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25th September 2024
Therapeutic drug monitoring (TDM) can be useful in monitoring non-adherence in patients with hypertension to improve blood pressure control. It can also optimise antihypertensive drug (AHD) treatment in specific patient groups, such as female versus male or elderly patients, where their pharmacokinetic parameters are altered.
In a new review article, clinicians at the University Medical Centre Rotterdam examined the challenges around non-adherence and highlighted how TDM can be used to manage hypertension.
AHDs do not usually qualify as optimal candidates for TDM because of their physiological effect, poor correlation between blood concentrations and therapeutic outcomes, and wide therapeutic range. Despite the availability of several categories of AHDs with different drug makeups, a significant proportion of patients with hypertension remains poorly controlled with a ‘one-size fits all’ approach often used, the researchers said.
The review cites research showing that TDM alone will not improve adherence and highlights the need for additional interventions, such as personalised feedback sessions with patients to discuss the results of the AHD concentrations measured by TDM.
TDM of AHDs can also offer benefits in optimising therapy for specific populations. Females exhibit higher peak concentrations of metoprolol and have a higher average exposure time to the drug (area under the curve, AUC) compared to males. However, there have been a limited number of studies that use TDM to investigate the underlying differences in how each sex responds to AHDs, but the work so far shows that TDM for AHDs might be useful.
Another population where TDM is used to optimise AHD treatment is the elderly. Recent work indicates that elderly patients would benefit from lower AHD dosages than are currently available on the market. In addition, further work shows that a population pharmacokinetic model could be used to predict the correct starting dose in elderly patients with hypertension.
TDM is perceived as a costly method, however, concentrating measurements in specialist hospitals would cut costs and increase efficiency and expertise, the researchers said.
Having reviewed recent developments, the researchers stated that ‘the journey of AHD TDM is just beginning’. TDM could provide valuable insights into the optimal AHD and dose and offer the potential to individualise treatment, benefitting specific patient groups and helping others adhere to AHD therapy.
Reference
Versmissen, J et al. ‘Under pressure’: The role of therapeutic drug monitoring in the treatment of hypertension. British Journal of Clinical Pharmacology. 2024; 90(8): 1884-1891. doi: 10.1111/bcp.16125doi.org/10.1111/bcp.16125.
23rd May 2024
Taking antihypertensive medication at a time aligned with a patient’s body clock could reduce the risk of myocardial infarction, a study has revealed.
Researchers from the University of Dundee, UK, found that a patient’s chronotype – the time a person feels most suited to sleeping or being awake – can impact how they interact with their antihypertensive treatment.
The findings are published in the journal eClinicalMedicine, and the researchers suggest these could represent a ‘paradigm shift’ in the treatment of hypertension.
Arterial hypertension can cause myocardial infarction, strokes and heart failure. Despite significant progress in evidence-based lifestyle interventions such as diet and exercise guidance, as well as drug therapies which can help with blood pressure control and prevent related complications, hypertension remains a significant public health concern.
Using data collected as part of the Treatment in Morning versus Evening (TIME) randomised clinical trial, the researchers asked over 5,000 participants to complete an online questionnaire designed to assess their chronotype and determine whether they were ‘morning larks’ or ‘night owls’. Half of the participants took their medications in the morning, and the remaining half took their medication in the evening.
The results suggest that taking antihypertensive medication at a time aligned with personal chronotype can provide extra protection for the heart.
The researchers found that when the morning larks – participants who had an earlier chronotype – took their medication in the morning, their risk of myocardial infarction was reduced when compared with the ‘misaligned’ morning larks who took their medication in the evening.
Similarly, the night owls who took their medication in the evening, which aligned with their body clock, were less likely to be hospitalised for myocardial infarction than those who took their medication in the morning.
Dr Filippo Pigazzani, clinical senior lecturer and honorary consultant cardiologist from the University of Dundee, said: ‘These results are exciting because they could represent a ‘paradigm shift’ in the treatment of hypertension. Our research has shown for the first time that considering chronotype when deciding dosing time of antihypertensives – personalised chronotherapy – could reduce the risk of heart attack.’
He stressed that the results needed to be confirmed in new randomised clinical trials of personalised chronotherapy before patients change when they take their antihypertensive medications.
Dr Kenneth Dyar, a circadian biologist from Helmholtz Munich, who helped design the study, said that a person’s internal biological clock determines their chronotype and whether they are more of a ‘morning’ or ‘evening’ person.
He explained: ‘This internal time is genetically determined and affects biological functions over 24 hours, including gene expression, blood pressure rhythms, and how we respond to medications. It’s important for physicians to remember that not all patients are the same. Humans show wide inter-individual differences in their chronotype, and these personal differences are known to affect disease risk.’
The researchers said assessing a patient’s chronotype could be incorporated into clinical practice, providing a straightforward and cost-effective way to prevent myocardial infarction in hypertensive patients using their existing antihypertensive therapies.
A version of this article was originally published by our sister publication Nursing in Practice.
10th May 2023
A study of nearly 27,000 hypertensive patients identified how roughly a third (32.5%) of patients had uncontrolled disease. Therapy guidelines invariably recommend monotherapy as a first-line approach and combination treatment only if this fails to control blood pressure (BP). Despite this, a meta-analysis of 354 RCTs in 2003, found that a low-dose combination of BP lowering drugs increases efficacy and reduces adverse effects. More recently, another analysis revealed how use of three drugs gave better blood pressure control than increasing dual therapy doses. Whether a low-dose combination (LDC) of three to four drug classes as an initial therapy provides better blood pressure control than monotherapy or usual care is uncertain.
In a recent systematic review and meta-analysis, researchers set out to determine the efficacy and safety of a LDC initial approach to hypertension management. They looked for RCTs that compared LDC to either monotherapy, usual care, or placebo. The primary outcome was the decrease in systolic hypertension using either LDC, monotherapy, usual care or placebo. Other measures assessed were the proportion achieving a BP <140/90 mm Hg, rates of adverse effects and treatment withdrawal.
Low-dose combination and systolic hypertension
A total of 7 trials with 918 patients with a mean age of 59 years (38% female) met the inclusion criteria.
Mean systolic BP was significantly lower with LDC than either monotherapy or usual care (mean difference, MD = 7.4 mmHg). LDC also increased the proportion of participants achieving BP < 140/90 mm Hg at 4 to 12 weeks (Risk Ratio, RR = 1.40, 95% CI 1.27-1.52). These findings were maintained at 6 to 12 months.
Although LDC led to more dizziness (RR = 1.28, 95% CI 1.00-1.63) no other adverse effects or treatment withdrawal occurred.
These findings suggest that LDCs with 3 or 4 antihypertensives is effective and well-tolerated as an initial treatment of hypertension.
14th April 2023
German researchers have observed significant reduction in blood pressure (BP) following a moderate dietary reduction of salt intake in patients with primary aldosteronism.
The link between intake of sodium (in the form of salt) and hypertension is widely recognised such that reducing dietary intake not only lowers BP but is also associated with a reduction in morbidity and mortality from cardiovascular diseases. The presence of primary aldosteronism (PA) is a common cause of secondary hypertension and associated with excess cardiovascular morbidities. In fact, having PA is associated with more end-organ damage and an excess cardiovascular morbidity, including heart failure, stroke, nonfatal myocardial infarction, and atrial fibrillation compared to primary hypertension. An unfortunate consequence for patients with PA is a decreased taste sensitivity for salt, favouring high sodium consumption. Given this relationship, the German researchers wondered if a moderate dietary reduction in salt in patients with PA could reduce blood pressure.
Researchers identified a group of PA patients already under treatment with anti-hypertensives from a national registry. Individuals were recruited for a dietary salt restriction over 12 weeks with structured nutritional training and consolidation by a mobile health app. Salt intake and adherence were monitored every 4 weeks using 24-h urinary sodium excretion.
Moderate dietary salt reduction and blood pressure
A total of 41 participants with a mean age of 50 years (52.2% female) were included in the analysis.
At the end of the study, dietary salt intake which was originally estimated from urinary excretion to be 9.1 g/day, fell to 5.2 g/day (p < 0.001). In addition, systolic blood pressure reduced from 130 at baseline to to 121 mm Hg (p < 0.001) and diastolic blood pressure from 84 to 81 mm Hg (p = 0.003).
In addition, participants noted a significant weight loss of 1.4 kg (p < 0.001), largely due to water loss and an improvement in pulse pressure, an indicator of arterial stiffness (p < 0.001). Interestingly, there were also improvements in depression scores (p = 0.008).
The authors concluded that moderate dietary salt restriction intake in patients with PA substantially reduces BP and depressive symptoms.
Citation
Schneider H et al. Moderate dietary salt restriction improves blood pressure and mental well-being in patients with primary aldosteronism: The salt CONNtrol trial. J Intern Med 2023
24th October 2022
Angiotensin receptor blocker (ARB) therapy is associated with a reduced risk of epilepsy development over the next 5 years compared to other anti-hypertensive agents according to a cohort analysis by German researchers.
The epilepsies are one of the most common serious brain disorders and which can occur at any age with different presentations and causes. The World Health Organisation estimates that globally, around 5 million people are diagnosed with epilepsy each year and that across the world, roughly 50 million people are affected.
Interestingly, it has been suggested that based on both preclinical and clinical studies, that hypertension may be a cause of seizures and epilepsy through direct or indirect mechanisms and that the renin-angiotensin system might play a central role. Indeed, animal studies indicate that one class of antihypertensive medicines, ARB therapy and in particular, losartan, might be effective against seizure activity and neuronal damage in co-morbid hypertension and epilepsy.
Moreover, a study on cognition and prognosis in the Elderly with the ARB drug candesartan found that it may also have positive effects on cognitive function and quality of life. Taken to together, these findings would suggest that ARB therapy by protecting cognitive function may also reduce the risk of epilepsy development.
Since there are no data to support the theory that ARB therapy may affect the development of epilepsy, in the present study, the German researchers set out to compare the incidence of epilepsy after patients had been initiated on a range of different anti-hypertensive drug classes.
The team included adult patients with hypertension and an initial prescription for beta-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEi) and ARB therapy. These four anti-hypertensive classes were propensity matched 1:1:1:1 according to sex, age, index year and diagnosis. The researchers set the main outcome of interest as the incidence of epilepsy associated with ARB therapy compared to the other drug classes.
ARB therapy and epilepsy development
A total of 168,612 patients with a mean age of 62.3 years (48.6% male) were included with 42,153 individuals prescribed a drug from each of the different classes were followed-up for 5 years.
After 1 year, 0.27% of patients prescribed ARB therapy developed epilepsy and this increased to 0.99% after 5 years. In comparison, after 5 years, 1.47% of those prescribed beta-blockers and 1.48% of those given calcium channel blockers developed epilepsy.
ARB therapy was associated with a significantly reduced incidence of epilepsy (Hazard ratio, HR = 0.77, 95% CI 0.65 – 0.90, p < 0.002) compared with other anti-hypertensives drug classes. However, while this reduced risk in comparison to other drug classes was lower for all drugs within the ARB class examined, the association was only statistically significant for losartan.
The authors concluded that there was an association between a lower incidence of epilepsy in hypertensive patients prescribed ARB therapy compared to other anti-hypertensive drug classes. They called for additional research to better understand whether this relationship was causal and suggested that anti-hypertensives may represent a novel approach to the management of epilepsy in hypertensive patients.
Citation
Doege C et al. Association Between Angiotensin Receptor Blocker Therapy and Incidence of Epilepsy in Patients With Hypertension JAMA neurol 2022.
29th August 2022
The risk of developing open angle glaucoma is significantly elevated in patients with hypertension who frequently add salt to their food either from the table or through cooking according to the findings of study by an international group of researchers.
Glaucoma is a multifactorial optic neuropathy characterised by the degeneration of retinal ganglion cells. The condition is associated with intra-ocular pressure-related damage to the optic nerve. Glaucoma is a leading cause of blindness and a 2017 analysis estimated that prevalence of blindness due to glaucoma worldwide was 75.6 per 100 000 in 2017.
The treatment of glaucoma is directed towards a lowering of the intra-ocular pressure in the eye through medication, laser surgery, incisional surgery or a combination of these. The two main types of glaucoma are open angle glaucoma (OAG) and closed angle glaucoma, although there at least 8 different additional types.
Furthermore, some research indicates a connection between OAG and blood pressure, although the findings are equivocal. For instance, one study found that hypertension, particularly if poorly controlled, appears to be related to a modest increased risk of OAG.
In contrast, another suggested that among patients with existing glaucoma, the nocturnal reduction in blood pressure might be an additional risk factor for such patients. A factor known to affect blood pressure is intake of sodium through salt and there is a good deal of evidence indicating that a reduction in dietary sodium (via salt) decreases both blood pressure and the incidence of hypertension.
But whether a greater intake of salt, particularly in those with existing hypertension, would also increase the the risk of OAG is unclear. As a result, in the present study, researchers examined the relationship between glaucoma and salt intake, among patients with hypertension and who were receiving anti-hypertensive treatment.
The researchers used data from the Thessaloniki Eye Study which was designed to examine the prevalence of open angle glaucoma in adults age 60 years and older. All study participants had in-clinic examinations which included blood pressure measurement and were interviewed about co-morbidities and lifestyle factors.
Participants were asked about salt intake and were categorised as ‘never users’, ‘rare/occasional’ (i.e., rare or occasional salt use at the table or during cooking) and ‘frequent users’ who normally added salt to food at the table and through cooking.
For the study, researchers considered the occurrence of any OAG, primary open angle glaucoma (POAG) and pseudo-exfoliation syndrome, regardless of whether these individuals also had glaucoma. Any OAG did include POAG even though the effect of salt intake was analysed separately for this form of glaucoma.
Open angle glaucoma and salt intake among hypertensives
The study included 1076 participants with a mean age of 80.5 years (48.1% female) of whom, 51.3% did not have OAG and 8.3% had any OAG.
Among the whole cohort, there was no association between the frequency of salt intake and any form of OAG. This was apparent for occasional vs never salt users (odds ratio, OR = 1.02, 95% CI 0.59 – 1.79, p = 0.93) and between often (or frequent) users vs never users (OR = 1.38, 95% CI 0.66 – 2.89, p = 0.39).
However, when the researchers looked at those with hypertension and currently taking treatment, there was a significant association for any type of OAG but only for the comparison of often vs never salt users (OR = 2.65, 95% CI 1.12 – 6.28, p = 0.03).
Using the same comparison, i.e. often vs never salt users, the relationship was also significant for POAG (OR = 3.59, 95% CI 1.16 – 11.11, p = 0.03). However, there were no significant effects from frequent salt intake among those with pseudo-exfoliation syndrome.
There was also a significant relationship between frequent use of salt and any OAG in patients with a diastolic blood pressure below 90 mmHg (OR = 2.42, 95% CI 1.0 – 5.84, p = 0.05).
Based on these findings, the authors concluded that frequent dietary salt intake may be associated with an increased prevalence of OAG in those currently taking anti-hypertensive drugs. They called for future studies to examine the pathophysiological changes to optic nerves vascular supply caused by salt load.
Citation
Tseng VL et al. Association Between Dietary Salt Intake and Open Angle Glaucoma in the Thessaloniki Eye Study J Glaucoma 2022
14th February 2022
The use of anti-hypertensive drugs when combined with healthy lifestyle measures appears to be the best strategy to reduce all-cause and cause-specific mortality. This is according to a study by Chinese researchers from the Department of Epidemiology and Biostatistics, School of Public Health, Huazhong University of Science and Technology, Hubei, China.
Hypertension significantly increases the risks of heart, brain, kidney and other diseases and according to the World Health Organization, an estimated 1.28 billion adults aged 30-79 years worldwide have hypertension, most of whom are living in low- and middle-income countries.
Furthermore, a 2019 analysis calculated that a high systolic blood pressure accounted for approximately 10·8 million deaths which was 19.2% of all recorded deaths in 2019. Hypertension is managed with a range of different classes of medicines, yet non-adherence to anti-hypertensive treatment affects 10%–80% of hypertensive patients and is one of the key drivers of suboptimal BP control.
With respect to lifestyle modification, there is strong evidence supporting the benefits of regular physical activity and exercise for the prevention and management of hypertension. However, whether the combination of anti-hypertensive medication and healthy lifestyle measures yields additional benefits and if adoption of healthy lifestyle measures after a diagnosis of hypertension provides a mortality benefit remains uncertain.
For the present study, the Chinese team examined the relationship between anti-hypertensive use and lifestyle measures and the effect of this on all-cause and cause-specific mortality among hypertensive patients.
They used data from the Dongfeng-Tongji cohort, which prospectively followed hypertensive patients for a median of 7.3 years. The team assessed specific lifestyle factors including body mass index, smoking status, diet, physical activity and sleep duration and computed an overall lifestyle score based on these five attributes, with higher scores (ranging from 0 to 10) indicating a healthier lifestyle.
In addition, participants were categorised into the following subgroups: favourable lifestyle (scores 8 – 10), intermediate (5- 7) and unfavourable (0 – 4). The use of anti-hypertensive medication was dichotomised into yes or no.
Anti-hypertensive use and subsequent mortality
A total of 14,392 participants with a mean age of 65.6 years (50.6% male) using anti-hypertensive medicines were included in the analysis. Over a median of 7.3 years, there were 2015 deaths including 761 due to cardiovascular disease and 525 from cancer.
Taking individuals not using anti-hypertensives and following an unfavourable lifestyle as the reference group, individuals using anti-hypertensives and with a favourable lifestyle had the lowest risk of all-cause mortality (hazard ratio, HR = 0.32, 95% CI 0.25 – 0.42). This was also true for cardiovascular mortality (HR = 0.33) and death due to cancer (HR = 0.30).
Interestingly, when using the same reference group, individuals who were not using anti-hypertensives but adopted a favourable lifestyle, also had a lower risk of all-cause mortality (HR = 0.34), cardiovascular (HR = 0.40) and cancer mortality (HR = 0.33).
In fact, there was a linear association with lifestyle score and mortality, such that regardless or anti-hypertensive medication use, each 1-point increase in lifestyle score was associated with a 17% lower risk of all-cause mortality, with similar reductions for cardiovascular and cancer deaths.
There was also a reduced mortality risk through the adoption of lifestyle measures after a diagnosis of hypertension. For example, compared to those with a consistently low lifestyle score between baseline and the first follow-up, those who instigated a change in lifestyle score from low to high also had a significantly reduced risk for all-cause (HR = 0.52), cardiovascular (HR = 0.53) mortality although the reduced risk of cancer mortality was non-significant.
The authors concluded that the combined effect of anti-hypertensive medication and adoption of a healthy lifestyle resulted in a significantly reduced risk of all and specific cause mortality.
Citation
Lu Q et al. Association of Lifestyle Factors and Antihypertensive Medication Use With Risk of All-Cause and Cause-Specific Mortality Among Adults With Hypertension in China JAMA Netw Open 2022
4th October 2021
According to the World Health Organization (WHO), the number of adults aged 30–79 years with hypertension is estimated to be 1.28 billion. However, perhaps more concerning are the WHO statistics suggesting that approximately 46% of adults are unaware that they have hypertension and that only 21% of patients have their condition under control. Various hypertension guidelines recognise that adequate blood pressure control is often only achieved with several medicines, yet guidance from NICE, for example, still recommends initiating mono-therapy. The potential value of using combination therapy as an initial approach to the management of hypertension, was explored in a small trial with 55 patients in 2017. A research team from the George Institute for Global Health, Camperdown, Australia, examined the value of using a single quad-pill with four anti-hypertensives, at a quarter of the normal treatment dose, as an initial therapy for patients with high blood pressure compared with placebo. After only 4 weeks, all patients given the quad-pill achieved a satisfactory blood pressure control (<140/90mmHg). However, these results were not surprising given the findings of a 2009 meta-analysis, which concluded that the additional blood pressure reduction from combining drugs from two different classes was approximately five-times greater than doubling the dose of one drug.
Now, the same Australian team has published the results of a randomised trial which they termed Quadruple UltrA-low-dose tReaTment for hypErTension (QUARTET). This randomised, double-blind study in adults with hypertension, allocated individuals, on a 1:1 basis, to either the quad-pill, which contained irbesartan (37.5mg), amlodipine (1.25mg), indapamide (0.625mg) and bisoprolol (2.5mg), or an indistinguishable, mono-therapy with irbesartan 150mg. The primary outcome was the difference in unattended office systolic blood pressure at 12 weeks. Moreover, a sub-cohort of patients from the trial continued with treatment for up to 52 weeks.
Findings
A total of 591 patients with a mean age of 59 years (60% male) and a mean baseline unattended blood pressure of 141mm/85mmHg, were randomised to quad-pill (300) or mon-therapy with irbesartan . By week 12 only 15% of those receiving the quad-pill compared to 40% on mono-therapy, required additional blood pressure medication. Furthermore, at week 12, a higher proportion of patients given the quad-pill (76% vs 58%) achieved a blood pressure < 140/90mmHg (relative risk, RR = 1.30, 95% CI 1.20–1.50, p < 0.0001). In addition, a blood pressure of less than 120/80mmHg, was also achieved by more patients in the quad-pill group (46% vs 26%, RR = 1.75, 95% CI 1.38–2.22, p < 0.0001). After 52 weeks, mean unattended systolic blood pressure remained 7.7mmHg lower in the intervention group. At 12 months, blood pressure control rates were also higher for the intervention group (81% vs 62%, RR 1.32, 95% CI 1.16–1.50) as were the proportion achieving a blood pressure < 120/80mmHg (53% vs 25%, intervention vs control, RR = 2.1 95% CI 1.60–2.8, p < 0.0001).
The authors concluded that “a strategy with early treatment of a fixed-dose quadruple quarter-dose combination achieved and maintained greater blood pressure lowering compared with the common strategy of starting mono-therapy.”
Citation
Chow CK et al. Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose mono-therapy in patients with hypertension (QUARTET): a phase 3, randomised, double-blind, active-controlled trial. Lancet 2021
27th August 2021
According to the World Cancer Research Fund, colorectal cancer (CRC) is the third most commonly cancer in men and the second most common cancer in women. Moreover, the most recent data from 2018, shows that worldwide, there were over 1.8 million new cases of CRC. The relationship between cancer and hypertension is uncertain although in a retrospective study of over 25,000 cancer patients, new onset hypertension was found in a third of individuals. This relationship might be related to the vascular endothelial growth factor (VEGF) proteins, which are mediators of angiogenesis and lymphangiogenesis in tumours and have been found to be elevated in patients with hypertension. It is conceivable therefore, that the use of anti-hypertensives may exert a protective effect in those with cancer. This was the theory behind a retrospective study of patients with CRC undertaken by a team from the University of Virginia, School of medicine, Virginia, US. They examined a Medicare database which contained patient demographic information for those with cancer. They focused on patients with CRC aged 65 years and older but excluded those with any stage of CRC prescribed anti-hypertensives prior to the cancer diagnosis. The researchers extracted data on the clinical characteristics of CRC including stage and tumour grade and examined adherence to anti-hypertensive therapy based on the proportion of days covered (PDC), which is a measure of adherence with values greater than 0.80 used to define patients who are adherent to their anti-hypertensive therapy. All classes of anti-hypertensives were included and the period of follow-up started 1 year after the initiation of blood pressure lowering therapy. The primary outcome was CRC-specific mortality and the team used hazard regression models to examine the association between the use of individual anti-hypertensives and mortality.
Findings
A total of 13,982 patients were included in the analysis. A range of factors were found to be associated with CRC mortality including male gender (hazard ratio, HR = 1.07, 95% CI 1.03 – 1.13) and interestingly, being single, rather than married (HR = 1.08). The use of anti-hypertensives was associated with a decreased CRC-specific mortality (HR = 0.79, 95% CI 0.75 – 0.83). Furthermore, there was a significant association between adherence to treatment (i.e., those with a PDC greater than 0.80 and decreased mortality (HR = 0.94, 95% CI 0.90 – 0.98). Among the different types of drugs, significant associations were found for only angiotensin enzyme converting enzyme inhibitors (HR = 0.84), beta-blockers (HR = 0.87) and thiazide diuretics (HR = 0.83).
In discussing these results, the authors were cautious that these novel findings would need to be researched further as a potential tool to improve cancer-related mortality. However, they concluded that anti-hypertensive medications might represent a promising pathway to supporting patients with CRC.
Citation
Balkrishnan R et al. Associations between initiating antihypertensive regimens on stage I–III colorectal cancer outcomes: A Medicare SEER cohort analysis. Cancer Med 2021
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