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The domino effect of hypertension
The domino effect of hypertension
May is designated as High Blood Pressure Awareness Month, with the culmination being World Hypertension Day on May 17. The American Heart Association describes hypertension as a domino effect, which can lead to an increased risk of stroke, coronary artery disease (CAD), heart failure (HF), myocardial infarction (MI), vision impairment, chronic kidney disease, dyslipidaemia, impaired glucose tolerance, type 2 diabetes, and sexual dysfunction.1,2
An estimated 1.28 billion adults between 30- and 79-years are living with hypertension globally.
More than 60% live in low- and middle-income countries. In South Africa >30% of adults are currently living with the condition, which are responsible for ~50% of strokes and ~40% of MIs.3,4
Often referred to as a ‘silent killer’, hypertension typically manifests without noticeable symptoms or visible warnings, leaving >50% of affected individuals unaware of their condition.4
While symptoms like headaches, visual disruptions, nosebleeds, nausea, vomiting, facial flushing, and sleepiness may arise in cases of exceptionally high blood pressure (BP), the absence of overt signs highlights the urgent need for proactive monitoring and awareness of this potentially lifethreatening condition.
Men have a higher risk of hypertension (34%) compared to women (32%). Furthermore, only ~20% of adults living with hypertension have it under control.2,3,4
Defining and classifying hypertension
According to the 2023 European Society of Hypertension (ESH) guidelines, hypertension is defined as: Repeated office systolic BP (SBP) values of 140mmHg and/or diastolic BP (DBP) 90mmHg. The society cautions that life-threatening cardiovascular (CV) and renal events can also occur at low BP levels (eg 115mmHg/75mmHg).2
Hypertension is classified into:2,5
Primary hypertension
Responsible for the majority of cases. Caused by an interplay between genetic and environmental factors, as well as the ageing process. Genetic and environmental factors induce changes in CV regulatory systems, leading to increased systemic vascular resistance – a key haemodynamic abnormality in hypertension. Studies show that alterations in major CV control systems, including the renin-angiotensinaldosterone system (RAAS), autonomic cardiac and vascular regulation, the endothelin system, nitric oxide, natriuretic peptides, and gut microbial dysbiosis, contribute to chronic BP elevation.2
The immune system, particularly inflammation, has also been implicated in the pathophysiology of hypertension. Inflammation is thought to influence BP regulation and has been implicated in the onset of, and progression to hypertensive target organ damage (HMOD).2
Secondary hypertension
Accounts for 5%-10% of cases. More common (prevalence ~30%) in younger individuals (18- to 40-years). Arises from specific causes such as:2,5
Renovascular hypertension: Defined as systemic hypertension that manifests secondary to the compromised blood supply to the kidneys, usually due to an occlusive lesion in the main renal artery
Renal disease
Aldosteronism: A disorder caused by autonomous production of aldosterone by the adrenal cortex due to hyperplasia, adenoma, or carcinoma
Obstructive sleep apnoea.
Secondary hypertension can also be caused by mutations in specific genes, mostly coding for proteins involved in sodium tubular reabsorption or steroid metabolism.2,5
A diagnosis of secondary hypertension should be considered when a young individual presents with symptoms such as either severe hypertension (>180mmHg/120mmHg), resistant hypertension (defined as BP that remains >140/90mmHg despite optimal use of three antihypertensive medications of different classes, including a diuretic), or malignant/accelerated hypertension (defined as a recent significant increase over baseline BP that is associated with target organ damage).2,5
Management of hypertension: Antihypertensive treatment
Antihypertensive treatment is crucial to reduce CV events, mortality, and organ damage associated with hypertension. The main objective of antihypertensive treatment should be to lower BP to <140/90mmHg in all patients.2
If treatment is well tolerated, treated BP values should be targeted to ≤130/80mmHg, with the caveat that in some clinical conditions (eg chronic kidney disease), the evidence for this lower BP target is uncertain. It is also recommended that treatment should never target BP values to <120/70mmHg because of the lack of consistent evidence.2
The benefits of antihypertensive treatment are well-supported by numerous outcomebased randomised controlled trials (RCTs). While lifestyle changes (see below) can improve BP and overall CV risk, the majority of patients will require pharmacotherapy.2
Meta-analyses have consistently shown that a 7mmHg average reduction in SBP lowers the risk of major CV events such as stroke, CAD and HF, as well as all-cause mortality.2
Antihypertensive treatment has also demonstrated a protective effect against asymptomatic CV and kidney damage. Furthermore, increasing evidence suggests that antihypertensives resulting in lowered BP levels can prevent cognitive decline and dementia, irrespective of baseline BP, CV risk, comorbidities, age, sex, or ethnicity.2
Recent meta-analyses indicate that the advantages of antihypertensive treatment remain consistent, even with the concomitant use of other pharmacotherapies such as lipid-lowering, antidiabetic, and antiplatelet agents.2
Furthermore, comprehensive costeffectiveness analyses support the use of pharmacological treatment for hypertension. The prevention of fatal and non-fatal events, which can lead to hospitalisation and morbidity, result in a substantial reduction in healthcare-related costs. The cost-effectiveness is attributed to the use of inexpensive drug classes, often available as generics.2
When to initiate treatment
According to the ESH, the decision to initiate treatment should be based on office BP levels rather than CV risk alone. Grade 2 or 3 hypertension typically requires drug treatment (see Table 1). Together with pharmacotherapy, lifestyle changes (see below) is recommended for the treatment for grade 1 hypertension in patients at high risk of CVD.2
Regarding treatment initiation in patients with BP <140/90mmHg, the guidelines discourage antihypertensive treatment in patients who have a low-to-moderate risk of CVD with high-normal BP. Lifestyle changes are recommended for these patients. In patients with BP >140/90mmHg, but at high risk of CVD, treatment initiation is warranted.2
Initiating pharmacotherapy in older patients
For patients aged 60- to 79-years, the guidelines recommend initiating treatment when SBP is ≥140mmHg, regardless of DBP levels. This recommendation includes patients with isolated systolic hypertension even if DBP is <90mmHg or <80mmHg.2
Recent trials have shown significant CV benefits with BP-lowering treatment in this age group. In patients aged ≥80-years. However, the Hypertension in the Very Elderly Trial (HYVET) demonstrated benefits in patients with SBP ≥160mmHg.2
The recommended SBP threshold for pharmacotherapy in this age group is 150mmHg based on extrapolation from HYVET data. A critical recommendation is to continue antihypertensive treatment in patients who tolerate treatment. Discontinuation is associated with a rebound increase in adverse outcomes.2
Exceptions can be considered for very old patients with low SBP values (≤120mmHg) or severe orthostatic hypotension, especially those who use polypharmacy and have high frailty levels.2
Choice of treatment
Key drug classes include:
Angiotensin-converting enzyme inhibitors (ACEis)
Angiotensin II receptor blockers (ARBs)
Beta-blockers (BBs)
Calcium channel blockers (CCBs)
Thiazide/thiazide-like diuretics.
These agents along with their combinations, are recommended as first-line therapy in the management of hypertension. Initiation of therapy with a two-drug combination is recommended for the majority of patients living with hypertension.2
Single- or multi-pill combinations are preferred. Recommended combinations are an ARB with a CCB or a thiazide/ thiazide-like diuretic. BBs should be used at therapy initiation or any treatment step – particularly in conditions like HF with reduced ejection fraction, antiischaemic therapy in chronic coronary syndromes, and heart rate control in atrial fibrillation. However, caution is advised, when considering BBs appropriate patient selection is crucial.2
Furthermore, combinations that provide 24-hour BP control and once-daily drug administration are preferred. Extendedrelease formulations and bedtime administration may be considered, with evidence suggesting no harm in taking antihypertensive drugs at bedtime.2
In certain cases, initiation with monotherapy may be considered for patients with grade 1 hypertension and low risk, highnormal BP with very high CV risk, or those exhibiting frailty and advanced age.2
If BP control is not achieved with the initial two-drug combination, escalation to a three-drug combination is recommended, typically comprising a RAAS blocker, CCB, and thiazide/thiazide-like diuretic. The combination of two RAAS blockers is discouraged due to an increased risk of adverse events, particularly acute kidney injury (AKI). In cases where BP remains uncontrolled with a three-drug combination, treatment for true resistant hypertension is recommended.2
Should two antihypertensives be initiated at the onset of treatment?
Several arguments support the use of two antihypertensives at the onset of treatment. Firstly, evidence suggests that initial combination therapy is consistently more effective in lowering BP than monotherapy. Even low-dose combination therapy tends to surpass the efficacy of maximal dose monotherapy.2
This approach not only reduces the heterogeneity of BP response but also provides a steeper dose-response effect compared to escalating doses of monotherapy. Moreover, it is considered safe and well-tolerated, with minimal increase in the risk of hypotensive episodes, even in patients with grade 1 hypertension.2
Secondly, the use of a two-drug combination leads to a faster reduction in BP compared to monotherapy. Observational evidence indicates that the time taken to achieve BP control is a critical determinant of clinical outcomes, particularly in high-risk patients, with shorter time to control associated with lower risk.2
Thirdly, studies show that patients starting treatment with a two-drug combination are more likely to achieve frequent BP control after one year. This is attributed to the prevention of therapeutic inertia, better long-term adherence, and persistence to the prescribed treatment regimen.2
For patients whose BP is not adequately controlled with two-drug combination therapy, options include:2
Using a different two-drug combination
Increasing the dose of the current combination components
Transitioning to three-drug combination therapy, usually involving a RAAS inhibitor, a CCB, and a thiazide/thiazide-like diuretic.
FDC therapy improves patient adherence to treatment
What about fixed-dose combination therapy?
Although single-pill combinations are preferred, Verma et al found that fixed-dose combination (FDC) therapy improves patient adherence to treatment. The team conducted a retrospective cohort study comparing clinical outcomes and medication adherence in a real-world setting between FDC therapy and single-pill combination therapy.5
The study included 13 350 participants who were newly prescribed either an ACEi or ARB in combination with a thiazide diuretic, with a follow-up period of up to five years.5
To minimise selection bias, the researchers employed high-dimensional propensity score matching to compare outcomes between those receiving FDC and single-pill therapy.5 The primary outcome was a composite of death or hospitalisation for acute MI, HF, or stroke. Two analyses were performed to assess the association between medication adherence and patient outcomes.5
In the on-treatment analysis, where patients were censored upon discontinuation of treatment, no significant difference in the primary outcome was observed between the two groups.5
However, in the intention-to-treat analysis, which allowed for breaks in treatment, FDC recipients showed a significantly higher proportion of total follow-up days covered with medications (70%) compared to the single-pill combination group (42%). The primary outcome was less frequent in the FDC group (3.4 versus 3.9 events per 100 person-years).5
Lifestyle interventions
Lifestyle changes in preventing and managing hypertension is extremely important. These interventions not only contribute to lowering BP but also have broader CV benefits.2
Individuals following a healthy lifestyle have 4mmHg-5mmHg lower BP, regardless of underlying genetic risks. Lifestyle changes not only lower BP but also improves the effectiveness of pharmacological interventions, potentially reducing the need for multiple therapies.2
Various lifestyle interventions have demonstrated heart-healthy benefits beyond BP reduction, with the most established approaches being weight loss, the Dietary Approaches to Stop Hypertension (DASH) diet, salt reduction, increased potassium intake, regular physical activity, and moderation of alcohol consumption. These interventions are pivotal in reducing premature CV morbidity and mortality.2
Weight reduction: Being overweight or obese is directly associated with hypertension. Weight-loss interventions, particularly through a low-caloric diet and exercise, have shown significant reductions in both systolic and diastolic BP. Modest weight loss is recommended and should be tailored to individual needs.2
Restriction of sodium intake: High sodium consumption is strongly associated with increased BP. Lifestyle interventions restricting sodium intake to <5.844 grams per day have been shown to result in an average 5/2mmHg reduction in BP. However, the debate over optimal sodium restriction levels and potential adverse effects requires further research.2
Augmentation of dietary potassium intake: Dietary potassium is associated with BP regulation, with evidence supporting both the effectiveness of potassium supplementation and potassium-rich diets in lowering BP. The recommended population goal for potassium intake is ~3.5 grams.2
Increase in physical activity: Habitual physical activity has an inverse relation with the incidence of hypertension. Structured exercise, especially dynamic aerobic exercise, has demonstrated BP-lowering effects, contributing to ~2-4mmHg and 5mmHg-8mmHg reductions in systolic BP for normotensive and hypertensive adults, respectively.2
Moderation of alcohol intake: Observational studies highlight a positive linear association between alcohol consumption and BP. Reduction in alcohol intake, especially close to abstinence, has been associated with a 3.3mmHg/2mmHg reduction in systolic and diastolic BP. The hypertensiogenic effect of binge drinking should be avoided.2
Smoking cessation: Tobacco smoking is a significant contributor to hypertension and cardiovascular risk. Smoking cessation is crucial, and health professionals should counsel and support individuals in quitting. Water pipe and e-cigarette smoking, once considered alternatives, have been associated with increased BP and CV risks.2
Other dietary interventions: Diets, such as the DASH and Mediterranean diets, have synergistic effects on BP reduction beyond individual foods or nutrients. These diets promote the consumption of fruits, vegetables, low-fat dairy, and whole grains. Coffee consumption, within moderation, appears not to adversely affect BP.2
Stress management: Stress and anxiety are linked to an increased risk of hypertension. Mind-body stress-reducing interventions, such as meditation and yoga, have shown promise in reducing both stress levels and BP.2
Exposure to noise and air pollution: Environmental noise and air pollution contribute to increased BP and CV risks. Reduction in exposure to traffic noise and air pollution, both on a policy level and individual efforts, can contribute to better BP control and overall CV health.2
Conclusion
Hypertension is a global healthcare challenge, affecting >1.28 billion adults, with a significant burden in low- and middleincome countries. Often asymptomatic, it earns its ‘silent killer’ moniker, leading to severe consequences, including strokes and myocardial infarctions.
The interplay of genetic, environmental, and immunological factors underscores the complexity of hypertension. Management, primarily through antihypertensive treatment is essential, supported by robust evidence of reduced CV events and mortality. Lifestyle changes complement pharmacotherapy.
References
American Heart Association. Consequences of High Blood Pressure. 2022. [Internet]. Available at: https://www.heart.org/-/media/files/health-topics/ high-blood-pressure/consequences-of-highblood-pressure-infographic.pdf
Mancia G, Kreutz R, Brunström M, et al. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension. Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA). Journal of Hypertension, 2023.
World Health Organization. Hypertension. Updated 2023. [Internet]. Available at: https:// www.who.int/news-room/fact-sheets/detail/ hypertension
The Heart and Stroke Foundation South Africa. Blood Pressure. [Internet]. Available at: https://heartfoundation.co.za/blood-pressure/#:~:text=In%20South%20Africa%20 more%20than,that%20blood%20pressure%20 is%20high
Verma AA, Khuu W, Tadrous M, et al. Fixed-dose combination antihypertensive medications, adherence, and clinical outcomes: A populationbased retrospective cohort study. PLoS Med, 2018.
Vemu PL, Yang E, Ebinger J. 2023 ESH Hypertension Guideline Update: Bringing Us Closer Together Across the Pond. JACC, 2024. SF
