Hydrochlorothiazide vs Chlorthalidone
Replacement to the List
Peer Feedback:
“chlorthalidone - thiazde diuretic with evidence to supports its use, covered by ODB, supports evidence based care”
Literature Review Question:
Is chlorthalidone a more efficacious thiazide diuretic then hydrochlorothiazide?
Literature Search:
eCPS – Hypertension
ODB
Cochrane - Hydrochlorothiazide OR Chlorthalidone
Pubmed – “Hydrochlorothiazide AND Chlorthalidone AND meta-analysis/review”
Misconceptions about Treating HTN (2015)
Hydrochlorothiazide is one of the weakest antihypertensive agents available. In head-to-head comparison by 24-hour ambulatory monitoring, the antihypertensive efficacy was shown to be inferior to other drug classes, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and calcium channel blockers.5 Moreover, hydrochlorothiazide’s antihypertensive effect does not last 24 hours, thereby leaving the critical early morning hours unprotected.5-7 2.
Hydrochlorothiazide in its usual dose of 12.5 to 25 mg per day has never been shown to reduce the risk of myocardial infarction, stroke, or death.4 In fact, higher doses have been shown to increase the risk of sudden cardiac death in a dose-dependent fashion.8 3.
Even in combination with an angiotensin-converting enzyme inhibitor, hydrochlorothiazide has been shown to be inferior to a calcium channel blocker, such as amlodipine. In the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension trial, despite identical blood pressure reduction, the amlodipine-based combination reduced cardiovascular events by 20% better than the hydrochlorothiazide combination, a fact that led to a prematuretermination of the study.9 4.
All efficacy and outcome data for thiazides are solely derived from chlorthalidone and indapamide. Antihypertensive therapy based on both of these drugs have been shown repeatedly to decrease the risk of heart attack, stroke, heart failure, and even death in several prospective randomized trials, such as Systolic Hypertension in the Elderly Program, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), Hypertension in the Very Elderly Trial, and Perin-dopril Protection against Recurrent Stroke Study.10-13 However, both of these drugs, chlorthalidone and indapamide, are distinctly different from hydrochlorothiazide and have been documented to exert pleiotropic effects that may account for their superior efficacy.4,14
It is clear that hydrochlorothiazide should be avoided as the first-line therapy for hypertension. If a thiazide is deemed to be appropriate, our choice should be chlorthalidone or indapamide, as is stated in the British National Institute for Health and Clinical Excellence guidelines.15
Argulian, Edgar, Ehud Grossman, and Franz H. Messerli. "Misconceptions and Facts About Treating Hypertension."The American journal of medicine128.5 (2015): 450-455.
Cochrane (2014)
In 33 trials with a baseline blood pressure of 155/100 mmHg, hydrochlorothiazide lowered blood pressure based on dose, with doses of 6.25 mg, 12.5 mg, 25 mg and 50 mg/day lowering blood pressure compared to placebo by 4 mmHg (95% CI 2 to 6, moderatequality evidence)/2 mmHg (95% CI 1 to 4, moderate-quality evidence), 6 mmHg (95% CI 5 to 7, high-quality evidence)/3 mmHg (95% CI 3 to 4, high-quality evidence), 8 mmHg (95% CI 7 to 9, high-quality evidence)/3 mmHg (95% CI 3 to 4, high-quality evidence) and 11 mmHg (95% CI 6 to 15, low-quality evidence)/5 mmHg (95% CI 3 to 7, low-quality evidence), respectively.
Direct comparison of doses did not show evidence of dose dependence for blood pressure-lowering for any of the other thiazides for which RCT data were available: bendrofluazide, chlorthalidone, cyclopenthiazide, metolazone or indapamide.
In seven trials with a baseline blood pressure of 163/88 mmHg, chlorthalidone at doses of 12.5 mg to 75 mg/day reduced average blood pressure compared to placebo by 12.0 mmHg (95% CI 10 to 14, low-quality evidence)/4 mmHg (95% CI 3 to 5, low-quality evidence).
Thiazides reduced potassium, increased uric acid and increased total cholesterol and triglycerides. These effects were dose-related and were least for hydrochlorothiazide. Chlorthalidone increased serum glucose but the evidence was unclear for other thiazides. There is a high risk of bias in the metabolic data. This review does not provide a good assessment of the adverse effects of these drugs because there was a high risk of bias in the reporting of withdrawals due to adverse effects.
This systematic review shows that hydrochlorothiazide has a dose-related blood pressure-lowering effect. The mean blood pressurelowering effect over the dose range 6.25 mg, 12.5 mg, 25 mg and 50 mg/day is 4/2 mmHg, 6/3 mmHg, 8/3 mmHg and 11/5 mmHg, respectively. For other thiazide drugs, the lowest doses studied lowered blood pressure maximally and higher doses did not lower it more. Due to the greater effect on systolic than on diastolic blood pressure, thiazides lower pulse pressure by 4 mmHg to 6 mmHg. This exceeds the mean 3 mmHg pulse pressure reduction achieved by ACE inhibitors, ARBs and renin inhibitors, and the 2 mmHg pulse pressure reduction with non-selective beta-blockers as shown in other Cochrane reviews, which compared these antihypertensive drug classes with placebo and used similar inclusion/exclusion criteria. Thiazides did not increase withdrawals due to adverse effects in these short-term trials but there is a high risk of bias for that outcome. Thiazides reduced potassium, increased uric acid and increased total cholesterol and triglycerides.
Musini, Vijaya M., et al. "Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension."Cochrane Database Syst Rev5 (2014).
Is chlorthalidone better then HCTZ (2013)
· Randomized trial data show that CTDN has superior 24-h antihypertensive potency, particularly at night (7.1 mmHg difference in systolic BP).
· In an observational cohort study of MRFIT data, relative to HCTZ, CTDN was associated with lower development of LVH.
· In an observational cohort study of MRFIT data, when comparing the two drugs, CTDN had significantly fewer CVEs by about one-fifth, P = 0.002.
· In a network meta-analysis of randomized trials, relative to HCTZ, CTDN again reduced CVEs by about one-fifth, P < 0.0001; this result was validated in a second type of network analysis, in which CTDN was superior to HCTZ even after adjustment for changes in office systolic blood pressure produced by the two agents.
· Because HCTZ is so widely used, these results imply that millions of people are taking an inferior diuretic.
Table 2 summarizes the differences between CTDN and HCTZ, reflecting data on more than 60 000 participants. All available evidence supports the superiority of CTDN. Relative to HCTZ, the best estimate is that CTDN reduces CVEs by 21%. Recent guidelines are congruent with this evidence. Because of HCTZ’s widespread use, it is likely that millions of people are taking an inferior diuretic. Changes in prescribing practices and greater availability of CTDN-containing pharmaceutical preparations are needed to give our patients better care.
Roush, George C., Venkata Buddharaju, and Michael E. Ernst. "Is chlorthalidone better than hydrochlorothiazide in reducing cardiovascular events in hypertensives?."Current opinion in cardiology28.4 (2013): 426-432.
ODB Formulary (2015)
Generic Name / Brand Name, Strength & Dosage Form / MFR / Drug Benefit Price / Amount MOHLTC PaysHYDROCHLOROTHIAZIDE / Apo-Hydro (Not a Benefit)
12.5mg Tab / APX / N/A / N/A
HYDROCHLOROTHIAZIDE / Apo-Hydro 25
25mg Tab / APX / 0.0157 / 0.0157
HYDROCHLOROTHIAZIDE / Apo-Hydro 50
50mg Tab / APX / 0.0217 / 0.0217
CHLORTHALIDONE / Chlorthalidone
50mg Tab / AAP / 0.1242 / 0.1242
Accessed July 6, 2015
eCPS (2015)
Extensive evidence supports low-dose thiazide or related diuretics (e.g., indapamide) as first-line therapy for uncomplicated hypertension. They should generally be selected unless there are specific indications for other drugs (see Table 5). Diuretics are inexpensive and well tolerated. They have proven antihypertensive effectiveness in patients with isolated systolic hypertension, the elderly and black patients.
Diuretics can cause hypokalemia that may be associated with adverse cardiovascular outcomes. Consider alternative first-line agents in those with or strongly predisposed to a serious arrhythmia, for example, prolonged QT syndrome. Consider using a combination product to minimize the risk of hypokalemia (hydrochlorothiazide plus a potassium-sparing diuretic—spironolactone, amiloride or triamterene). Reserve the use of high doses (e.g., >25 mg/day of hydrochlorothiazide) for patients with resistant hypertension unresponsive to treatment with multiple drugs or secondary to renal impairment. Consider using a loop diuretic in patients with renal impairment. Diuretics may worsen dysglycemia, although cardiovascular outcomes in patients with diabetes who are treated with diuretics are similar to those treated with ACE inhibitors.
Table 6:Drugs Used for Hypertension
Class / Drug / Dosage / Adverse Effects / Drug Interactions / Comments / Cost /Diuretics / hydrochlorothiazide
generics / Initial: 12.5 mg/day
Usual: 25 mg/day
Once daily po / Hypotension, weakness, muscle cramps, impotence. Hypokalemia, hyponatremia, hyperuricemia, hyperglycemia, hyperlipidemia.
Rare: azotemia, blood dyscrasias, allergic reactions (potential cross sensitivity with other sulfonamide derivatives), photosensitivity, fatigue. / Li+excretion reduced (monitor Li+levels, adjust dose).
NSAIDs reduce hypotensive efficacy.
Diuretic-induced hypokalemia increases the risk of digoxin toxicity.
Reduced efficacy of antihyperglycemic agents.
. / · Particularly effective in ISH, the elderly and black patients.
Monitor SCr and K+.
Consider alternatives in patients with or predisposed to arrhythmias.
Can exacerbate gout and diabetes (biochemical abnormalities are less frequent at low doses).
Ineffective in patients with ClCr<30to 40 mL/min. / $
Diuretics / chlorthalidone
generics / Initial: 12.5 mg/day
Usual: 12.5–25 mg/day
Once daily po / · Lowest available tablet strength is 50 mg. Tablet (or “pill”) splitters, widely available in pharmacies, can be used to derive a dose of 12.5 mg (one quarter tablet) with reasonable accuracy.
·
· Particularly effective in ISH, the elderly and black patients.
Monitor SCr and K+.
Consider alternatives in patients with or predisposed to arrhythmias.
Can exacerbate gout and diabetes (biochemical abnormalities are less frequent at low doses).
Ineffective in patients with ClCr<30to 40 mL/min. / $
Legend: $<$20 $-$$ <20–40 $$ 20–40 $$$ 40–60 $$$$ 60–80
Cardiovascular Disorders: Hypertension; Norm R.C. R. C. Campbell, MD, FRCPC, Paul Gibson, MD, FRCPC, and Ross T. Tsuyuki, PharmD, MSc, FCSHP, FACC; Date of Revision: March 2015
(common and severe) / Initial dose; typical dose / Monitoring
hydrochlorothiazide / hypertension, heart failure / CI: anuria, severe sulphur allergy, symptomatic hyperuricemia, hyponatremia
DI: Digoxin, lithium, NSAID, steroids / increases calcium, uric acid, glucose, cholesterol, triglycerides, decreases sodium, potassium, magnesium and zinc / 12.5mg; 12.5-25mg one time a day / BP