ACE inhibitor-based combination therapy important for improving BP control in the Asia Pacific region

Prof. Abdul Rashid
Prof. Martin Strauss
Prof. Alistair Hall
12 Dec 2016
ACE inhibitor-based combination therapy important for improving BP control in the Asia Pacific region
Hypertension is a leading cause of mortality globally and is of particular concern in the Asia Pacific region where there are more deaths due to poor blood pressure (BP) control than in any other region in the world. At a recent Servier-sponsored satellite symposium held during the ASEAN Federation of Cardiology Congress in Yangon, Myanmar, Professor Abdul Rashid, An Nur Specialist Hospital, Selangor, Malaysia, discussed the challenges associated with managing hypertension in the region. In addition, Professor Martin Strauss, North York General Hospital, Toronto, Canada and Professor Alistair Hall, Leeds General Infirmary, UK, discussed the different effects of angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) on cardiovascular (CV) outcomes, highlighting the additional protection against myocardial infarction (MI) offered by ACE inhibitors such as perindopril.

Hypertension in the Asia Pacific region
“Two-thirds of CV events in the Asia Pacific region are directly attributable to hypertension and proper BP control could prevent an estimated 800,000 CV events annually in China alone,” said Rashid. “However, despite the increasing prevalence of hypertension, detection and control rates in the region have remained static or even deteriorated over recent years.” [J Hypertens 2003;21:707-716; Lancet 2009;374:1765-1772; PLoS Med 2015;12e1001850]

According to Rashid, key challenges associated with managing hypertension in the Asia Pacific are poor medication compliance, possible ethnicity-based differences in response to pharmacological therapy, and differing expectations between doctors and patients as to what constitutes successful hypertension management. [Asia Pac Fam Med 2015;14:2]

“An overreliance on monotherapy may also be contributing to the poor BP control rates in the region and the recent consensus among Asia Pacific experts is that combination therapy should be more extensively utilized in the region,” said Rashid. “ACE inhibitors, diuretics and calcium channel blockers are essential in this respect as not only do they effectively lower BP, but they also offer additional CV benefits by protecting against CV events and improving overall survival. This is especially true for perindopril in combination with either amlodipine or indapamide,” said Rashid. [Curr Med Res Opin 2015;26;1-10].

ACE inhibitors offer greater cardioprotective benefits than ARBs 
“Although both ACE inhibitors and ARBs effectively lower BP, reduce the risk of stroke and progression of diabetic renal disease, and improve symptoms of congestive heart failure, they are not equivalent with respect to mortality,” said Strauss. 

He highlighted the findings from a number of trials to support this contention. For example, in a parallel meta-analysis of ACE inhibitor and ARB hypertension trials vs all comparators, ACE inhibitors reduced all-cause mortality by 10 percent, whereas ARBs did not reduce mortality. [Eur Heart J 2012;33:2088-2097]

In hypertension trials where the comparator was limited to placebo, a parallel meta-analyses of  ACE inhibitor and ARB trials found a significant reduction in mortality risk with ACE inhibitors (relative risk 0.91, 95 percent confidence interval [CI], 0.85–0.98), while ARBs lacked any mortality benefit  (HR, 1.01, 95 percent CI, 0.97–1.06) (Figure 1). [J Hypertens 2015;33:1321-1341]

ACE Figure 1 

“The divergent cardioprotective benefits of ACE inhibitors and ARBs are also seen in high-risk patients with diabetes mellitus,” said Strauss.

In a parallel meta-analysis of 23 trials that compared ACE inhibitor therapy with placebo or active treatment and 13 trials that compared ARBs with no therapy in patients with comorbid hypertension and diabetes mellitus, ACE inhibitor therapy reduced the risk of all-cause mortality by 13 percent (relative risk [RR], 0.87, 95 percent CI, 0.78–0.98], CV deaths by 17 percent (RR, 0.83, 95 percent CI, 0.70–0.99), and MI by 21 percent (RR, 0.79, 95 percent CI, 0.65–0.95). No such benefits were observed with ARBs. [JAMA Intern Med 2014;174:773-785]

A meta-regression analysis of ACE inhibitor and ARB trials in “high risk” patients by the Blood Pressure Lowering Treatment Trialists collaboration confirmed that  the cardioprotective effects of ACE inhibitors were over and above and “independent” of  the effects of BP lowering. [Prog Cardiovasc Dis 2015;]

“The evident lack of CV protection that occurs with ARBs vs ACE inhibitors despite their similar efficacy with respect to BP control is referred to as the ARB-MI Paradox and may be related to AT1 receptor blockade with ARB inhibiting a negative feedback loop that increases angiotensin II levels – a toxic molecule – as well as the upregulation of bradykinin that occurs in response to ACE inhibitor therapy,” said Strauss. 

Fixed-dose combination therapy with perindopril
“Dysfunction of the CV endothelium is a precursor to the development of atherosclerosis and thrombotic disease, and protection of the endothelium is thus vital for achieving the primary goal of antihypertensive therapy, namely the prevention of major CV events,” said Hall. 

He noted that perindopril is a useful agent in this context since it has both antihypertensive activity and the ability to normalize abnormal endothelial function. “There is a strong rationale supporting combination therapy with perindopril and the long-acting calcium channel antagonist amlodipine as this combination has been shown to significantly reduce mortality.” 

The prospective ASCOT trial, which included more than 19,257 patients with hypertension and ≥3 CV risk factors, was stopped early after clear evidence of a survival  benefit emerged  with perindopril plus amlodipine combination therapy vs standard beta-blocker therapy. Beneficial effects included a significant 11 percent reduction in all-cause mortality and 24 percent reduction in CV mortality despite similar BP reduction among the two regimens (Figure 2). [Lancet 2005;366:907-913]

ACE Figure 02

“Similar benefits have been observed in elderly patients and those with diabetes mellitus,” said Hall. Combination perindopril plus indapamide therapy effectively reduced BP as well as CV events in patients 80 years or older in the HYVET trial — all-cause mortality was reduced by 24 percent and CV mortality by 23 percent vs placebo. The ADVANCE trial showed that the same combination reduced all-cause mortality by 14 percent and CV mortality by 18 percent in patients with comorbid diabetes mellitus. [
N Engl J Med 2008;358:1887-1898, Lancet 2007;370:829-840]

Triple fixed-dose combination therapy with perindopril, amlodipine and indapamide has also been shown to be beneficial when dual-combination therapy fails to adequately control BP. [Clin Drug Investig 2014;34:701-708]

“Over half of all patients diagnosed with hypertension have BP readings above those recommended by guidelines. These patients should be offered evidence-based fixed combination therapy with perindopril, not only to ensure the achievement of BP targets, but also because such therapy will lead to long-term vascular protection,” Hall concluded.                  
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