Efficacy of fixed-dose, triple therapy in essential hypertension

Efficacy of fixed-dose, triple therapy in essential hypertension

Hypertension is the leading cause of mortality worldwide, accounting for more than 10 million deaths every year. The majority of deaths occur in low-and middle-income counties. An estimated one billion people in these countries have hypertension, according to the International Society of Hypertension (ISH).1

Apart from cardiovascular disease (CVD), people with hypertension are also at increased risk of diabetes (15%-20%), lipid disorders (elevated low-density lipoprotein-cholesterol and triglycerides [30%]), overweight/obesity (40%), hyperuricaemia (25%) and metabolic syndrome (40%). Hypertensive patients, who have one or more of these risk factors, have an additional risk of cerebrovascular and renal diseases.1

Essential versus secondary hypertension

Hypertension diagnosis is based on: If the average of two or more diastolic blood pressure (BP) measurements on at least two subsequent visits is ≥90mmHg or when the average of multiple systolic BP (SBP) readings on two or more subsequent visits is consistently ≥140mmHg.3

In about 95% of cases, no clear cause can be determined. These patients are classified as having essential, also referred to as primary or idiopathic hypertension.

According to the ISH, isolated systolic hypertension (defined as SBP ≥140mmHg and diastolic BP (DBP) <90mmHg) is the most common form of essential hypertension in young individuals, including children, adolescents, and young adults.1,3

In 5% of patients, an identifiable and potentially reversible cause can be identified. This is known as secondary hypertension. Secondary hypertension should be considered in the presence of suggestive symptoms and signs, such as:2

» Severe or resistant hypertension

» Age of onset younger than 30 years (especially before puberty)

» Malignant or accelerated hypertension

» An acute rise in blood pressure (BP) from previously stable readings.

Essential hypertension is defined as high BP in which secondary causes such as renovascular disease, renal failure, pheochromocytoma, aldosteronism, or other causes of secondary hypertension or mendelian forms (monogenic) are not present. Essential hypertension is defined as high blood pressure (BP) in which secondary causes are not present.2,3

Suboptimal BP control

According to the ISH, nonadherence to treatment recommended by a physician, is one of the main causes of sub-optimal BP control. These include for example taking medication, following a diet, or implementing lifestyle changes.Nonadherence to treatment is an indicator of poor prognosis in hypertensive patients.1

Some 45.2% of all hypertensive patients do not adhere to treatment. In uncontrolled patients, this number is much higher (83.7%). Studies show that 25% of patients do not buy all the medications prescribed by their physicians, 10% often forget to take the prescribed medication on a daily basis, 30% discontinue initial treatment after six months and 50% after one year.4

There are numerous reasons why patients do not adhere to treatment. These include for example:

» Hypertension has no obvious symptoms, which led to the dubbing of the disease as the ‘silent killer’

» Patients do not understand their disease

» Patients are often not involved in the treatment decision-making process and therefore do not understand the seriousness of their disease

» Others stop treatment because of the side effects associated with some medications such as fatigue, headache, peripheral oedema, cough, allergy, polyuria, erectile and libido dysfunction, and metabolic changes.4

Physicians play an important role in addressing issues of nonadherence. Physician-related factors are very common, when prescribing complex drug regimens, when failing to explain the benefits and risks of the medication, and when disregarding the financial burden to the patient. Doctor-patient communication is crucial and should always be reinforced.4

Combination therapy improves adherence

One of the most effective strategies to improve adherence is the use of combination antihypertensive therapy. About 70% of hypertensive patients require the combination of at least two antihypertensive agents to reduce BP levels below the recommended goals.5

Combination therapy should be initiated in patients with SBP 20mmHg above the target or DBP 10mmHg above the recommended goal.5

Combination therapy provides greater antihypertensive power than the use of high doses of monotherapy, adding several mechanisms of action that block various pathways of increased BP, in addition to providing greater protection to target organs than monotherapy, and reduced potential for side effects.5

Mazza and colleagues compared the efficacy of a fixed-dose triple combination therapy and a free combination of three antihypertensives in patients with uncontrolled hypertension.6

Participants (n=92) with uncontrolled essential hypertension previously treated with a renin-angiotensin-aldosterone system inhibitor, plus hydrochlorothiazide were switched to once-daily fixeddose triple combination therapy with perindopril/indapamide/amlodipine (5mg-10mg/1.25mg-2.5mg/5mg-10mg).6

Patients were age- and sex-matched with a control group of hypertensive patients receiving free combination therapy with three drugs including a RAAS inhibitor, a diuretic, and a calcium channel blocker. Office BP and 24-hour ambulatory BP monitoring (ABPM) were evaluated at baseline and after one and four months.6

The team reported significant reductions in ambulatory 24-hour, day-time, and nighttime SBP, and pulse pressure (PP) were found in the fixed-dose triple combination therapy group relative to reductions seen with free combination therapy, after the first month only of follow-up.6

Target BP values (mean 24-hour ambulatory SBP/DBP <130/80 mmHg) were reached by more recipients of fixed-dosed triple combination therapy group than free combination therapy (64.8% versus 46.9%) at month four of follow-up, despite reductions in 24-hour ABPM values from baseline being similar in both groups at this time point.6

They concluded that a fixed-dose triple combination therapy (perindopril/indapamide/ amlodipine) was effective at reducing SBP and PP in previously treated patients with uncontrolled hypertension, and well tolerated, providing support for clinicians in choosing a fixed-dose triple combination over the freecombination of a RAAS inhibitor, a diuretic, and a calcium antagonist.6

Mourad et al conducted a four month, double-blind, randomised, controlled trial to demonstrate the superiority of perindopril/ indapamide/amlodipine single pill, over perindopril/indapamide after one month and to determine further up-titration efficacy and safety in patients with mild-to-moderate hypertension.7

After a one-month run-in period on perindopril/indapamide 5mg/1.25mg, patients with SBP/DBP at least 150/95mmHg and no diabetes or renal insufficiency, received perindopril/indapamide/amlodipine 5mg/1.25mg/5mg single pill or continued on the same treatment. 7

At one, two, and three months, patients with uncontrolled BP (SBP/DBP ≥140/90mmHg) were gradually up-titrated with a higher dose of the triple therapy up to perindopril/indapamide/ amlodipine 10mg/2.5mg/10mg in both groups. 7

Efficacy was assessed on office supine SBP (main criterion) and DBP, BP control, and response rates. Treatment effect on ABPM and home blood pressure monitoring (HBPM) parameters was also assessed in two subpopulations of 276 and 263 patients, respectively. 7

A total of 454 hypertensive patients were randomised (227 to each group). After a month, superior SBP (-3.1mmHg) and DBP (-2.8 mmHg) reductions were observed with perindopril/indapamide/amlodipine, which were even more pronounced after excluding white-coat effect in the sustained hypertension population (-5.3mmHg/-3.7mmHg). 7

Similar results were observed in terms of BP response (72% versus 53%) and control rates (32% versus 25%). Up-titration was effective at each visit in both treatment arms. 7

Both ABPM and HBPM results confirmed the superiority of the triple therapy at a month on ASBP/ADBP and HSBP/HDBP (-4.5mmHg/2.0mmHg for ABPM, and -4.9mmHg/-3.1mmHg for HBPM. Up-titration steps resulted in further significant decreases in both ABPM and HBPM.7

The team concluded that perindopril/ indapamide/amlodipine in a single pill produces superior reductions in blood pressure compared with dual therapy. Triple therapy up-titration was well tolerated and effective leading to BP control rates of over 80%. Analysis of 24-hour ABPM and HBPM results corroborated these findings.7

In the Perindopril-Indapamide plus AmlodipiNe in high rISk hyperTensive patients or PIANIST STUDY, Tóth et al evaluated fixeddose triple combination therapy (perindopril 10mg/indapamide 2.5mg/amlodipine 5mg or 10mg) in difficult-to-treat hypertension.

This was an observational, four-month, openlabel study (n=4731).8

Patients at high or very high CV risk and suboptimal hypertension control were included. After four months of therapy, office BP (OPB) decreased by 28.3mmHg ± 13.5mmHg/13.8mmHg ± 9.4mmHg to 132.2mmHg ± 8.6/80.0mmHg ± 6.6mmHg.8

BP targets were reached by 72% of patients and by 81% and 91% of patients previously treated with an angiotensin-converting enzyme inhibitor/hydrochlorothiazide or an angiotensin receptor blocker/ hydrochlorothiazide, respectively.8

Changes in OBP were 18.7mmHg ± 8.3/9.7mmHg ± 7.2mmHg for grade 1, 30.4mmHg ± 10.1mmHg/14.7mmHg ± 8.6mmHg for grade 2, and 45.4mmHg ± 15.1mmHg/20.7mmHg ± 12.1mmHg for grade 3 patients. In patients who underwent AMBP monitoring, 24-hour mean blood pressure decreased from 147.4mmHg ± 13.8mmHg/82.1mmHg ± 11.9mmHg to 122.6mmHg ± 9.1mmHg/72.8mmHg ± 7.4mmHg.8

Tóth and team concluded that triple combination perindopril/indapamide/amlodipine was effectively and safely administered to a large population of high- and very high-risk hypertensive patients who had not reached target OBP values with previous treatment.8

Box 1: Hypertension definitions, according to SAHS

The following BP definitions are recommended by the South African Hypertension Society:9

BP category*: SBP: DPB:

BP category*: Normal - SBP: <120mmHg DPB: <80mmHg

BP category*: Optimal - SBP: 120–129mmHg DPB: <80mmHg

BP category*: High normal - SBP: 130–139mmHg DPB: 80–89mmHg

BP category*: Grade 1 - SBP: 140–159mmHg DPB: 90–99mmHg

BP category*: Grade 2 - SBP: 160–179mmHg DPB: 100–109mmHg

BP category*: Grade 3 - SBP: ≥180mmHg DPB: ≥110mmHg

BP category*: Isolated systolic - SBP: ≥140mmHg DPB: <90mmHg

* Individuals with SBP and DBP in two categories should be designated to higher BP based on two or more careful readings obtained on two or more occasions.9

Conclusion

Hypertension is the leading cause of mortality worldwide. LMICs carry the highest burden. Despite the efficacy, safety and costeffectiveness of antihypertensive agents, nonadherence among patients is high, increasing the risk of CVD, morbidity, and mortality. One of the most effective strategies to improve adherence, is the use of fixed-dose combination therapy.

References available on request. SF