[133] Primary hypertension therapy: after thiazide, an ACEI or an ARB?

[133] Primary hypertension therapy: after thiazide, an ACEI or an ARB?

Therapeutics Letter 7 summarized the evidence about optimal drug therapy for primary (idiopathic) hypertension in 1995, concluding that thiazide-like drugs should be first choice.1 With additional evidence, we reiterated that conclusion in 20032 and in 20173.

In 2021, evidence from randomized controlled trials (RCTs) still favours thiazide-like drugs over angiotensin converting enzyme inhibitors (ACEIs), and ACEIs over angiotensin receptor blockers (ARBs). Yet the number of British Columbians who started a thiazide as first-line antihypertensive decreased by 54% from about 20,600 in 2004 to just under 9,400 in 2019.4 This Letter reiterates the best evidence for one of the most frequent treatment decisions in primary care.

Over 648,000 British Columbians took an ACEI or an ARB during 2020. Many such prescriptions are for hypertension, with or without complications such as diabetes, atherosclerosis, or heart failure.

Background

Elevated blood pressure increases the risk of premature mortality and morbidity. Despite this long-recognized relationship, uncertainty remains about the benefits for mortality and morbidity vs. harms of treating hypertension in low risk patients with BP in the range 140-159/90-99.5 For “moderate to severe” hypertension (>160/100) in adults (including people > 60) we have clear evidence from RCTs that drug treatment can reduce mortality and morbidity.6 We also have substantial evidence to guide which drug class to prescribe first.

To make informed choices about medications, patients and prescribers need to know how drugs impact clinical outcomes that are meaningful to those taking the treatment. Best studied and most important are the risk of premature death, disabling stroke and myocardial infarction.

Antihypertensive medications lower various measures of blood pressure (BP); but not all BP-lowering drugs are proven to reduce both morbidity and mortality in patients with primary hypertension.7,8 Therefore, basing drug choice only on the magnitude of BP lowering cannot guarantee the best clinical outcomes. The ALLHAT trial demonstrated the relevance of such reasoning when its α-blocker arm (doxazosin) had to be terminated prematurely due to increased incidence of heart failure vs. chlorthalidone (a thiazide-like diuretic).9 Chlorthalidone reduced stroke compared with lisinopril (an ACEI), and both outperformed the calcium channel antagonist amlodipine for clinically important secondary outcomes.2,10

Optimal first line treatment: thiazides and thiazide-like diuretics

Several Cochrane reviews concluded that low-dose thiazide/thiazide-like diuretics are the best choice for first-line therapy.8,11-13 This class reduces mortality and morbidity and is inexpensive.  ACEIs also reduce mortality and morbidity. In ALLHAT, one of the largest antihypertensive trials, over half of 33,357 patients had atherosclerotic cardiovascular disease at baseline, and 36% had type 2 diabetes. People with clinically significant heart failure or LVEF < 35% were excluded.9 The ALLHAT results favoured thiazides over ACEIs, including in people with diabetes or impaired fasting glucose levels.14 A 2019 comparative effectiveness analysis of multiple databases including 4.9 million patients also favours thiazide or thiazide-like diuretics over ACEIs, ARBs and calcium channel blockers. The conclusion was based on both clinical outcomes and safety measures.15

Since evidence from individual RCTs, meta-analyses, and observational sources consistently favours thiazide-like drugs for initial therapy of most people with primary hypertension, the 54% reduction in new thiazide prescriptions in BC is surprising and warrants the attention of prescribers.

Optimal second line treatment: ACEIs over ARBs

Evidence from Cochrane reviews indicates that ACEIs and ARBs are equally effective in lowering BP. However, RCTs comparing ACEIs with placebo showed that ACEIs reduce mortality and cardiovascular events. Similar placebo-controlled RCTs using ARBs for primary hypertension do not exist. Clinical benefits for hypertension proven for ACEIs cannot be extrapolated to ARBs based only on their equivalent effects on BP. There is not enough evidence from head-to-head RCTs comparing ACEIs with ARBs for hypertension to conclude with any certainty that the two classes yield similar benefits for mortality and morbidity.16 The weight of currently available evidence suggests that we reserve ARBs for patients who cannot tolerate an ACEI.

Up to 13% of patients experience cough associated with ACEIs, although only about 1-3% stop taking them.17-19 Fortunately, serious hypersensitivity reactions to ACEIs, such as angioedema, are much rarer.

Are higher doses superior?

Cochrane reviews report that both ACEIs and ARBs achieve an average 8/5 mm reduction of trough BP (just before a dose).20,21 There are no meaningful differences in BP lowering between ACEIs or between ARBs. On average, higher doses of both ACEIs and ARBs reduce BP minimally compared with lower doses. Most of the antihypertensive effect is achieved with recommended starting doses.

  • Ramipril starting dose: 2.5 mg/d yields about 60-70% of BP lowering.
  • Candesartan starting dose: 16 mg/d yields about 60-70% of BP lowering.

We do not have evidence that higher doses of ACEIs and ARBs increase clinically meaningful benefits in hypertension.

Choose within a class by price 

There is no available evidence for different clinical effectiveness of drugs within each class. Thus cost is a rational basis for most prescribing decisions. In BC, ARBs receive PharmaCare coverage only under Special Authority, for patients who experienced intractable cough or angioedema on an ACEI.22 Of the $22 million spent on ARBs in BC during 2020, over 84% was out-of-pocket or from private drug insurance. People taking higher cost unsubsidized ARBs may prefer ACEIs, and be more likely to refill prescriptions.23

Generic ramipril is the least expensive ACEI in BC

Costs vary considerably between ACEIs and over time. In 2020, 90% of the 403,000 British Columbians who received an ACEI were prescribed ramipril or perindopril. In BC, the lowest cost ACEI is generic ramipril. The current annual ingredient cost of ramipril 10 mg/d is $40, vs. $117 for perindopril 8 mg/d (without markup or dispensing fees).24 Ramipril is available only as a capsule in Canada. Splitting a high dose tablet (e.g. perindopril 8 mg) can reduce cost if one accepts that most of the BP effect occurs at a sub-maximal dose.

For an ARB choose generic candesartan or telmisartan

ARB costs are even more disparate. In 2020, 80% of the 246,000 British Columbians who received an ARB took candesartan, losartan or telmisartan. The current annual ingredient cost of generic candesartan 32 mg/d is $91, vs. $544 for the same dose of brand name candesartan (without markup or dispensing fees).24 In addition, splitting a high dose tablet can further reduce cost because the three most frequently prescribed ARBs are priced the same for different doses.

Table: Annual ingredient cost of the most-prescribed ACEIs and ARBs (without markup or dispensing fees)  in BC

ACEIs

Ramipril

1.25 mg: $29

5 mg:  $33

10 mg: $40

Perindopril

 2 mg:  $66

4 mg:  $84

 8 mg: $117

ARBs

Candesartan

 8 mg:  $91

16 mg: $91

32 mg: $91

Losartan

25 mg: $99

50 mg: $99

100 mg: $99

Telmisartan

40 mg: $84

80 mg: $84

Conclusions

  • Low-dose thiazides are the best drug class for starting antihypertensive therapy.
  • ACEIs are the preferred second line treatment.
  • Antihypertensives achieve most of their BP lowering effect at starting or low doses.
  • Reserve ARBs for patients with ACEI cough or angioedema.
To accompany this Letter, an individual Portrait on prescribing of thiazides, ACEIs and ARBs was sent to approximately 3850 eligible family doctors in BC. You can view a sample Portrait containing fictional individual physician data. If you are a family doctor practicing in BC you can sign up to receive your own individual prescribing Portrait.
The draft of this Therapeutics Letter was submitted for review to over 100 experts and primary care physicians in order to correct any inaccuracies and to ensure that the information is concise and relevant to clinicians.
The Therapeutics Initiative is funded by the BC Ministry of Health. The Therapeutics Initiative provides evidence-based advice about drug therapy, and is not responsible for formulating or adjudicating provincial drug policies.
ISSN: 2369-8691 (Online) || ISSN: 2369-8683 (Print)
International Society of Drug Bulletin LogoThe Therapeutics Letter is a member of the International Society of Drug Bulletins (ISDB), a world-wide network of independent drug bulletins that aims to promote international exchange of quality information on drugs and therapeutics.

References

  1. Therapeutics Initiative. Drugs of Choice in the Treatment of Hypertension (Part 1). Therapeutics Letter. Jun 1995; 7:1-2. https://www.ti.ubc.ca/1995/06/30/drugs-of-choice-in-the-treatment-of-hypertension-part-1/
  2. Therapeutics Initiative. The Answer: Thiazides First-line for Hypertension. Therapeutics Letter. Jan-Mar 2003; 47:1-2. https://www.ti.ubc.ca/2003/03/31/the-answer-thiazides-first-line-for-hypertension/
  3. Therapeutics Initiative. Using Best Evidence for the Management of Hypertension. Therapeutics Letter. May-Jun 2017; 106:1-2. https://www.ti.ubc.ca/2017/09/15/106-using-best-evidence-management-hypertension/
  4. Therapeutics Initiative Pharmacoepidemiology Group. Unpublished data, 2021 (manuscript in preparation).
  5. Diao D, Wright JM, Cundiff DK, Gueyffier F. Pharmacotherapy for mild hypertension. Cochrane Database of Systematic Reviews 2012, Issue 8. Art. No.: CD006742. DOI: 10.1002/14651858.CD006742.pub2
  6. Musini VM, Tejani AM, Bassett K, Puil L, Wright JM. Pharmacotherapy for hypertension in adults 60 years or older. Cochrane Database of Systematic Reviews 2019, Issue 6. Art. No.: CD000028. DOI: 10.1002/14651858.CD000028.pub3
  7. Musini VM, Nazer M, Bassett K, Wright JM. Blood pressure‐lowering efficacy of monotherapy with thiazide diuretics for primary hypertension. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD003824. DOI: 10.1002/14651858.CD003824.pub2
  8. Wright JM, Musini VM, Gill R. First‐line drugs for hypertension. Cochrane Database of Systematic Reviews 2018, Issue 4. Art. No.: CD001841. DOI: 10.1002/14651858.CD001841.pub3
  9. Davis BR. Major Cardiovascular Events in Hypertensive Patients Randomized to Doxazosin vs. Chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). Journal of the American Medical Association2000; 283(15):1967-75. DOI: 10.1001/jama.283.15.1967
  10. Furberg CD, Wright Jr. JT, Davis BR et al. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). Journal of the American Medical Association 2002; 288(23):2981-97. DOI: 10.1001/jama.288.23.2981
  11. Chen N, Zhou M, Yang M, et al. Calcium channel blockers versus other classes of drugs for hypertension. Cochrane Database of Systematic Reviews 2010, Issue 8. Art. No.: CD003654. DOI: 10.1002/14651858.CD003654.pub4
  12. Wiysonge CS, Bradley HA, Volmink J, et al. Beta-blockers for hypertension. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD002003. DOI: 10.1002/14651858.CD002003.pub5
  13. Chen YJ, Li LJ, Tang WL, et al. First-line drugs inhibiting the renin angiotensin system versus other first-line antihypertensive drug classes for hypertension. Cochrane Database of Systematic Reviews 2018, Issue 11. Art. No.: CD008170. DOI: 10.1002/14651858.CD008170.pub3
  14. Whelton PK, Barzilay J, Cushman WC, et al. Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2005; 165(12):1401-9. DOI: 10.1001/archinte.165.12.1401
  15. Suchard MA, Schuemie MJ, Krumholz HM, et al. Comprehensive comparative effectiveness and safety of first-line antihypertensive drug classes: a systematic, multinational, large-scale analysis. Lancet 2019; 394(10211):1816-26. DOI: 10.1016/S0140-6736(19)32317-7
  16. Li ECK, Heran BS, Wright JM. Angiotensin converting enzyme (ACE) inhibitors versus angiotensin receptor blockers for primary hypertension. Cochrane Database of Systematic Reviews 2014, Issue 8. Art. No.: CD009096. DOI: 10.1002/14651858.CD009096.pub2
  17. Vukadinović D, Böhm M. Response to “Clinical Factors and Rate of Cough During Angiotensin-Converting Enzyme Inhibitor Treatment”. Clin Pharmacol Ther 2019; 105(3):567. DOI: 10.1002/cpt.1217
  18. Vukadinović D, Vukadinović AN, Lavall D, et al. Rate of Cough During Treatment With Angiotensin-Converting Enzyme Inhibitors: A Meta-Analysis of Randomized Placebo-Controlled Trials. Clin Pharmacol Ther 2019; 105(3):652-60. DOI: 10.1002/cpt.1018
  19. Borghi C, Veronesi M. Cough and ACE Inhibitors: The Truth Beyond Placebo. Clin Pharmacol Ther 2019; 105(3):550-2. DOI: 10.1002/cpt.1040
  20. Heran BS, Wong MMY, Heran IK, Wright JM. Blood pressure lowering efficacy of angiotensin converting enzyme (ACE) inhibitors for primary hypertension. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD003823. DOI: 10.1002/14651858.CD003823.pub2
  21. Heran BS, Wong MMY, Heran IK, Wright JM. Blood pressure lowering efficacy of angiotensin receptor blockers for primary hypertension. Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD003822. DOI: 10.1002/14651858.CD003822.pub2
  22. Pharmacare Limited Drug Coverage Program. Angiotensin Receptor Blockers – Candesartan, 2021. https://www2.gov.bc.ca/gov/content/health/practitioner-professional-resources/pharmacare/prescribers/limited-coverage-drug-program/angiotensin-receptor-blockers-candesartan
  23. Yaphe H, Adekoya I, Steiner L, et al. Exploring the experiences of people in Ontario, Canada who have trouble affording medicines: a qualitative concept mapping study. BMJ Open2019; 9:e033933. DOI: 10.1136/bmjopen-2019-033933
  24. Eugene Leduc. Medi-Mouse A powerful little site for busy doctors. 2021.  http://www.medi-mouse.com/drugfind.php
5 Comments
  • Mariana
    Posted at 10:00h, 31 January Reply

    Thank you. Great article with valuable information for day-to-day practice!

  • Janine Farrell
    Posted at 00:17h, 10 February Reply

    In medical school and training we are taught to choose ARB for black patients. Is this considered in the above review? Thanks!

    • Alan Cassels @ TI
      Posted at 14:15h, 11 February Reply

      Hi Janine, Thank you for this question. This issue was not considered in our Therapeutics Letter because we did not find any placebo-controlled RCTs showing that 1st-line ACEIs have a diminished beneficial impact on morbidity and mortality in Black patients. Also, we did not find any subgroup analysis exploring this question. As our Therapeutics Letter clearly states, there are no RCTs comparing 1st-line ARBs with placebo in any patients, of any genetic ancestry. Our conclusions are based on currently available evidence. Not everything that is being taught in medical school and training, or included in clinical practice guidelines, is based on evidence. I hope this helps.
      Cheers, Alan Cassels, Deputy Editor, Therapeutics Letter, Therapeutics Initiative. alan.cassels@ubc.ca

  • Sadie Quintal
    Posted at 13:51h, 10 February Reply

    Curious if you would still use a thiazide as first line in a man or women with urinary frequency. Often older adults struggle with this, and adding in a diuretic may reduce quality of life.
    Sadie Quintal, Primary Care Network Pharmacist in Comox, BC, Canada

    • Jim Wright
      Posted at 12:25h, 11 February Reply

      In my experience people who take HCTZ daily do not complain of urinary frequency after the first few days. They achieve a new equilibrium. They also do not get volume depleted or have dry mouth as a side effect.
      Jim Wright, Coordinating Editor, Cochrane Hypertension Group, UBC

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