Emily Atkins

Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review.

BACKGROUND Globally, most patients with hypertension are treated with monotherapy, and control rates are poor because monotherapy only reduces blood pressure by around 9/5 mm Hg on average. There is a pressing need for blood pressure-control strategies with improved efficacy and tolerability. We aimed to assess whether ultra-low-dose combination therapy could meet these needs. METHODS We did a randomised, placebo-controlled, double-blind, crossover trial of a quadpill-a single capsule containing four blood pressure-lowering drugs each at quarter-dose (irbesartan 37·5 mg, amlodipine 1·25 mg, hydrochlorothiazide 6·25 mg, and atenolol 12·5 mg). Participants with untreated hypertension were enrolled from four centres in the community of western Sydney, NSW, Australia, mainly by general practitioners. Participants were randomly allocated by computer to either the quadpill or matching placebo for 4 weeks; this treatment was followed by a 2-week washout, then the other study treatment was administered for 4 weeks. Study staff and participants were unaware of treatment allocations, and masking was achieved by use of identical opaque capsules. The primary outcome was placebo-corrected 24-h systolic ambulatory blood pressure reduction after 4 weeks and analysis was by intention to treat. We also did a systematic review of trials evaluating the efficacy and safety of quarter-standard-dose blood pressure-lowering therapy against placebo. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614001057673. The trial ended after 1 year and this report presents the final analysis. FINDINGS Between November, 2014, and December, 2015, 55 patients were screened for our randomised trial, of whom 21 underwent randomisation. Mean age of participants was 58 years (SD 11) and mean baseline office and 24-h systolic and diastolic blood pressure levels were 154 (14)/90 (11) mm Hg and 140 (9)/87 (8) mm Hg, respectively. One individual declined participation after randomisation and two patients dropped out for administrative reasons. The placebo-corrected reduction in systolic 24-h blood pressure with the quadpill was 19 mm Hg (95% CI 14-23), and office blood pressure was reduced by 22/13 mm Hg (p<0·0001). During quadpill treatment, 18 (100%) of 18 participants achieved office blood pressure less than 140/90 mm Hg, compared with six (33%) of 18 during placebo treatment (p=0·0013). There were no serious adverse events and all patients reported that the quadpill was easy to swallow. Our systematic review identified 36 trials (n=4721 participants) of one drug at quarter-dose and six trials (n=312) of two drugs at quarter-dose, against placebo. The pooled placebo-corrected blood pressure-lowering effects were 5/2 mm Hg and 7/5 mm Hg, respectively (both p<0·0001), and there were no side-effects from either regimen. INTERPRETATION The findings of our small trial in the context of previous randomised evidence suggest that the benefits of quarter-dose therapy could be additive across classes and might confer a clinically important reduction in blood pressure. Further examination of the quadpill concept is needed to investigate effectiveness against usual treatment options and longer term tolerability. FUNDING National Heart Foundation, Australia; University of Sydney; and National Health and Medical Research Council of Australia.

Impact of medical consultation frequency on risk factors and medications 6 months after acute coronary syndrome.

OBJECTIVE Initiatives that support primary care to better enable delivery of optimal prevention services are of great importance. The purpose of this study was to examine the frequency of medical consultations by patients with acute coronary syndrome (ACS) in the 6 months after hospital discharge and to determine whether the frequency of visits was associated with differences in lifestyle, clinical measures and medication prescription. METHODS We conducted a retrospective subgroup analysis of data collected in the Cooperative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events (CONCORDANCE), which is an ongoing (prospective) clinical initiative providing continuous real-time reporting on the clinical characteristics, management and outcomes of patients admitted to Australian hospitals with ACS. We compared clinical measures, medications, smoking status and receipt of cardiac rehabilitation with frequency of medical consultations 6 months after hospital discharge. RESULTS Patients with ACS visited their general practitioner (GP) a mean of 4.4 (± 3.8) times and their cardiologist 1.2 (± 0.9) times in the 6-month period after their index admission. Patients who saw a GP in the 6-month period had significantly higher rates of participation in cardiac rehabilitation, receipt of dietary advice and prescription of cardioprotective medications. Factors associated with increased frequency of GP visits were older age groups (oldest fourth vs youngest fourth incidence rate ratio (IRR) 1.08; 95% CI 1.01, 1.14), being female (male vs female IRR 0.83; 95% CI 0.80, 0.86), diagnosis of ST-segment elevation myocardial infarction (STEMI) (STEMI vs non-STEMI IRR 1.08; 95% CI 1.04, 1.13; STEMI vs unstable angina IRR 1.01; 95% CI 0.95, 1.06), being a current smoker (IRR 1.09; 95% CI 1.05, 1.15), history of cardiovascular disease (IRR 1.06; 95% CI 1.01, 1.12), history of diabetes (IRR 1.25; 95% CI 1.21, 1.31), inpatient revascularisation (IRR 0.95; 95% CI 0.91, 0.99), receipt of cardiac rehabilitation referral (IRR 0.93; 95% CI 0.89, 0.97), and discharged on four or more out of five indicated medications (IRR 1.04; 95% CI 1.00, 1.08). CONCLUSION The majority of ACS survivors in this study saw their GP frequently and their cardiologist at least once during the 6 months after index admission. Seizing these opportunities to engage, manage and support patients is important for strengthening prevention in primary care.

Intensive blood pressure lowering – Authors' reply

www.thelancet.com Vol 387 June 4, 2016 2291 6 Rubini Gimenez M, Twerenbold R, Jaeger C, et al. One-hour rule-in and rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I. Am J Med 2015; 128: 861–70. 7 Jaff e AS. TRAPID or Trapped? Ann Emerg Med 2016; published online Feb 10. doi:10.1016 /j.annemergmed.2016.01.009. 8 Shah AS, Newby DE, Mills NL. High sensitivity cardiac troponin in patients with chest pain. BMJ 2013; 347: f4222.

More Versus Less Blood Pressure Lowering: An Update

PURPOSE This article summarizes the results of a recent systematic review and meta-analysis of the safety and efficacy of intensive blood pressure (BP) lowering, including an update with the SPRINT (Systolic Blood Pressure Intervention Trial) results. We discuss the consistency of results within this set of trials (eg, ACCORD [Action to Control Cardiovascular Risk in Diabetes] and SPRINT) and the results in the context of other BP-lowering trials, including the recently published HOPE3 (Heart Outcomes Prevention Evaluation-3) study. METHODS This study was a narrative review with updated meta-analysis from systematic review of trials comparing more- versus less-intensive BP lowering. FINDINGS With the addition of SPRINT, there are >20 trials comparing more- versus less-intensive treatment with 54,350 participants overall. Over an average of 3.9 years of follow-up, the average systolic BP was 133 mm Hg in the more-intensive treatment arms and 140 mm Hg in the less-intensive treatment arms. More-intensive BP lowering reduced the risk of major vascular events, with benefits seen across a range of groups defined according to baseline systolic BP (120-139 mm Hg, 140-159 mm Hg, or ≥160 mm Hg), age (<70 or >70 years), and main entry criterion (hypertension, diabetes, or renal disease). IMPLICATIONS The evidence accumulated thus far provides clear evidence of the benefits of BP lowering in the 120- to 140-mm Hg range for various high-risk patient groups. Although intensive BP lowering has side effects, these trials indicate that the benefits will predominate for those at high risk of major vascular events.

Rapid‐access cardiology services: can these reduce the burden of acute chest pain on Australian and New Zealand health services?

Chest pain is common and places a significant burden on hospital resources. Many patients with undifferentiated low‐ to intermediate‐risk chest pain are admitted to hospital. Rapid‐access cardiology (RAC) services are hospital co‐located, cardiologist‐led outpatient clinics that provide rapid assessment and immediate management but not long‐term management. This service model is described as part of chest pain management and the National Service Framework for coronary heart disease in the United Kingdom (UK). We review the evidence on the effectiveness, safety and acceptability of RAC services. Our review finds that early assessment in RAC outpatient services of patients with suspected angina, without high‐risk features suspicious of an acute coronary syndrome, is safe, can reduce hospitalisations, is cost effective and has good medical practitioner and patient acceptability. However, the literature is limited in that the evaluation of this model of care has been only in the UK. It is potentially suited to other settings and needs further evaluation in other settings to assess its utility.

Side effects and tolerability of combination blood pressure lowering according to blood pressure levels: an analysis of the PROGRESS and ADVANCE trials

Objective: To measure the placebo-controlled effects of combination therapy on hypotension, treatment discontinuation, and major renal outcomes, according to baseline blood pressure. Methods: We conducted an analysis of the action in diabetes and vascular disease: preterax and diamicron-MR controlled evaluation ADVANCE and perindopril protection against recurrent stroke study PROGRESS trials, including 14 684 participants allocated combination therapy or placebo. The mean age was 65 years, 61% were men, and 64% were receiving background blood pressure lowering (BPL) therapy. Participants were stratified into five subgroups by baseline SBP less than 120, 120–129, 130–139, 140–159, and at least 160 mmHg. Discontinuation of study treatment during the active run-in phase and postrandomization follow-up was assessed for hypotension/dizziness and other causes. Major renal outcomes (sustained doubling in creatinine or renal death) were also assessed. Results: Discontinuation during the 4–6-week active run-in phase due to hypotension/dizziness ranged from 3.6% in those with SBP less than 120 mmHg to 1.3% in those with SBP at least 160 mmHg. Median follow-up in the randomized phase was 5.6 years, and discontinuation for hypotension was higher with combination therapy compared with placebo in the less than 120 mmHg group (4.7 vs. 1.2%). However, for each subgroup with baseline SBP 120–129, 130–139, and 140–159 mmHg, the absolute excess of discontinuation due to hypotension with combination therapy was 0.7%. Total discontinuations were only increased in the less than 120 mmHg group (18.4 vs. 12.5%) and the 120–129-mmHg subgroup (17.6 vs. 14.2%). There were no clear differences across the SBP subgroups for the combined renal outcome (overall, 0.8 vs. 0.6%). Conclusion: Compared with those with baseline SBP 140–159 mmHg, side effects of dual combination BPL are essentially the same for people with SBP 130–139 mmHg and only modestly increased among patients with SBP 120–129 mmHg. During long-term therapy, side effects sufficient to stop treatment that are treatment related (i.e. occur in excess of rates seen with placebo) occur at less than 0.5%/year in patients with baseline SBP 120–139 mmHg. These results have important implications in assessing the likely balance of benefits and side effects of BPL with combination therapy among those with SBP 120–139 mmHg.

Redefining blood pressure targets

The debate around blood pressure (BP) targets is long-standing. Half a century ago treatment below 200/100 mmHg was not recommended and the steady decrease in acceptable BP levels has generated controversy at each step. One source of vexation is the frequent failure to reach and maintain BP targets. Even in the setting of clinical trials, most patients in most trials have not achieved target BP levels, (see Table 1, from Xie et al.). In this article, we discuss some under-recognized reasons why BP targets are rarely met in practice, why they continue to be contentious and we recommend an alternative to the ever-elusive search for ‘the right number’ for a BP target.

Utilisation of Medicare-funded schemes for people with cardiovascular disease

The aim of this study is to investigate the utilisation of Medicare Benefit Scheme items for chronic disease in the management of cardiovascular disease (CVD) in general practice and to compare characteristics of CVD patients with and without a General Practice Management Plan (GPMP). Subgroup analysis of Treatment of Cardiovascular Risk using Electronic Decision Support (TORPEDO) baseline data was collected in a cohort comprising 6123 patients with CVD. The mean age (s.d.) was 71 (±13) years, 55% were male, 64% had a recorded diagnosis of coronary heart disease, 31% also had a diagnosis of diabetes and the mean number of general practice (GP) visits (s.d.) was 11 (±9) in 12 months. A total of 1955/6123 (32%) received a GPMP in the 12 months before data extraction; 1% received a Mental Health Plan. Factors associated with greater likelihood of receiving a GPMP were: younger age, had a diagnosis of diabetes, BMI > 30kgm-2, prescription of blood pressure-lowering therapy and more than ten general practice visits. Enhancing utilisation of existing schemes could augment systematic follow up and support of patients with CVD.

Preprocedural High-Sensitivity C-Reactive Protein Predicts Contrast-Induced Nephropathy and Long-Term Outcome After Coronary Angiography:

We investigated whether high-sensitivity C-reactive protein (hsCRP) levels were associated with contrast-induced nephropathy (CIN) and long-term mortality after coronary angiography (CAG). Patients (N = 2133) undergoing CAG with preprocedural hsCRP were consecutively enrolled. High-sensitivity C-reactive protein was measured before angiography. Median follow-up was 2.3 years. The overall incidence of CIN was 2.77% (59 of 2133). There was a positive trend of hsCRP quartiles (Q) with rates of CIN: 0.9% for Q1 (<1.6 mg/L), 0.9% for Q2 (1.6-3.9 mg/L), 2.4% for Q3 (4.0-11.3mg/L), and 6.8% for Q4 (>11.3 mg/L; P < .05). The receiver operating characteristic (ROC) analysis showed that the cutoff point of hsCRP was 7.3 mg/L for predicting CIN with a 72.7% sensitivity and a 67.0% specificity (area under the curve [AUC] = 0.742, 95% confidence interval [CI] 0.672-0.810; P < .05). The predictive value of hsCRP was similar to the Mehran score for CIN (AUChsCRP = 0.742 vs AUCMehran = 0.801; P = .228). After adjustment for other potential risk factors, hsCRP >7.3 mg/L still was an independent predictor of CIN (odds ratio [OR] = 2.83, 95% CI: 1.44-5.58; P = .003). Furthermore, hsCRP >7.3 mg/L was associated with higher mortality (OR = 2.04, 95% CI: 1.30-3.19; P = .002).

Use of cardiovascular prevention treatments after acute coronary syndrome in China and associated factors

BACKGROUND Prevention of repeat cardiovascular events is an important means of addressing the increasing burden of coronary heart disease in China, however there is minimal information about the use of cardiovascular prevention treatment following acute coronary syndrome (ACS) in China. METHODS We analysed data from baseline and 6, 12, 18, and 24-month follow-up surveys of 15,140 consecutive ACS patients recruited in 70 hospitals from 17 provinces of China. We describe the use of indicated cardiovascular prevention medicines, risk factor control, change over time and factors associated with continued prevention. RESULTS 12,094 patients had follow-up data up to 12months. At discharge, 86.1% were on a combination of antiplatelet, statin and blood pressure (BP) lowering drugs. Use of this combination fell to 68.0% at 12months and 59.7% in patients followed to 24months. Patients admitted to tertiary hospitals were more likely to be on the combination compared to secondary hospitals (at discharge 90.1% vs. 79.5%, p<0.0001; at 12months 71% vs. 64%, p<0.001 respectively). At 12months 25.2% achieved control in ≥four of five guideline levels of risk factors and this was similar by hospital level. Prescription of BP-lowering drugs and statins at discharge was the strongest predictor of use at 12months follow-up. Lower income was associated with less use of both. CONCLUSIONS Use of cardiovascular prevention treatment declines steadily over time following an ACS. The largest proportional decline is in the first six months. Ensuring patients are discharged on these therapies and addressing barriers for low-income earners may help address this gap.