Chlorthalidone vs Hydrochlorothiazide What’s the difference?

Choosing Wisely Academic Detailing Conference

St. Andrews NB May 31, 2019

Pam McLean-Veysey

Dr. Allison Dysart

Disclosures

Pam McLean-Veysey, Team Leader Drug Evaluation Unit

DEU funded by the Drug Evaluation Alliance of NS. (DEANS).

DEU prepares Drug Evaluation Reports for the Atlantic Common

Drug Review (ACDR)

Has no conflicts of interest

Objectives

To present and critique the evidence behind the Canadian

Hypertension Guideline recommendation for the preferential use of

long acting thiazide like diuretics (e.g., chlorthalidone indapamide)

versus hydrochlorothiazide.

To discuss a case and application of this evidence to practice,

including safety considerations.

To present costs of various diuretic products

Outline

Case

General knowledge of evidence for thiazides

Statements from Hypertension Canada for role of longer acting thiazide diuretics (thiazide like) and evidence cited to support HC recommendations

Adverse effect considerations

International Guideline Recommendations

Cost considerations

Case Discussion

CASE HT

45 yo male, Caucasian, 200 pounds ( 91 Kg) 5’11” (1.8 m)

Hypertension diagnosed after several measurements and using automated office

BP 148/93; p 85 BPM.

Family history of hypertension (Mother and Father). Mother died of stroke.

No diabetes, coronary artery or kidney disease. Non-smoker

Self employed in IT

Patient wants to start treatment.

You generally start Hydrochlorothiazide 12.5 mg daily but…

What was it you read in latest Canadian guidelines about diuretics?

What we know about thiazides…

“Seek simplicity, and mistrust it.” Alfred North Whitehead

GENERAL “THIAZIDE” EVIDENCECochrane Systematic Review

First-line drugs for hypertension. Wright JM, et al 2018

First-line low-dose thiazides reduce all morbidity and mortality outcomes in adult patients with moderate to severe primary hypertension. High quality evidence (19 trials in 39,713 patients).

mortality (11.0% vs 9.8%)

total CVS (12.9% vs 9.0%)

stroke (6.2% vs 4.2%;)

coronary heart disease (3.9% vs 2.8%)

First line high-dose thiazides and first-line beta-blockers were inferior to first-line low-dose thiazides.

Wright JM, Musini VM, Gill R. First-line drugs for hypertension. Cochrane Database of Systematic Reviews 2018, Issue 4.

Magnitude of benefit from low dose diuretics Wright et al 2018

1.2% NNT 83

2% NNT 50

1.1% NNT 91

ARR NNT

3.9% NNT 26

ARI 6.8% NNH 15

Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension Cochrane Review Musini VM 2014

The maximal blood pressure-lowering effect of different thiazides is similar.

• 33 trials with a baseline blood pressure of 155/100 mmHg

• Thiazides reduced average blood BP vs placebo by

• 9 mmHg (95% CI 9 to 10)/4 mmHg (95% CI 3 to 4)

• High-quality evidence. (33 trials)

Adverse effects not well documented

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.

Chlorthalidone BP reduction Systolic: 12.0 mmHg (95% CI 10 to 14)Diastolic 4 mmHg (95% CI 3 to 5, low-quality evidence).

Hydrochlorothiazide Systolic 4-11 mmHg (95% CI 2 to 15)Diastolic 2-5 mmHg (95% CI 1 to 7) primarily moderate to high quality evidence.

Indapamide BP reduction Systolic 9 mmHg (95% CI 7 to 10)Diastolic 4 (95% CI 3 to 5) low-quality evidence.

Canadian Hypertension Guidelines

2018

What is different about long acting thiazides compared with HCTZ?

e.g., chlorthalidone, indapamide

http://guidelines.hypertension.ca/chep-resources/

Slides (English and French)

On-LineGuidelines

HT in pregnancy

BookletSlides

2020 HYPERTENSION HIGHLIGHTS BOOKLEThttp://guidelines.hypertension.ca/chep-resources/

Need more details…

http://guidelines.hypertension.ca/chep-resources

2018 Guideline: Indications for drug therapy for adults with

diastolic hypertension with or without systolic hypertension

Initial therapy should be with either monotherapy or single pill

combination (SPC).

Recommended monotherapy choices are:

Thiazide/thiazide-like diuretic (Grade A), with longer-acting

diuretics preferred (Grade B) (Not referenced in publication)

OR

β-blocker (in patients younger than 60 years; Grade B),

ACE inhibitor (in non-black patients; Grade B)

ARB (Grade B)

Long-acting calcium channel blocker (CCB) (Grade B).

http://guidelines.hypertension.ca/chep-resources

Indications for drug therapy for adults with

isolated systolic hypertension

Initial therapy should be

single-agent therapy with a thiazide/thiazide-like diuretic (Grade A),

a long-acting dihydropyridine CCB (Grade A),

ARB (Grade B)

• If there are adverse effects, another drug from this group should be

substituted.

Hypokalemia should be avoided in patients treated with thiazide/thiazide-

like diuretic monotherapy (Grade C).

No mention OF long-acting diuretic being “preferred” for ISH

http://guidelines.hypertension.ca/chep-resources

GRADING OF EVIDENCE IN GUIDELINES

https://www.clinicalkey.com/#!/content/playContent/1-s2.0-

S0828282X18301831?returnurl=https:%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0828282X18301831%3Fshowall%3Dtrue&referrer=&scrollTo=%23appsec1

Slide DeckHypertension Canada 2018

http://guidelines.hypertension.ca/chep-resources/

Not referenced in slide deck

… slide deck:

Reference Olde Engberink RH, et al. Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and

mortality: systematic review and meta-analysis. Hypertension. 2015; 65: 1033-1040.

Olde Engberink 2015

Meta analysis of 21 RCTs

> 1 year Follow-up;

>480,000 patient-years

Mean age 60-68

Thiazide Type = 17 studies vs. placebo or

other antihypertensive

9 of 17 studies included HCTZ

12.5 mg dose (1 study)

25, 50,100 mg (remaining studies)

2 HCTZ monotherapy; remaining

combination therapy

BP lowering effect placebo subtracted

TT -14.5/6.7 mm Hg

Thiazide Like = 8 studies vs. placebo or other antihypertensive

7 studies chlorthalidone 12.5 -25 mg

1 study indapamide 1.5 mg

All monotherapy vs placebo or active comparison

BP lowering -13.0/4.6 mm Hg

Limitations

No head to head TT vs TL studies

Quality ratings not reported

Reference Olde Engberink RH, et al. Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and

mortality: systematic review and meta-analysis. Hypertension. 2015; 65: 1033-1040.

2nd Reference in slide deck 24 hour ABPPareek AK, et al. Efficacy of low-dose chlorthalidone and hydrochlorothiazide as

assessed by 24-h ambulatory blood pressure monitoring. J Am Coll Cardiol. 2016; 67:

379-389.

Pareek AK, 2016

12 week, DB, DD, PG N=54, conducted in India

Patients: Stage 1 hypertension (BP 140-159/90-99 ); mean age 45, mostly non-

smokers. Excluded those with comorbid conditions.

Interventions/Comparisons

Chlorthalidone 6.25 mg daily N=16,

HCTZ 12.5 mg daily N=18

Controlled Release HCTZ N=20 (not available in Canada)

Outcome

Change in BP 24-h ambulatory blood pressure (ABP) monitoring and office based

BP.

Pareek Outcome -Office BPRed – HCTZ 12.5 mg; Grey Chlorthalidone 6.25 mg; blue – product not available

Office DBP Office SBP

Pareek AK, et al. Efficacy of low-dose chlorthalidone and hydrochlorothiazide as assessed by 24-h ambulatory blood pressure

monitoring. J Am Coll Cardiol. 2016; 67: 379-389.

Any missing pieces?

Additional evidence?

Potential harm?

Roush 2015 Network Meta Analysis (indirect comparisons)

N= 4 randomized trials; N=883 patients

Comparisons: HCTZ vs. indapamide or chlorthalidone

Outcome: Difference in SBP

INDAP vs. HCTZ: −5.1mm Hg (95% CI, −8.7 to −1.6); P=0.004

Chlorthalidone vs. HCTZ: −3.6 mm Hg (95% CI, −7.3 to 0.0); P=0.052

HCTZ vs INDAP no difference in metabolic adverse effects, or K+.

All trials lacked cardiovascular events as outcomes.

Roush et al Network Meta Analysis Head-to-Head Comparisons of Hydrochlorothiazide With Indapamide and Chlorthalidone:

Antihypertensive and Metabolic Effects Hypertension 2015;65: 1041-6.

Examples of trials with clinical outcomes

Thiazide–like diuretics

• Clinical trials

• SHEP 1991

• ALLHAT 2002

• MRFIT 2011

Chlorthalidone

(CTD)

• Clinical trials

• Post stroke (PATS 1995)

• PROGRESS 2001

• HYVET 2008 pts> 80 yo

Indapamide

Outcomes

• CTD vs usual care: decrease CV mortality SHEP 1991

• Fatal or nonfatal CHD: CTD= Amlod=Lisin; CTD> Lisin or amlod for some outcomes ALLHAT 2002

• CTD and HCTZ lower CVE vs neither; CTD> HCTZ. CTD lower K+ MRFIT 2011

Amlod= amlodipine; CTD= chlorthalidone; HCTZ = hydrochlorothiazide; Indap= indapamide; Lisin= Lisinopril; perind= perindopril; PBO= placebo

Outcomes

• Indap 2.5 mg decreased fatal & non fatal stroke post TIA or stroke vs placebo PATS 1995

• Perind + indap decreased stroke and MVE vs PBO Progress 2001

• Indap ± perind decreased fatal & nonfatal stroke, all cause death , CV death, heart failure elderly HYVET

Electrolyte abnormalities with diuretics

RCTS Chlorthalidone

ALLHAT

SHEP

Meta analysis – Chlorthalidone lower K than HCTZ and indapamide Musini 2014

Observational chlorthalidone vs HCTZ

MRFIT – statistically significant lower K+ and higher uric acid vs HCTZ Dorsh et al 2011

Dhalla 2013 – statistically significant lower K+ and Na+ vs HCTZ

Monitor electrolytes, especially in first 2 weeks of therapy.

7-8% required treatment for hypokalemia

Health Canada 2018

Prolonged use of HCTZ may be associated with a risk of non-

melanoma skin cancer at least 4 times the risk of not using HCTZ

Skin more sensitive to ultraviolet radiation and sunlight – i.e., sunburn more easily.

HC reviewed the best available evidence on the issue. Findings suggest an increased risk of non-melanoma skin cancer for patients who have used hydrochlorothiazide for more than three years.

Important to note that the studies reviewed had significant limitations.

lack of patient data on sun exposure and severity, and duration of high blood pressure.

Such data could help clarify the cause of the increased risk.

https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/68976a-eng.php

What are other guidelines saying?

ACC Results of Network Meta analysis

No class of medications (i.e., angiotensin-converting enzyme inhibitors, angiotensin-

receptor blockers, calcium channel blockers, or beta blockers) was significantly better

than thiazides and thiazide-like diuretics as a first-line therapy for any outcome.

UK - NICE 2011 (Guideline under revision but appears unchanged)

If diuretic treatment is to be initiated or changed,

offer a thiazide-like diuretic, in preference to a conventional thiazide diuretic such as bendroflumethiazide or hydrochlorothiazide.

chlorthalidone (12.5–25.0 mg once daily) or

indapamide (1.5 mg modified-release once daily or 2.5 mg once daily)

If already on bendroflumethiazide or hydrochlorothiazide and BP stable and well controlled, continue treatment with the bendroflumethiazide or hydrochlorothiazide.

Drug Cost Comparisons

Single entity thiazidesTHIAZIDES UNIT COST

( Pharmacare Prices)

Hydrochlorothiazide

12.5 mg 0.03

25 mg 0.02

50mg 0.02

100mg 0.12

Chlorthalidone

50 mg 0.13 – dose ¼ to ½ tablet

Indapamide

(e.g., Lozide and generics)

1.25 mg 0.08

2.5 mg 0.12

Combination Products

Thiazide-like Diuretics

Thiazide like diuretic

(strengths in mg)

Unit Cost

(Pharmacare)

Atenolol+ Chlorthalidone

(e.g. Tenoretic and generics)

50/25 0.32

100/25 0.52

Perindopril+ Indapamide

(e.g. Coversyl Plus and generics)

Low dose 2/0.625 Non benefit on NB Pharmacare

4/1.25 0.51

8 /2.5 0.57

Note: many combinations with hydrochlorothiazide (e.g. with ACEI or ARB

ranging from $0.20 to $0.69 per tablet depending on agent and strength

CASE HT

You have considered all the evidence on which the Guideline Statement was based … and then some!

You decide to

A. Prescribe chlorthalidone 50 mg ¼ tablet once daily

B. Prescribe HCTZ 12.5 mg once daily

C. Prescribe HCTZ 25 mg daily

D. Prescribe Indapamide 1.25 mg daily

E. Other

Discussion

Discussion and Wrap up

Can we answer the following questions?

Is there evidence to support a “preference” for long acting thiazides over HCTZ?

Is there high quality evidence to support a “preference”?

Do we need to monitor electrolytes – i.e., risk/ benefit?

Will we get more evidence?

Point of Care prospective study – w

Veterans Affairs Co-operative study #597 – completion April 15, 2023