The title of the recent editorial by Prof. Kjeldsen et al. [Citation1] suggests that the latest guidelines of the International Society of Hypertension (ISH) [Citation2] have introduced a drug treatment recommendation which may go ‘in the wrong direction’?
The treatment favoured by ISH [ACE-inhibitor (ACEi)/angiotensin receptor blocker (ARB) + dihydropyridine calcium channel blocker (CCB)] for most patients, was also recommended by the NICE (National Institute for Health and Care Excellence) guidelines after systematic review of the evidence in 2011 [Citation3] and is one of the two drug combinations recommended in the latest European guidelines of 2018 [Citation4] and two of the three combinations recommended in the latest US guidelines [Citation5].
As for being ‘in the wrong direction’, – this implies that the ACEi/ARB + CCB combination has been bettered by another combination in terms of cardiovascular (CV) prevention in any trial carried out to date. It has not. Indeed, the authors of the editorial point out the superiority of ACEi/ARB + CCB over ACEi/ARB + diuretic in the ACCOMPLISH (Benazepril plus Amlodipine or Hydrochlorothiazide for Hypertension in High-Risk Patients) trial [Citation6] and over beta-blocker + diuretic in the ASCOT (Anglo-Scandinavian Cardiac Outcomes) trial [Citation7]. Why then might ACEi/ARB + CCB be deemed ‘in the wrong direction’.
The authors correctly claim that ‘numerous outcome trials’ have shown the benefits of thiazide or thiazide-type diuretics when used as first line therapy. But incorrectly claim that diuretics ‘show no inferiority when administered as the first or second line drug’. A critical systematic review of the data on diuretics reveals that thiazides have only shown CV benefits as first line therapy when used at high doses (often with added potassium supplementation). Thiazides are effectively no longer used at such high doses.
Whenever low-dose thiazides (the vast majority of thiazide prescriptions) have been compared with other agents, they were always inferior to the comparator agent (ANBP2 - Australian National Blood Pressure Study Group [Citation8], ASCOT [Citation7], ACCOMPLISH [Citation6]). However, we do agree that thiazide-like diuretics have a better track record in terms of preventing CV events than thiazides and hence they, and not thiazides, are preferred as the add-on drug to the drug combination of ACEi/ARB + CCB recommended in the ISH 2020 guidelines [Citation2].
It must be conceded that there are very few head to head comparisons of different two-drug combinations of antihypertensive agents and hence when promoting two-drug combinations as first-line therapy for most patients (as both the ISH [Citation2] and European guideline [Citation4] do) the definitive evidence for the best combination is limited. Nevertheless, what comparative evidence is available supports the use of ACEi/ARB plus CCB, as espoused originally by NICE in 2011 [Citation3] on the basis of a truly systematic review of the evidence. Those same guidelines also reported that the CCB was preferred to the diuretic because ‘the CCB performed better in meta-analyses than the diuretic’, especially for stroke outcomes [Citation3]. They also noted significantly less new onset diabetes associated with the use of the CCB compared with the diuretic. This reflects that ACEi/ARB + CCB is easier to use than ACEi/ARB + diuretic by virtue of needing minimal monitoring needed due to less concern about electrolyte and metabolic disturbance. This adds further support for the selection of ACEi/ARB + CCB over ACEi/ARB + diuretic.
Nevertheless, importantly, the ISH guidelines of 2020 [Citation2] do recommend the use of ACEi/ARB + diuretic as an alternative starting combination of therapies for some subgroups of patients where evidence exists or pragmatism applies (post stroke, the very elderly, incipient heart failure or CCB intolerance). This advice, which was included in the ISH guidelines was omitted from Figure 1 of the editorial in Blood Pressure [Citation1].
The treatment algorithm recommended in the ISH guideline [Citation2] were designed to be simple (whilst allowing flexibility) and represent a distillate of the best currently available evidence. They are entirely consistent with the European and US treatment guidance but give a stronger steer towards the more common use of A + C for the majority of patients, whilst highlighting that ACEi/ARB + diuretic (or CCB + diuretic) might be the preferred option for others. There was nothing ‘new’ and nothing ‘wrong’ with that approach.
Disclosure statement
NP, BW, AES and TU report no relevant conflicts of interest to disclose related to this response.
References
- Kjeldsen SE, Narkiewicz K, Burnier M, et al. The International Society of Hypertension Guidelines 2020 – a new drug treatment recommendation in the wrong direction? Blood Pressure.
- Unger T, Borghi C, Charchar F, et al. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension. 2020;75(6):1334–1357.
- National Institute for Health and Care Excellence. Hypertension (NG136): clinical management of primary hypertension in adults. National Institute for Health and Care Excellence. Available from: https://www.nice.org.uk/guidance/ng136
- Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021–3104.
- Whelton PK, Carey RM, Aronow WS, et al. ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, 5. Detection, evaluation, and management of high blood pressure in adults. A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines 2017. Hypertension. 2018;71:1269–1324.
- Jamerson K, Weber MA, Bakris G, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417–2428.
- Dahlöf B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding Bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366(9489):895–906.
- Wing LM, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 2003;348(7):583–592.