The risk of CVD increases steadily with progressively higher levels of baseline SBP and DBP, above a usual SBP and DBP of 115mmHg and 75mmHg, respectively.⁴

For a 20mmHg higher level of SBP and 10mmHg higher level of DBP the risk of CVD is 2-fold higher. The risk of mortality is greatest in patients with stage 2 and 3 hypertension (see Table 1).^2,4

Hypertension is also closely related to other adverse outcomes including chronic kidney disease (CKD) and cognitive impairment/dementia.¹

Table 1: Southern African Hypertension Society BP categories³

*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.

When should treatment be initiated?

Most patients with an average SBP ≥140mmHg or DBP ≥90mmHg are at high risk for CVD and initiation of antihypertensive drug therapy is indicated. Globally, <14% of patients have controlled hypertension using antihypertensive medication. In LMICs this figure is <8%. 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.^1,5

The WHO recommends initiation of antihypertensive treatment in patients with a confirmed diagnosis of hypertension (SBP ≥140mmHg or DBP ≥90mmHg).¹

Furthermore, the WHO recommends antihypertensive treatment in patients with existing CVD and SBP of 130mmHg-139mmHg and in those without CVD but high CVD risk (eg diabetes, CKD and SBP of 130mmHg-139mmHg.¹

Recommended first-line therapies

Combination therapy is recommended as initial therapy for adults with hypertension as opposed to monotherapy to improve adherence and persistence. The WHO states that antihypertensive medications combination therapy should be chosen from the following three drug classes:¹

• Diuretics (thiazide or thiazide-like)
• Angiotensin-converting enzyme (ACE) inhibitor/angiotensin-receptor blocker (ARB)
• Long-acting dihydropyridine calcium channel blockers (DCCB).

The majority of patients with hypertension require a combination of two to three antihypertensives to achieve control. In 2019, the WHO included single-pill or FDC antihypertensive medications on their essential medicines list to encourage uptake and improve hypertension control.⁶

The International Society of Hypertension 2020 guidelines recommend dual low FDCs as the optimal initial treatment for hypertension with the exception of ‘low risk grade 1 hypertension or in very old (≥ 80 years) or frailer patients’ who should be considered for monotherapy.⁷

Similarly, the European Society of Cardiology 2018 guidelines recommend initial therapy with dual combination of ACEI or ARB with CCB or diuretic, preferably as an FDC, with the same aforementioned recommendations of monotherapy in certain groups.⁸

The 2017 American College of Cardiology/American Heart Association guidelines support initiation of dual combination therapy as either separate agents or FDCs in adults with grade 2 hypertension (defined as SBP ≥140mmHg and/or DBP ≥90mmHg) and an average BP >20/10mmHg above their BP target.⁹

First-line treatment with FDC therapy has been associated with a significant (34%) risk reduction of CV events or all-cause death, when compared to those who received delayed combination treatment initiation due to initial monotherapy treatment. This was primarily due to the more rapid and effective BP control (see results from the PRECIOUS trial below).⁶

FDCs are also associated with lower healthcare resource use, which is particularly important for LMICs such as South Africa. In South Africa available fixed dose combination antihypertensive agents include for example perindopril (ACE inhibitor)/amlodipine (DCCB), and perindopril/indapamide (thiazide-like diuretic) 8mg/2.5mg. Perindopril/amlodipine is available in 4 mg/5mg, 4mg/10mg, 8mg/5mg and 8mg/10mg tablets.^6,10,11

Which patients will benefit most from combination perindopril/amlodipine FDC therapy?

In the Anglo-Scandinavian 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%.¹²

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.¹³

Adults (n=1175) aged 40–70 years with newly diagnosed/untreated stage 2 hypertension (BP ‡160/100mmHg), hypertension uncontrolled with monotherapy (BP >140/90 mmHg), or hypertension inadequately managed with another combination therapy. Only the starting dose of perindopril/amlodipine4mg/5mg was used in this study and no titration was made to higher doses.¹³

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.¹³

Target BP was achieved in 66.1% of patients in the total population within 60 days, 68.3% of untreated patients, 68.4%of patients uncontrolled with monotherapy, and 59.9% of patients inadequately managed with combination therapy.¹³

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.¹³

Which patients will benefit most from perindopril/indapamide 8mg/2.5mg FDC therapy?

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.^14,15

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 perindopril4mg/indapamide1.25mg 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).¹⁴

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.¹⁴

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 17.5 g/m²decrease from baseline in patients whose maximum dose was perindropil 8mg/indapamide 2.5mg (from 148.5 g/m² +/- 39.5 to 131 g/m².¹⁴

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.¹⁴

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.¹⁴

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.¹⁶

PRECIOUS trial confirms efficacy of fixed dose combinations

In the Management of Newly Diagnosed and Uncontrolled Hypertension With Fixed-Dose Combination of Perindopril/Amlodipine and Perindopril/Indapamide/Amlodipine (PRECIOUS) trial,  Brguljan et al assessed the efficacy and safety of guidelines’ FDC recommendations.¹⁷

The study included 450 adults with essential hypertension. Treatment duration was 16 weeks, divided into four treatment periods. Office BP was measured with a validated automated BP-measuring device by a qualified healthcare professional following guidelines protocol.¹⁷

At the inclusion naïve or patients uncontrolled on previous mono or dual therapy (other than perindopril/amlodipine were assigned to dual FDC arm with initial dose of 4/5mg perindopril/amlodipine. Those uncontrolled on previous dual or triple therapy were assigned to triple FDC arm with initial dose of 4/5/1.25 mg perindopril/amlodipine/indapamide.¹⁷

If BP control was not reached, the initial dose was up-titrated in four-week intervals to 8/5mg perindopril/amlodipine, 8/10mg or 8/10/2.5mg perindopril/amlodipine/indapamide in dual FDC arm and to 8/5/2.5mg, or 8/10/2.5mg perindopril/amlodipine/indapamide in triple FDC arm.¹⁷

After four months of treatment mean office BP lowered from 159.5 ± 11.6/ 99.6 ± 8.6mmHg to 128.6 ± 9.4/81.7 ± 7.2mmHg and from 162.4 ± 14.3/ 99.5 ± 9,6mmHg to 127.8 ± 11.3/80.2 ± 7.5mmHg in dual and triple FDC arm (all p < 0.001), respectively.¹⁷

Significant decrease by -17.1/-10.9mmHg in dual and -14.4/-9.0mmHg in triple FDC arm was achieved after one month of treatment (both p < 0.001). Target BP of <140/90mmHg was achieved in 77.7% of patients in dual and in 83.0% of patients in triple FDC arm.¹⁷

The majority of the effect was observed within three months. About 30% of patients remained on initial dose, and 30% needed one up-titration of the therapy. About 85% of patients experienced no adverse events, recorded ones were clinically irrelevant.¹⁷

Conclusion

Hypertension is the leading cause of CVD. International guidelines recommend FDC therapy at initiation of treatment. Numerous studies have shown the benefits of FDC therapy in patients with existing hypertension as well as treatment naïve patients. BP control was achieved rapidly and effectively.

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