2. dose anti-hypertensive combination therapy compared to usual care
(64.7% versus 52.7%; absolute difference: 12.0%; 95% CI: 1.5% to 22.4%;
p=0.026) [13].
The accumulated evidence from studies focussing on more structured
management of hypertension and pharmacological studies investigating
the benefits of greater BP control with combination anti-hypertensive
therapy is clear [14–16]. The key ingredients for achieving optimal BP
control, which can be overlooked in (busy) real-life clinical care, are to not
only set an appropriate BP target, but also establish a schedule of
treatment and contacts between individuals and their GP to achieve the
target goal. This is in parallel with achieving an overall reduction in cardiac
risk given that BP targets are now being stratified according to the risk of a
subsequent cardiovascular event [1]. In light of some evidence to suggest
that early BP control in hypertensive individuals confers longer-term
benefits in respect to reduced risk of fatal and non-fatal CV events [14], it is
worthconsideringtheadditionalbenefitsofapplyingintensive,structured
management with pharmacological therapy that achieves optimal BP
control as early as possible. To attain long-term BP control in a real-world
setting, therefore, a currently unproven but promising strategy involves
combining two independently effective components of BP control in the
primary care setting: 1) intensive initiation of BP management for early
control to provide potential prognostic benefits as well as early
identification of patients who require more aggressive anti-hypertensive
treatment, and 2) more pro-active application of modern “combination”
anti-hypertensiveformulationsthatmayprovideincreasedBPcontrol and
greater treatment adherence. We hypothesised that this type of strategy is
not a common feature of contemporary hypertension management in
Australia.
2. Pilot survey of BP management in primary care
In order to identify the features of contemporary primary care
management of hypertension we surveyed (unpaid) 500 national GPs
using a case scenario (see Box 1), similar to the application of a recent
lipid management survey in primary care [17]. The following
characteristics of hypertension management in primary care became
apparent:
• Variable BP surveillance and follow-up patterns to determine
treatment efficacy.
• Low uptake of individualised BP targets advocated by the National
Heart Foundation of Australia (NHFA) [1] based on their clinical
profile.
• Application of a wide variety of anti-hypertensive therapies
(reflecting the lack of precise guidelines for BP lowering in this
setting).
• Lack of ancillary profiling to calculate absolute cardiovascular risk in
eligible individuals (i.e. adults aged N45 years with a history of CVD)
to determine the need for more integrated primary (and secondary)
prevention in hypertensive individuals.
The study cohort appeared to be broadly representative of
Australian primary care in that 69% (n=347) of GPs were male
with a mean age of 48 years (range 28–80 years). A total of 475 GPs
(95%) used a computerised record/prescription system. Overall, 70%
(n=365) of GPs employed at least one practice nurse, with 22% of
these having 3 or more practice nurses. The estimated case load was
on average 5400 patients per year (104 per week) with an annual
range between 100 and 48,000 patients per year.
Overall, 140 GPs (28%) nominated a higher than recommended [1]
(N130/80 mm Hg) BP target for this hypothetical patient. In order to
reduce their BP, a majority of GPs indicated that a combination of
lifestyle modification and prescribed pharmacotherapy (72%) would
best achieve their nominated BP target; 19% nominated lifestyle
modifications alone and 9% pharmacotherapy alone. The most popular
“first-line” agent was the angiotensin converting enzyme inhibitor
perindopril (204 GPs, 49%) followed by the beta blocker carvedilol (80
GPs, 20%) and the angiotensin receptor blocker candesartan (54 GPs,
13%). Overall, therefore, a range of pharmacological agents were
nominated to control this individual's BP.
When asked to nominate the likely impact of their chosen therapy,
80% of GPs (387 of 445 with a valid response) expected a reduction in
systolic BP of up to 20 mm Hg with around one in two (46%) expecting
a reduction between 11 and 20 mm Hg. Approximately 70% of GPs
expected a reduction in diastolic BP of up to 10 mm Hg yet many GPs
(n=328, 70%) nominated a reduction in systolic BP as their most
important therapeutic target. In order to determine the impact of their
management, just over half (53%) would review this patient within
2 weeks and one third (33%) between 2 and 4 weeks; the remainder
nominating a longer period.
When informed that Mr Smith returns with a BP of 138/85 mm Hg
and an improved CVD risk profile but has developed proteinuria (N1 g
per day confirmed by urine dipstick), 90% of GPs nominated an original
or revised (336, 67%) BP target that is consistent with NHFA guidelines
[1]. If further management resulted in “ideal” BP control, more than half
of the GPs (53%) would schedule a follow-up visit N2 months later while
42% nominated a follow-up review between 1 and 2 months.
Overall, these data confirm a large degree of variability in respect
to a number of important features relating to the contemporary
management of BP in Australian primary care. These include:
1) Identification of ideal BP targets — despite being (reassuringly)
largely consistent with relevant guidelines.
2) Strategies used to control the BP of a high risk individual — a majority
of GPs indicated they would apply anti-hypertensive treatment but
in relatively low doses and rarely as combination therapy.
3) Follow-up monitoring and ongoing surveillance.
Within the many caveats inherent to the methodology applied, the
findings broadly support the need to apply a more structured
approach to hypertension management in primary care.
3. The Viper-BP Study
In view of the literature supporting the application of more intensive
and aggressive anti-hypertensive therapy as part of structured BP
management and our own data suggesting that this is rarely applied in
Australian primary care, we planned the Valsartan Intensified Primary
carE Reduction of Blood Pressure Study (VIPER-BP) Study. This study
was specifically designed to address that outside of the clinical trial
setting (i.e. in a real world environment), it is unknown whether it is safe
and efficacious to apply a pro-active and aggressive form of BP
management.
3.1. Objective and hypothesis
The VIPER-BP Study seeks to examine the safety and efficacy of a
more intensive approach to BP management from both pharmacologic
and non-pharmacologic perspectives. It was hypothesised that in a
primary care setting, a greater proportion of patients with a sub-optimal
BP according to their clinical profile (contemporary NHFA criteria [1])
who are exposed to the VIPER-BP intervention (an intensive BP
Box 1
Case scenario: Mr Smith has a history of coronary artery
disease. He has multiple risk factors including:
• Fasting total cholesterol level=5.81 mmol/L
• Excess body weight (body mass index=27.8 kg/m2
)
• Two sitting BP readings providing an average value of 166/
92 mm Hg
318 S. Stewart et al. / International Journal of Cardiology 153 (2011) 317–322
3. management strategy using three forms of valsartan-based therapy) will
demonstrate greater BP control against their individualised BP target at
26 weeks follow-up post initiation of the VIPER-BP intervention, relative
toa controlgroup of patients exposed tousualcareforthemanagementof
their hypertension (as determined by baseline profiling using the same
type of scenario-based questionnaire described above).
4. Methods
4.1. GP Investigators
Based on the pilot survey of 500 Australian GPs, we estimated that a minimum of 250 GP
Investigators would be required to recruit an average target of 10 eligible patients during a
12–18 month recruitment period commencing in July 2009. During the active recruitment
phase of the study, information about the VIPER-BP Study was presented to more than 6000
GPs(including 4900mail-outs)throughout Australia.A total of620GPslocated in every State
and Territory of Australia (except the Northern Territory) initially registered their interest in
being a GP Investigator. After reviewing the full protocol and study requirements, 455 of
these GPs (72%) received a formal site initiation visit. Of these, just over half (272, 60%) of GPs
from 122 primary care clinics had formally entered at least one patient into the study at
November 2010. The greatest contribution of study patients came from GPs located in New
South Wales (around 40%) and Western Australia (around 20%). A total of 104 GPs (38%)
practice in a non-metropolitan area (N30 km from the CBD). A separate manuscript
describing the location, characteristics and indicative hypertension management of the
VIPER-BP GP Investigators is planned for the near future.
4.2. Participants
Primary care patients being managed by the VIPER-BP Study GP Investigators are eligible
to participate if they are: 1) aged 18 years or more; 2) determined to have hypertension
requiring active pharmacological treatment (based on current guidelines [1]) and; 3) consent
to participate. Key exclusion criteria include: 1) a mean sitting systolic BP≥180 mm Hg at
study visits1 or2; 2)currently prescribed three or moreanti-hypertensive agentstomaintain
an optimal BP; 3) history of severe renal disease and/or; 4) contra-indications to an
angiotensin receptor blocker, calcium channel blocker or a thiazide diuretic.
Ethics approval for the VIPER-BP Study was received from the Alfred Human
Research Ethics Committee, the Royal Australian College of General Practitioners and
the Australian Institute of Health and Welfare. Approval for GP Investigators to access
Medicare reimbursement for the gold-standard management of hypertension
(additional funding to support study activities was provided) and for Baker IDI to
access participant Medicare claims information was sought from Medicare Australia.
The ClinicalTrials.gov registry number for VIPER-BP is NCT00902304.
4.3. Design
Fig. 1 shows the overall design of the VIPER-BP Study. This is an open-label,
randomised trial comparing usual primary care with an intensive BP management
strategy, using three standardised forms of angiotensin receptor blocker-based therapy
(valsartan alone and in combination with a thiazide diuretic or calcium channel
blocker) to determine its impact on achieving a pre-designated individualised BP
target. At the point of study design, valsartan and its combinations (in a single pill) had
been newly approved under the Pharmaceutical Benefits Scheme for subsidised
prescriptions and offered the unique flexibility built into the combination arm of the
study. The study is being undertaken according to the CONSORT guidelines [18].
Blinded randomisation at a ratio of 1:2 (usual care versus intervention arm) is stratified
according to each patient's individualised BP target with block randomisation for each
GP Investigator. The increased ratio of intervention patients reflects randomisation to two
different strategies using valsartan-based therapies; initial mono therapy versus combination
therapy at a ratio of 1:2, further reflecting the availability of mono versus combination
therapies.
A standardised protocol for recording study BP measurements is applied. Specifically,
after an initial rest period of approximately 5 min, three systolic and diastolic BP
measurements separated by one-minute intervals, are obtained in the sitting position
using an appropriate size cuff and an automated BP monitor approved by the Therapeutic
Goods Administration of Australia. Aberrant readings are defined as those whereby the
difference between the lowest and highest of the three seated readings is ≥10 mm Hg
(systolic) or ≥5 mm Hg (diastolic). When this occurs, thepatient isrested for anadditional
3 min and another set of three readings are taken for study documentation.
As also shown in Fig. 1, all patients undergo baseline assessment of their absolute
CVD risk [19] and identification of their ideal risk factor levels (including their
individualised BP target according to the presence or absence of target organ damage
and/or established CVD [1]). Eligible patients then commence a standard 28 day run-in
period of treatment with open-label, oral valsartan 80 mg per day, with a mandatory BP
check 14 days after the initiation of treatment to determine the need for “rescue
randomisation” (if systolic BP is N180 mm Hg or clinically indicated). In addition to
standardising initial anti-hypertensive therapy, this phase of the study permits the
application of combination therapy at the point of randomisation. All other anti-
hypertensive treatments are ceased at the commencement of this run-in phase of the
study. Those who achieve their target BP at either their 14 or 28 day visit take no
further part in the study. If, however, BP remains sub-optimal after the 28-day run-in
period, patients are randomised to usual care or to the study intervention comprising an
intensive BP management strategy using titrated treatment regimens which include three
alternate forms of valsartan-based therapy (VIPER-BP intervention).
For those randomised to usual care (Group 1), GPs apply their usual pattern of patient
visitsandtreatmentstrategiestoachievetheirindividualisedBPtarget, withafinalstudyvisit
at week 26. Those randomised to the VIPER-BP intervention (Group 2) follow an intensive 6
to 18 week period of BP management (with a final study visit at week 26). Within Group 2,
patients are further randomised to treatment according to the following algorithms of open-
label, oral valsartan-based therapy: Group 2a (initial mono-therapy arm) — GPs initially
utilise valsartan 160 mg per day for 6 weeks, followed by (if required) dose titrations every
4 weeks thereafter until week 14 (valsartan 320 mg per day, then valsartan 320 mg plus
hydrochlorothiazide[HCTZ]12.5 mg perdayand thenvalsartan320 mg plus HCTZ25 mgper
day — maximal dose). For patients not at BP target at week 18 (after 4 weeks on the maximal
dose), triple or alternative therapy is considered for the remainder of the study follow-up
period; Group 2b (initial combination therapy arm) — GPs initially utilise single pill
combination products of either valsartan plus HCTZ or valsartan plus amlodipine for an initial
6 weeks of therapy (based on the treating GPs preference), with dose titrations (if required)
every 4 weeks thereafter until week 10. If the HCTZ combination is preferred, the schedule
followed isvalsartan 80 mg plus HCTZ 12.5 mg, then valsartan 160 mg plus HCTZ12.5 mg per
day, and then valsartan 160 mg plus HCTZ 25 mg per day (maximal dose). If the amlodipine
combination is chosen, the treatment strategy followed is valsartan 80 mg plus amlodipine
5 mg per day, valsartan 160 mg plus amlodipine 5 mg, and then valsartan 160 mg plus
amlodipine 10 mg — maximal dose. For those patients not at BP target at week 14 (after
4 weeks on the maximal dose of either regimen), triple or alternative therapy is considered
for the remainder of the study follow-up period.
4.4. Study endpoints
The primary endpoint is the percentage of patients randomised to the usual care
treatment group versus the VIPER-BP intervention treatment group who have achieved their
pre-specified (individualised NHFA criteria [1] — see Table 1) BP target at 26 weeks.
Secondary endpoints include change in mean sitting systolic and diastolic BP from baseline
(visit 4)to26 weeks(visit9),rateofadverseeventsattributabletoanti-hypertensivetherapy
and the proportion of “early responders” who achieve individualised BP control (recorded at
pre-specified study visits) after one or two adjustments in anti-hypertensive therapy. During
the 26 week follow-up period, changes in absolute CVD risk [19], health state [20], mental
health [21,22], evidence of end-organ damage, self-care and treatment compliance will also
be assessed. Major clinical end-points (at 26 weeks) are all-cause mortality and fatal and
non-fatal cardiovascular events (e.g. acute myocardial infarction, stroke and heart failure).
The proportion of patients (and GPs) who adhere to the VIPER-BP intervention (in respect to
drug titration and regular follow-up) will also be determined in addition to the potential
correlation between adherence to the intervention and degree of BP control.
4.5. Study power
We established a 7% absolute difference in individualised BP control at 26 weeks as
the minimum clinically significant difference between groups. Based on findings from
the literature [10], we anticipate that up to 12% difference (approximately 20% relative
difference when assuming a baseline rate of 50% control in the usual care arm of the
study) will be observed between groups. Given inherent uncertainties in the rate of
patient recruitment, the “conversion” of run-in to randomised patients and completion
of 26 week follow-up, a conservative approach to calculating the requisite sample size
was applied. Fig. 2 shows that assuming a two-sided alpha level of 0.05 and adjusting
for 2:1 randomisation for study intervention versus usual care, 1800 subjects who
complete 26 week follow-up will provide N80% power to detect a minimal 7% absolute
difference in BP control at 26 weeks on the basis that 50% of those allocated to usual
care are at their individualised target within this time point. In practice, we aim to
initially randomise up to 2250 subjects to achieve this target. However as demonstrated in
Fig. 2, a total of 1500–1800 subjects with complete follow-up will provide sufficient study
power to detect an 8–9% difference between groups at 85% study power.
5. Preliminary profile of study patients
By November 2010, a total of 2157 potentially eligible patients had
been subjected to initial screening. Of these, 1965 (91%) were entered into
the 28 day valsartan 80 mg “run-in” phase. Subsequently, 257 patients
achieved their individual BP target (13%) whilst at the other end of the
spectrum, 62 patients (3.2%) required a rescue randomisation for
markedly elevated BP. Of the remainder (n=361), 217 were still in the
run-in phase and 144 had prematurely withdrawn from the study; this
included 33 adverse events (1.7% of run-in patients) and two serious
adverse events. Thus, 1285 patients have been randomised to usual care
(n=435) or the VIPER-BP intervention (n=850). Of those randomised,
797 (62%) were male who were on average 3 years younger than female
patients (mean age 58±12 versus 61±12 years; pb0.05) and 63% (810)
had previous treatment for hypertension ceased at study run-in.
319S. Stewart et al. / International Journal of Cardiology 153 (2011) 317–322
4. Calculated BP targets (systolic/diastolic BP) were as follows: 125/75 mm
Hg (18% with proteinuria), 130/80 mm Hg (55% with diabetes or CVD)
and 140/90 mm Hg (27% without CVD or renal dysfunction). Mean
systolic and diastolic BP on randomisation was 148±15/88±11 mm Hg
with similar BP profiles for men and women respectively (148±15/88±
11 versus 148±18/87±10 mm Hg).
6. Discussion
To our knowledge, this study (incorporating a combined pharma-
cological and disease management approach to BP management using
computerised support) represents the largest of its kind in Australia
and indeed worldwide. Although there have been many large
Fig. 1. VIPER-BP study schema. Legend: GP, General Practitioner; CVD, cardiovascular disease; BP, blood pressure; NHFA, National Heart Foundation of Australia; HT, hypertension;
SBP, systolic blood pressure; Tx, treatment.
320 S. Stewart et al. / International Journal of Cardiology 153 (2011) 317–322
5. hypertension trials [14–16] with a major focus on the efficacy of
different combinations of pharmacological therapy (including the
ANBP2 Study in Australia [23]), there is a paucity of large-scale, multi-
centre studies combining pharmacological treatment with a structured
approach to management. As identified previously, there is sufficient
evidence to suggest that a step-wise, vigorous approach to the primary
care management of hypertension will provide improved BP control [10].
However, we have strong evidence, both from community-based studies
[3,4] and our direct survey of Australian GPs that a heterogeneous
approach to the management of hypertension has meant that the “rule of
halves” still applies; close to 50% of those treated for hypertension remain
hypertensive. Unfortunately, if we apply more rigorous BP targets to
prevent end-organ damage and subsequent morbidity and mortality [1],
such a treatment gap is likely to be wider. In support of a more aggressive
approach to hypertension management, results from both the VALUE
[14,16] and ACCOMPLISH [15] trials suggest there are potential
advantages to achieving BP control sooner and that early application of
combination therapies are more likely to achieve this goal.
There are many challenges when engaging extremely busy GPs to
undertake a clinical research program such as VIPER-BP, particularly
smaller GP clinics where the capacity to support additional research
activities is limited. This is compounded by our attempt to apply a more
structured and uniformed approach to BP management. In order to
streamline clinical management according to the study protocol and
provide GPs with a practical tool that is relevant beyond the study, we
developed and applied the Baker IDI CVD Risk Assessment and Management
Tool that provides computer-based profiling for individual patients. This
identifies their key primary and secondary prevention goals (where
appropriate) and recommends incremental anti-hypertensive therapy
according to the patient's BP. It is interesting to note that many of the
prerequisites for progressing through the study rely upon the type of
individual profiling inherent to current guidelines (e.g. lipid profile and
albumin–creatinine ratio) [1,19]. However, many patients recruited are
being profiled (via the assessment tool) in this way for the first time.
Recruitment rates thus far demonstrate that achieving the target number
of patients will be challenging, yet still attainable, whilst retaining
statistical power to examine the primary endpoint.
The VIPER-BP Study is an innovative study of intensive BP
management in primary care that combines the application of more
intensive and aggressive anti-hypertensive therapy with structured BP
management to more rapidly attain and sustain individualised BP targets
in otherwise hypertensive individuals. Preliminary data suggest that we
have recruited a representative cohort of Australian GPs with the capacity
to recruit a sufficiently large cohort of eligible patients. If the primary
endpoint analysis favours the studyintervention, the VIPER-BP Studymay
have profound implications for the primary care management of elevated
BP to reduce the enormous burden imposed by hypertension-related
disease (particularly chronic heart failure) in Australia [7] and other high
Table 1
Australian treatment targets for optimal BP management [1].
⁎ Specific lower BP targets have not been established for other high-risk groups (e.g.
those with peripheral arterial disease, those with familiar hypercholesterolemia or
those at high absolute risk of cardiovascular disease) due to the current lack of
evidence from clinical trials. Targets will be set when evidence becomes available.
Fig. 2. Projected power of the VIPER-BP Study (primary endpoint). Legend: The shaded area shows the predicted range of patients subject to complete 26-week follow-up for
determination of the primary endpoint. The star shows that 1750 patients with complete 26-week follow-up will provide an estimated study power of 85% to detect an 8% absolute
difference between groups (assuming a 2-sided alpha of 0.05).
321S. Stewart et al. / International Journal of Cardiology 153 (2011) 317–322
6. income countries where the population burden of chronic heart disease
remains the number one health priority [24]. It may also be applicable to
low-to-middle income countries [8,9] where effective primary care
management of hypertension may avert an epidemic of hypertensive
heart disease.
Acknowledgement
We gratefully acknowledge all GP Investigators for participating in
the VIPER-BP Study and thank the Study Nurse Coordinators for
assisting with recruitment, the scheduling of visits and completion of
study forms. We thank Karen Best, VIPER-BP Clinical Trial Manager,
and Astrid Cuncins-Hearn, Fiona Howard, Andrew Sloane and Mitch
Kirkman for overseeing the execution of the Study and for their site
liaison. Sincere thanks to Anny Tandyo, Malika Senaratna, Nerolie
Strickland, Ann Nadonza and the Data Management Centre at Baker IDI
for database design, data programming and the ongoing processing and
verification of study data.
The authors of this manuscript have certified that they comply
with the Principles of Ethical Publishing in the International Journal of
Cardiology [25].
References
[1] National Heart Foundation of Australia (National Blood Pressure and Vascular
Disease Advisory Committee). Guide to management of hypertension 2008.
[2] Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure: the JNC 7 report. JAMA 2003 May 21;289(19):2560–72.
[3] Briganti EM, Shaw JE, Chadban SJ, et al. Untreated hypertension among Australian
adults: the 1999–2000 Australian Diabetes, Obesity and Lifestyle Study (AusDiab).
Med J Aust 2003 Aug 4;179(3):135–9.
[4] Carrington MJ, Jennings GL, Stewart S. Pattern of blood pressure in Australian
adults: results from a National Blood Pressure Screening Day of 13,825 adults. Int J
Cardiol 2010;145:461–7.
[5] Lawes CM, Vander Hoorn S, Law MR, Elliott P, MacMahon S, Rodgers A. Blood
pressure and the global burden of disease 2000. Part 1: estimates of blood pressure
levels. J Hypertens 2006 Mar;24(3):413–22.
[6] Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Measuring the global
burden of disease and risk factors, 1990–2001. In: Lopez AD, Mathers CD, Ezzati M,
Jamison DT, Murray CJ, editors. Global burden of disease and risk factors. New
York: Oxford University Press; 2006. p. 1–13.
[7] Australian Institute of Health and Welfare 2010. Australia's health 2010.
Australia's health series no. 12. Cat. no. AUS 122. Canberra: AIHW.
[8] Addo J, Smeeth L, Leon DA. Hypertension in sub-saharan Africa: a systematic
review. Hypertension 2007 Dec;50(6):1012–8.
[9] Stewart S, Libhaber E, Carrington M, et al. The clinical consequences and
challenges of hypertension in urban-dwelling black Africans: insights from the
Heart of Soweto Study. Int J Cardiol 2009 Jun 25.
[10] Glynn LG, Murphy AW, Smith SM, Schroeder K, Fahey T. Interventions used to
improve control of blood pressure in patients with hypertension. Cochrane
Database Syst Rev 2010;3:CD005182.
[11] Davis BR, Ford CE, Remington RD, Stamler R, Hawkins CM. The Hypertension
Detection and Follow-up Program design, methods, and baseline characteristics
and blood pressure response of the study population. Prog Cardiovasc Dis 1986
Nov–Dec;29(3 Suppl 1):11–28.
[12] Hypertension Detection and Follow-Up Program Cooperative Group. Persistence
of reduction in blood pressure and mortality of participants in the Hypertension
Detection and Follow-up Program. Hypertension Detection and Follow-up
Program Cooperative Group. JAMA 1988 Apr 8;259(14):2113–22.
[13] Feldman RD, Zou GY, Vandervoort MK, Wong CJ, Nelson SA, Feagan BG. A
simplified approach to the treatment of uncomplicated hypertension: a cluster
randomized, controlled trial. Hypertension 2009 Apr;53(4):646–53.
[14] Julius S, Weber MA, Kjeldsen SE, et al. The Valsartan Anti-hypertensive Long-Term
Use Evaluation (VALUE) trial: outcomes in patients receiving monotherapy.
Hypertension 2006 Sep;48(3):385–91.
[15] Kjeldsen SE, Jamerson KA, Bakris GL, et al. Predictors of blood pressure response to
intensified and fixed combination treatment of hypertension: the ACCOMPLISH
study. Blood Press 2008;17(1):7–17.
[16] Weber MA, Julius S, Kjeldsen SE, et al. Blood pressure dependent and independent
effects of anti-hypertensive treatment on clinical events in the VALUE Trial. Lancet
2004 Jun 19;363(9426):2049–51.
[17] Carrington MJ, Retegan C, Johnston CI, Jennings GL, Stewart S. Cholesterol
complacency in Australia: time to revisit the basics of cardiovascular disease
prevention. J Clin Nurs 2009 Mar;18(5):678–86.
[18] Moher D, Schulz KF, Altman D. The CONSORT statement: revised recommendations
for improving the quality of reports of parallel-group randomized trials. Jama 2001
Apr 18;285(15):1987–91.
[19] National Vascular Disease Prevention Alliance. Guidelines for the assessment of
absolute cardiovascular disease risk: National Heart Foundation of Australia; 2009.
[20] Devlin N, Hansen P, Herbison P, Macran S. A “new and improved” EQ-5D valuation
questionnaire? Results from a pilot study. Eur J Health Econ 2005 Mar;6(1):73–82.
[21] Arroll B, Khin N, Kerse N. Screening for depression in primary care with two verbally
asked questions: cross sectional study. BMJ 2003 Nov 15;327(7424):1144–6.
[22] Radloff LS. The CES-D Scale: a self-report depression scale for research in the
general population. Appl Psychol Meas 1977;1:385–401.
[23] Wing LM, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin-
converting-enzymeinhibitorsanddiureticsfor hypertension intheelderly.N EnglJMed
2003 Feb 13;348(7):583–92.
[24] Stewart S, Ekman I, Ekman T, Oden A, Rosengren A. Population impact of heart
failure and the most common forms of cancer: A study of 1,162,309 hospital cases
in Sweden (1988 to 2004). Circulation: Cardiovascular Quality and Outcomes
2010;3:573–80.
[25] Shewan LG, Coats AJ. Ethics in the authorship and publishing of scientific articles.
Int J Cardiol 2010;144:1–2.
322 S. Stewart et al. / International Journal of Cardiology 153 (2011) 317–322