What’s the difference? - Dalhousie University...Chlorthalidone vs Hydrochlorothiazide What’s the...
Transcript of What’s the difference? - Dalhousie University...Chlorthalidone vs Hydrochlorothiazide What’s the...
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