Chlorthalidone vs 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 Guideline recommendation for the preferential use of long acting thiazide like (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 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 . . 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” EVIDENCE Cochrane 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

ARR NNT

1.2% NNT 83

2% NNT 50

1.1% NNT 91

3.9% NNT 26

ARI 6.8% NNH 15 -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

On-Line Guidelines HT in pregnancy Booklet Slides

Slides (English and French)

http://guidelines.hypertension.ca/chep-resources/ 2020 HYPERTENSION HIGHLIGHTS BOOKLET http://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 (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 Deck Hypertension 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 . Thiazide Like = 8 studies vs. other antihypertensive placebo or other antihypertensive . 7 studies chlorthalidone 12.5 -25 mg . 9 of 17 studies included HCTZ . 12.5 mg dose (1 study) . 1 study indapamide 1.5 mg . 25, 50,100 mg (remaining studies) . All monotherapy vs placebo or active comparison . 2 HCTZ monotherapy; remaining combination therapy . BP lowering -13.0/4.6 mm Hg . BP lowering effect placebo subtracted Limitations

 TT -14.5/6.7 mm Hg . 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 ABP 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. 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 BP Red – 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 Outcomes Chlorthalidone • SHEP 1991 • CTD vs usual care: decrease CV mortality SHEP 1991 • ALLHAT 2002 • Fatal or nonfatal CHD: CTD= Amlod=Lisin; CTD> (CTD) • MRFIT 2011 Lisin or amlod for some outcomes ALLHAT 2002 • CTD and HCTZ lower CVE vs neither; CTD> HCTZ. CTD lower K+ MRFIT 2011

• Clinical trials Outcomes • Post stroke (PATS 1995) • Indap 2.5 mg decreased fatal & non fatal stroke PATS 1995 Indapamide • PROGRESS 2001 post TIA or stroke vs placebo • Perind + indap decreased stroke and MVE vs PBO • HYVET 2008 pts> 80 yo Progress 2001 • Indap ± perind decreased fatal & nonfatal stroke, all cause death , CV death, elderly HYVET

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

 RCTS Chlorthalidone

 ALLHAT 7-8% required treatment for hypokalemia  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. 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 thiazides THIAZIDES 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 Unit Cost (strengths in mg) (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