Fixed-dose combination therapy in hypertension

Fixed-dose combination therapy in hypertension

An estimated 1.4 billion people worldwide have hypertension, but only 14% have it under control. In South Africa more than 90% of patients with hypertension are uncontrolled primarily due to a lack of awareness about their condition, and access to treatment.1,2

Hypertension is a major risk factor for cardiovascular disease (CVD). More people die annually from CVDs than any other cause. An estimated 60% of CVD- and stroke-related deaths occur in low- and middle-income countries. Delay of treatment is particularly concerning since it can lead to losing the patient for follow up, potentially resulting in adverse CV outcomes.1

When to initiate antihypertensive treatment

The 2021 World Health Organization (WHO) guideline for the treatment of hypertension in adults, recommends initiating antihypertensive treatment in individuals with a confirmed diagnosis of hypertension (systolic BP [SBP] of ≥140mmHg or diastolic BP [DBP] of ≥90mmHg). The South African hypertension guideline also recommends initiating treatment in patients with BP levels in this range.1,2

Antihypertensive treatment is recommended in individuals with existing CVD, as well as those without CVD, but with an elevated risk of CVD, diabetes, or chronic kidney disease, and a SBP level of 130–139mmHg.1

Initiation of treatment should start no later than four weeks following diagnosis of hypertension. If BP level is high (eg SBP ≥160mmHg or DBP ≥100mmHg) or there is accompanying evidence of end organ damage, initiation of treatment should be started without delay.1

Recommended pharmacological treatment

For adults with hypertension, the WHO recommends the use of drugs from any of the following three classes as initial treatment:1

1. Thiazide and thiazide-like agents

2. Angiotensin-converting enzyme inhibitors (ACEis)/angiotensin-receptor blockers (ARBs)

3. Long-acting dihydropyridine calcium channel blockers (CCBs).

Long-acting antihypertensives are preferred. Examples of indications to consider specific agents include diuretics or CCBs in patients over 65 years or those of African descent, beta-blockers in ischaemic heart disease, ACEis/ARBs in patients with severe proteinuria, diabetes, heart failure or kidney disease.1

Fixed-dose combination preferred as initial treatment

The WHO recommends combination therapy, preferably with a single-pill combination as initial treatment. Initial first-line therapy recommended by the South African hypertension guideline includes: a diuretic (thiazide-like or thiazide), ACEi or ARB, and/or CCB used as mono- or combination therapy.1,4

Combination therapy should be considered if clinically appropriate ab initio if BP is ≥160/100mmHg as this is associated with better clinical outcomes and earlier achievement of target BP.4

How effective is fixed-dose combination therapy?

Hypertension is usually multifactorial, interfering with different pressor mechanisms. Thus, acting on several physiological systems improves BP goal attainment rates. Three main factors determine BP:3

» Renal sodium excretion and the resultant plasma and total body volume

» Vascular tone

» Cardiac performance.

Each of these factors controls determinants of BP (eg cardiac output, intravascular volume, and systemic vascular resistance). The reninangiotensin-aldosterone system plays a vital role in the regulation of BP and fluid balance. This hormone system regulates the secretion of renin, with feedback systems from sodium balance, arterial BP levels and angiotensin II.3

The rationale for combining drugs from different classes lies in reaching the goal BP more rapidly, as each drug works at a separate site, blocking different effector pathways.3

Studies show that fixed-dose combination therapy lowers SBP more than monotherapy. These combinations are also associated with fewer side-effects due to use of lower doses of each drug.1

European guidelines recommend combination therapy as first-line treatment when initial or when total CV risk is high or extremely high. According to the authors of the South African hypertension guideline, fixeddose combinations are preferred because of better patient adherence and control of BP.4

A large study from Italy (125 635 patients, age 40–85 years) evaluated patients started on antihypertensive treatment with one drug versus a two-drug single-pill or free combination. The study showed that initial treatment with a two-drug single-pill or free combination was associated with significant reductions in the risk of death (20%) and hospitalisation for CV events (16%) compared with initial monotherapy. Studies have also shown that fixed-dose combinations result in improved treatment adherence (from 6% to 20%).

Single-pill combinations available in South Africa

Perindopril/amlodipine: In the AngloScandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm, perindopril/amlodipine significantly reduced total mortality by 11%, major CV events and procedures by 16%, and new-onset diabetes by 30%.5

The SafeTy&efficacy analysis of coveRsyl amlodipine in uncOntrolled and Newly diaGnosed hypertension or STRONG study also evaluated the efficacy and tolerability of perindopril/amlodipine in a clinical setting.11

Adults (n=1175) aged 40–70 years with newly diagnosed/untreated stage 2 hypertension (BP ‡160/100mmHg), hypertension uncontrolled with monotherapy (BP >140/90mmHg), or hypertension inadequately managed with another combination therapy. Mean SBP/DBP decreased significantly from baseline (167.4 – 15.2/101.4 – 9.1mmHg) over 60 days (-41.9 – 34.8/-23.2 – 21.8mmHg.11

Target BP was achieved in 66.1% of patients in the total population, 68.3% of untreated patients, 68.4%of patients uncontrolled with monotherapy, and 59.9% of patients inadequately managed with combination therapy.11

In 161 patients with SBP >180mmHg at baseline BP was reduced by 63.2 – 32.5/29.0 – 21.9mmHg (p < 0.0001) at day 60. Perindopril/ amlodipine was safe and well tolerated. All patients completed the 60-day study (94%) adhered to their treatment regimen.11

Perindopril/indapamide: Treatment with perindopril 8mg/indapamide 2.5mg has been shown to reduce BP, end-organ damage, and CV morbidity and mortality in a wide range of hypertensive patients. Large outcome trials show that this combination has favourable prognostic effects in elderly as well as patients with high CV risk, regardless of their BP levels.6,7

In the Perindopril/indapamide combination more effective than enalapril in reducing blood pressure and left ventricular mass (PICXEL study), and the PREMIER Collaborative Research Group trials, SBP/DBP decreases of 16.3/8.1mmHg and 2.5/2.6mmHg, respectively, were noted when perindopril 4mg/indapamide 1.25mg was doubled to the 8mg/2.5mg combination (decreases from 167.7/101.7mmHg to 151.4/93.6mmHg in PICXEL and from 154.9/92.1mm/Hg to 152.4/89.5mmHg in PREMIER, respectively).6

As a consequence more patients had normalised BP (22% and 17%), more patients responded to treatment (68% and 45%), and 29% and 10% of non-responders became responders, in PICXEL and PREMIER, respectively.6

Additional end-organ benefits were also noted with perindropil 8mg/indapamide 2.5mg. In PICXEL, significant decreases from baseline in left ventricular mass were noted with all three doses, with a 17.5g/m2 decrease from baseline in patients whose maximum dose was perindropil 8mg/indapamide 2.5mg (from 148.5g/m2 +/- 39.5 to 131g/m2.6

In PREMIER, changes in albumin excretion rate were also noted with all three doses, with a 45% reduction from baseline in patients whose maximum dose was perindropil 8mg/indapamide 2.5mg. When safety data, including potassium levels, were analysed, the increase in dose to perindropil 8mg/ indapamide 2.5mg did not have a notable impact on the safety profile of perindopril/ indapamide.6

The authors concluded that based on data available from an evaluation of three randomised clinical trials, fixed-combination perindropil 8mg/indapamide 2.5mg provided a significant, incremental reduction in BP as well as cardiac and renal end-organ protection while remaining safe and well-tolerated.6

In South Africa, perindopril 8mg/ indapamide 2.5mg is indicated for patients with essential hypertension who are stabilised on the individual components at the same dosage range.8

Amlodipine/valsartan: Hu et al conducted a large observational study to evaluate the efficacy and safety of amlodipine 5mg/ valsartan 80mg in patients with hypertension whose BP was not adequately controlled by monotherapy in a real-world setting.9

A significant reduction of 27.1mmHg in SBP (159.6mmHg vs 132.5mmHg and 15.2mmHg in DBP (95.6mmHg vs 80.4mmHg) from baseline was observed at week eight. The BP-lowering efficacy of amlodipine 5mg/valsartan 80mg was independent of age and comorbidities. BP control of <140/90mmHg was achieved in 76.8% of the patients.9

In South Africa, amlodipine 5mg/valsartan 80mg is indicated for the treatment of mild to moderate hypertension in patients stabilised on same doses of individual component.8

Telmisartan/hydrochlorothiazide: Bays et al compared the effects of combination telmisartan/hydrochlorothiazide therapy with respective monotherapies at the earliest available time points (weeks one, two, three and/or four).10

During early time periods, combination telmisartan/hydrochlorothiazide reduced SBP and DBP significantly more than placebo or respective monotherapies in most treatment comparisons for patients initiated on monotherapy.10

Combination telmisartan/hydrochlorothiazide also allowed significantly more patients to achieve BP SBP (<14mmHg), and DBP (<9mmHg) goals compared with placebo, and numerically higher compared with telmisartan or hydrochlorothiazide monotherapy.10

In patients uncontrolled by monotherapy, combination hydrochlorothiazide significantly reduced SBP/DBP more than monotherapy. Similarly, BP, SBP and DBP goal attainment rates were significantly higher with combination telmisartan/ hydrochlorothiazide therapy.10

In summary, telmisartan/hydrochlorothiazide significantly lowered BP as early as one to four weeks after initiation of therapy, with greater BP lowering, and greater BP goal attainment than with monotherapies or placebo.10

In South Africa telmisartan/ hydrochlorothiazide is indicated for patients with mild to moderate hypertension.8

Valsartan/hydrochlorothiazide: This combination (administered once daily) has been evaluated in the treatment of patients with hypertension in clinical trials ranging in duration from eight weeks to three years.12

These studies showed that combination treatment with valsartan 80mg or 160mg and hydrochlorothiazide 12.5mg or 25mg induced significant reductions from baseline in SBP and DBP in patients with mild to severe hypertension.12

Clinical trials have demonstrated that the combination is significantly more effective than either drug alone. Furthermore, valsartan/ hydrochlorothiazide was effective at reducing BP in patients unresponsive to monotherapy with either agent alone.12

Effective BP control with valsartan/ hydrochlorothiazide was maintained in longterm studies, with reductions observed after three months of treatment being similar to those seen after one, two or three years. Fixed-dose valsartan/hydrochlorothiazide showed similar BP reductions to amlodipine and to valsartan plus benazepril. Valsartan/ hydrochlorothiazide also provided effective 24hour ambulatory SBP/DBP control.12

In South Africa valsartan/hydrochlorothiazide is indicated for mild to moderate hypertension in patients who are stabilised on the same dosage of the individual components.8

References

1. WHO (2021). Guideline for the pharmacological treatment of hypertension in adults. https://apps.who.int/iris/bitstream/han dle/10665/344424/9789240033986-eng.pdf

2. Rayner B, Jones E, Veriava Y, Seedat YK. South African Hypertension Society commentary on the American College of Cardiology/American Heart Association hypertension guidelines. Cardiovasc J Afr, 2019.

3. Schellack N and Malan L. An overview of fixed-dose combinations of antihypertensive drugs in South Africa. South African Family Practice, 2014.

4. Seedat YK, Rayner BL and Veriava Y. South African hypertension practice guideline 2014 Hypertension guideline working group: Cardiovasc J Afr, 2014.

5. Danchin N. Which patients would benefit the most from the perindopril–amlodipine combination? European Heart Journal Supplements, 2008.

6. Mourad JJ and Le Jeune S. Evaluation of high dose of perindopril/indapamide fixed combination in reducing blood pressure and improving end-organ protection in hypertensive patients. Curr Med Res Opin, 2009.

7. De Leew. Combination perindopril/indapamide for the treatment of hypertension: A review. Expert Opinion on Pharmacology, 2011.

8. Mobi Monthly Index of Medical Specialities (MIMS), 2021.

9. Hu D, Liu L, and Li W. Efficacy and safety of valsartan/amlodipine single-pill combination in 11,422 Chinese patients with hypertension: an observational study. Adv Ther, 2014.

10. Bays H, Zhu D, and Schumacher H. Singlepill combination of telmisartan and hydrochlorothiazide: studies and pooled analyses of earlier hypertension treatment. High Blood Press Cardiovasc Prev, 2014.

11. Bahl VK, Jadhav UM and Thacker HP. Management of Hypertension with the Fixed Combination of Perindopril and Amlodipine in Daily Clinical Practice. Results from the STRONG Prospective, Observational, Multicenter Study. Am J Cardiovasc Drugs, 2009.

12. Wellington K and Faulds DM. Valsartan/ hydrochlorothiazide: a review of its pharmacology, therapeutic efficacy, and place in the management of hypertension. Drugs, 2002. SF