ARB therapy associated with reduced risk of epilepsy

24th October 2022

ARB therapy is associated with a lower risk of subsequently developing epilepsy when compared to drugs from other anti-hypertensives classes

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.

Risk of open angle glaucoma increased in hypertensives consuming the most salt

29th August 2022

The risk of open angle glaucoma is higher in hypertensives who use consume more dietary salt intake from either the table or through cooking

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

Quad-pill more effective than mono-therapy in hypertension

4th October 2021

An anti-hypertensive quad-pill has been shown to provide better blood pressure control than the standard initial approach with mono-therapy.

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

Use of anti-hypertensives associated with reduced risk of colorectal cancer mortality

27th August 2021

An analysis of patients with colorectal cancer has shown the use of anti-hypertensives to be linked to a reduced risk of cancer mortality.

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