDonald TM. Aliskiren and
the calcium channel blocker amlodipine combination as an initial treatment
strategy for hypertension control (ACCELERATE): a randomised,
parallel-group trial. Lancet 2011; published online Jan 13. DOI:10.1016/
S0140-6736(10)62003-X.
14 Staessen JA, Li Y, Thijs L, Wang JG. Blood pressure reduction and
cardiovascular prevention: an update including the 2003–2004 secondary
prevention trials. Hypertens Res 2005; 28: 385–407.
15 Jamerson K, Weber MA, Bakris GL, et al, for the ACCOMPLISH Trial
Investigators. Benazepril plus amlodipine or hydrochlorothiazide for
hypertension in high-risk patients. N Engl J Med 2008; 359: 2417–28.
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