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VOL 58: JUNE JUIN 2012 | Canadian Family Physician Le Médecin de famille canadien 653
Tools for Practice
Tools for Practice articles in Canadian Family Physician
(CFP) are adapted from articles published on the Alberta
College of Family Physicians (ACFP) website, summarizing
medical evidence with a focus on topical issues and
practice-modifying information. The ACFP summaries and
the series in CFP are coordinated by Dr G. Michael Allan, and
the summaries are co-authored by at least 1 practising family
physician. Feedback is welcome and can be sent to toolsforpractice@cfpc.ca.
Archived articles are available on the ACFP website: www.acfp.ca.
Best thiazide diuretic for hypertension
G. Michael Allan MD CCFP Noah Ivers MD CCFP Raj S. Padwal MD MSc FRCP(C)
Clinical question
Is hydrochlorothiazide (HCTZ) a better choice than
chlorthalidone for hypertension?
Evidence
No trials compare HCTZ with other thiazide diuretics in
terms of cardiovascular or mortality outcomes. We must
rely on less rigorous study designs and other outcomes.
• Chlorthalidone reduces systolic blood pressure (BP)
better than HCTZ at equivalent doses with similar
effects on potassium levels1:
-25 mg of chlorthalidone, compared with 50 mg of HCTZ,
providedsuperiorBPreductionoverall(12vs7mmHg
on24-hourmonitor)andatnighttime(13vs6mmHg).2
• Retrospective (and thusnot denitive) analysis of the
MRFITtrialfoundthatthechlorthalidone-basedregimen
reducedmortalitycomparedwiththe HCTZ-based regi-
men(hazardratio0.79,95%CI0.68to0.92,P =.0016).3
• Large trials using chlorthalidone (like ALLHAT4 and
SHEP5)havedemonstrated reductions incardiovascu-
larendpoints;evidenceforHCTZislessrobust.
• A n etw ork meta-analysis of 5 trials6 comparing
chlorthalidonewithother thiazidesdidnot nddiffer-
ences in cardiovascular outcomes. However,
-these were indirect comparisons and
-the “other thiazides” were not just HCTZ, as many review-
ers assumed: 2 were HCTZ combined with potassium
-
sparingdiuretics;1wasindapamide(notHCTZ).
Context
• Thiazidediureticsarerst-lineforhypertensivepatients
without compelling indications for alternate drugs.7-9
• Meta-analysis10 of19trialsfound24-hourBPwashigher
with 12.5- to 25-mg doses of HCTZ compared with other
antihypertensivedrugs (systolic BP 4.5 to 6.2 mm Hg
higher,diastolicBP2.9to6.7mmHghigher).
• Chlorthalidonehasalongerhalf-lifethanHCTZ(50to
60vs9to10hours),whichmightexplainthesuperior
BPcontrol,especiallyatnighttime.11
• TheadvantageofHCTZisitsavailabilityinmanycom-
binationpreparations,whichcanimproveadherence.12
• Indapamideisanotherthiazide-likediureticwithgood
evidence for reduction in cardiovascular end points as
rst- or second-line antihypertensive therapy.13,14
Bottom line
Available data suggest HCTZ is at best equal to and
very likely inferior to chlorthalidone for improving
BP and clinical outcomes. Consider chlorthalidone
when initiating thiazide diuretics for hypertension.
Implementation
Prescribe 12.5 mg of chlorthalidone daily; this can be
increasedto25mgdaily(quarterandhalfa50-mgtablet,
respectively).Higherdosestendtocausemoresideeffects
(including hypokalemia) but minimal further BP reduc-
tion.15Precautionsandbloodworkmonitoringforchlortha-
lidone are similarto those for HCTZ. Patients requiring
antihypertensivesshouldberemindedthatdietarysodium
restriction(<1500mg/d)16remainskeytoBPmanagement
—handoutscouldbegivenwitheachprescription.17
Dr AllanisAssociateProfessor intheDepartmentofFamilyMedicineatthe University
ofAlbertainEdmonton.Dr Ivers is a family physician at Women’s College Hospital
in Toronto, Ont. Dr PadwalisAssociateProfessor intheDivisionofGeneralInternal
MedicineattheUniversityof AlbertaandcontributestotheCHEPobesityguidelines.
The opinions expressedin thisToolsforPracticearticlearethoseofthe authorsanddo
notnecessarilymirrortheperspectiveandpolicyoftheAlbertaCollegeofFamilyPhysicians.
References
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14.PROGRESSCollaborativeGroup.Randomised trialofaperindopril-basedblood-
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17.HypertensionCanada.Beyond the salt shaker: get the facts on sodium.Markham,ON:
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... Loop diuretics (e.g., furosemide, torasemide, bumetanide, and azosemide may be preferred in patients with heart failure (especially torasemide) and when estimated glomerular filtration rate is < 30 ml/min. [208,227,228] Steroidal mineralocorticoid receptor antagonists (MRA) such as spironolactone are often characterized as potassium sparing; however, especially in the presence of renal disease, spironolactone may cause hyperkalemia. Nonsteroidal MRA are in development for treatment of hypertension, heart failure, and to reduce the progression of renal disease (i.e., diabetes nephropathy) [229]. ...
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BACKGROUND: Sustained elevated blood pressure, unresponsive to lifestyle measures, leads to a critically important clinical question: What class of drug to use first-line? This review answers that question. OBJECTIVES: Primary objective: To quantify the benefits and harms of the major first-line anti-hypertensive drug classes: thiazides, beta-blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, alpha-blockers, and angiotensin II receptor blockers (ARB). SEARCH STRATEGY: Electronic search of MEDLINE (Jan. 1966-June 2008), EMBASE, CINAHL, the Cochrane clinical trial register, using standard search strategy of the hypertension review group with additional terms. SELECTION CRITERIA: Randomized trials of at least one year duration comparing one of 6 major drug classes with a placebo or no treatment. More than 70% of people must have blood pressure > 140/90 mmHg at baseline. DATA COLLECTION AND ANALYSIS: The outcomes assessed were mortality, stroke, coronary heart disease (CHD), cardiovascular events (CVS), decrease in systolic and diastolic blood pressure, and withdrawals due to adverse drug effects. Risk ratio (RR) and a fixed effects model were used to combine outcomes across trials. MAIN RESULTS: Of 57 trials identified, 24 trials with 28 arms, including 58,040 patients met the inclusion criteria. Thiazides (19 RCTs) reduced mortality (RR 0.89, 95% CI 0.83, 0.96), stroke (RR 0.63, 95% CI 0.57, 0.71), CHD (RR 0.84, 95% CI 0.75, 0.95) and CVS (RR 0.70, 95% CI 0.66, 0.76). Low-dose thiazides (8 RCTs) reduced CHD (RR 0.72, 95% CI 0.61, 0.84), but high-dose thiazides (11 RCTs) did not (RR 1.01, 95% CI 0.85, 1.20). Beta-blockers (5 RCTs) reduced stroke (RR 0.83, 95% CI 0.72, 0.97) and CVS (RR 0.89, 95% CI 0.81, 0.98) but not CHD (RR 0.90, 95% CI 0.78, 1.03) or mortality (RR 0.96, 95% CI 0.86, 1.07). ACE inhibitors (3 RCTs) reduced mortality (RR 0.83, 95% CI 0.72-0.95), stroke (RR 0.65, 95% CI 0.52-0.82), CHD (RR 0.81, 95% CI 0.70-0.94) and CVS (RR 0.76, 95% CI 0.67-0.85). Calcium-channel blocker (1 RCT) reduced stroke (RR 0.58, 95% CI 0.41, 0.84) and CVS (RR 0.71, 95% CI 0.57, 0.87) but not CHD (RR 0.77 95% CI 0.55, 1.09) or mortality (RR 0.86 95% CI 0.68, 1.09). No RCTs were found for ARBs or alpha-blockers. AUTHORS' CONCLUSIONS: First-line low-dose thiazides reduce all morbidity and mortality outcomes. First-line ACE inhibitors and calcium channel blockers may be similarly effective but the evidence is less robust. First-line high-dose thiazides and first-line beta-blockers are inferior to first-line low-dose thiazides.
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Evidence supporting the benefit of low-dose thiazide-based regimens to reduce cardiovascular events is primarily derived from studies using chlorthalidone, yet low-dose hydrochlorothiazide (HCTZ) (12.5-25 mg) remains more widely prescribed. We sought to describe their comparative dose-response relationships for changes in systolic blood pressure (SBP) and potassium. PubMed from 1948 to July 2008 was systematically searched to identify clinical trials using either HCTZ or chlorthalidone monotherapies. A total of 108 clinical trials with HCTZ and 29 with chlorthalidone were analyzed. Data were pooled to evaluate the effects on SBP and potassium of both drugs throughout their respective dose-response curves. Equivalence analysis was performed for the clinically recommended low-dose range of 12.5-25 mg, grouped by study duration, using the two one-sided tests procedure described by Schuirmann. When evaluated on a milligram-per-milligram basis using pooled data, chlorthalidone generally produces slightly greater reductions in SBP and potassium than HCTZ. In the low-dose range of 12.5-25 mg, equivalence analysis reveals that the reductions in SBP are not equivalent between the two drugs, using upper and lower equivalence bounds of 4 mm Hg. Within the same dosing range, the mean changes in potassium were determined to be equivalent when upper and lower equivalence bounds of 0.29 mEq/l are used. Equivalence analysis using data from several studies suggests that the SBP reductions achieved with HCTZ and chlorthalidone cannot be considered equivalent within the low-dose range currently recommended. However, within this dosing range, reductions in potassium can be considered equivalent.
Article
Objective. - To assess the ability of antihypertensive drug treatment to reduce the risk of nonfatal and fatal (total) stroke in isolated systolic hypertension. Design. - Multicenter, randomized, double-blind, placebo-controlled. . Setting. - Community-based ambulatory population in tertiary care centers. Participants. - 4736 persons (1.06%) from 447 921 screenees aged 60 years and above were randomized (2365 to active treatment, 2371 to placebo). Systolic blood pressure ranged from 160 to 219 mm Hg and diastolic blood pressure was less than 90 mm Hg. Of the participants, 3161 were not receiving antihypertensive medication at initial contact, and 1575 were. The average systolic blood pressure was 170 mm Hg; average diastolic blood pressure, 77 mm Hg. The mean age was 72 years, 57% were women, and 14% were black. Interventions. - Participants were stratified by clinical center and by antihypertensive medication status at initial contact. For step 1 of the trial, dose 1 was chlorthalidone, 12.5 mg/d, or matching placebo; dose 2 was 25 mg/d. For step 2, dose 1 was atenolol, 25 mg/d, or matching placebo; dose 2 was 50 mg/d. Main Outcome Measures. - Primary. - Nonfatal and fatal (total) stroke. Secondary. - Cardiovascular and coronary morbidity and mortality, all-cause mortality, and quality of life measures. Results. - Average follow-up was 4.5 years. The 5-year average systolic blood pressure was 155 mm Hg for the placebo group and 143 mm Hg for the active treatment group, and the 5-year average diastolic blood pressure was 72 and 68 mm Hg, respectively. The 5-year incidence of total stroke was 5.2 per 100 participants for active treatment and 8.2 per 100 for placebo. The relative risk by proportional hazards regression analysis was 0.64 (P = .0003). For the secondary end point of clinical nonfatal myocardial infarction plus coronary death, the relative risk was 0.73. Major cardiovascular events were reduced (relative risk, 0.68). For deaths from all causes, the relative risk was 0.87. Conclusion. - In persons aged 60 years and over with isolated systolic hypertension, antihypertensive stepped-care drug treatment with low-dose chlorthalidone as step 1 medication reduced the incidence of total stroke by 36%, with 5-year absolute benefit of 30 events per 1 000 participants. Major cardiovascular events were reduced, with 5-year absolute benefit of 55 events per 1000.
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Background Blood pressure is a determinant of the risk of stroke among both hypertensive and non-hypertensive individuals with cerebrovascular disease. However, there is uncertainty about the efficacy and safety of blood-pressure-lowering treatments for many such patients. The perindopril protection against recurrent stroke study (PROGRESS) was designed to determine the effects of a blood-pressure-lowering regimen in hypertensive and non-hypertensive patients with a history of stroke or transient ischaemic attack. Methods 6105 individuals from 172 centres in Asia, Australasia, and Europe were randomly assigned active treatment (n = 3051) or placebo (n = 3054). Active treatment comprised a flexible regimen based on the angiotensin-converting-enzyme inhibitor perindopril (4 mg daily), with the addition of the diuretic indapamide at the discretion of treating physicians. The primary outcome was total stroke (fatal or non-fatal). Analysis was by intention to treat. Findings Over 4 years of follow up, active treatment reduced blood pressure by 9/4 mm Hg. 307 (10%) individuals assigned active treatment suffered a stroke, compared with 420 (14%) assigned placebo (relative risk reduction 28% [95% Cl 17-38], p < 0.0001). Active treatment also reduced the risk of total major vascular events (26% [16-34]). There were similar reductions in the risk of stroke in hypertensive and non-hypertensive subgroups (all p < 0.01). Combination therapy with perindopril plus indapamide reduced blood pressure by 12/5 mm Hg and stroke risk by 43% (30-54). Single-drug therapy reduced blood pressure by 5/3 mm Hg and produced no discernable reduction in the risk of stroke. Interpretation This blood-pressure-lowering regimen reduced the risk of stroke among both hypertensive and nonhypertensive individuals with a history of stroke or transient ischaemic attack. Combination therapy with perindopril and indapamide produced larger blood pressure reductions and larger risk reductions than did single drug therapy with perindopril alone. Treatment with these two agents should now be considered routinely for patients with a history of stroke or transient ischaemic attack, irrespective of their blood pressure.
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This review addresses the rationale for lowering dietary sodium intake in Canada and recent progress in this direction. Data from trials involving moderate and sustained (≥ 4 weeks) reductions in sodium intake demonstrated significant dose-dependent effects on blood pressure (BP) with larger effects in hypertensive individuals. Average sodium intake in Canada (approximately 3500 mg per day) is well above currently recommended intake targets (≤ 1500 mg per day). Approximately one-eighth of sodium intake is a natural component of food, with the remainder added by food industries (approximately 3/4) or at home (approximately 1/8). Modelling results suggest that lowering Canadian sodium intake to near recommended levels would reduce hypertension prevalence by approximately 30%, prevent approximately 15,500 cardiovascular events per year, and yield savings of approximately CAD$2 billion per year. These estimates do not include the potential additional benefits of long-term sodium restriction on BP, nor BP-independent effects. Actions to facilitate lower sodium intakes in Canada included dietary intake recommendations, mandatory nutritional labelling, a national intake survey, and recommendations of a Government-appointed Sodium Working Group (SWG) that aims to reduce Canadian intakes below 2300 mg per day by 2016. SWG strategies included voluntary reductions in sodium added by food industries, increased education, and research. However, the SWG has recently been disbanded, its responsibilities passed to a Federal-Provincial-Territorial Committee and to a new Food Regulatory Advisory Committee, and the significance for implementing recommendations is unclear. Health care practitioners are encouraged to promote lower dietary sodium intake in their patients and to advocate continued Government efforts to reduce the sodium content of the Canadian food supply.
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We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2011. The major guideline changes this year are: (1) a recommendation was made for using comparative risk analogies when communicating a patient's cardiovascular risk; (2) diagnostic testing issues for renal artery stenosis were discussed; (3) recommendations were added for the management of hypertension during the acute phase of stroke; (4) people with hypertension and diabetes are now considered high risk for cardiovascular events if they have elevated urinary albumin excretion, overt kidney disease, cardiovascular disease, or the presence of other cardiovascular risk factors; (5) the combination of an angiotensin-converting enzyme (ACE) inhibitor and a dihydropyridine calcium channel blocker (CCB) is preferred over the combination of an ACE inhibitor and a thiazide diuretic in persons with diabetes and hypertension; and (6) a recommendation was made to coordinate with pharmacists to improve antihypertensive medication adherence. We also discussed the recent analyses that examined the association between angiotensin II receptor blockers (ARBs) and cancer.
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There is significant controversy around whether chlorthalidone (CTD) is superior to hydrochlorothiazide (HCTZ) in hypertension management. The objective of this analysis was to evaluate the effects of CTD compared with HCTZ on cardiovascular event (CVE) rates. We performed a retrospective observational cohort study from the Multiple Risk Factor Intervention Trial data set from the National Heart, Lung, and Blood Institute. The Multiple Risk Factor Intervention Trial was a cardiovascular primary prevention trial where participants were men 35 to 57 years of age enrolled and followed beginning in 1973. CVEs were measured yearly, and time to event was assessed by Cox regression. Systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, potassium, glucose, and uric acid were measured yearly. The difference between groups was evaluated by repeated-measures mixed modeling, and each model was adjusted for predictors of each variable. CVEs were significantly lower in those on CTD (adjusted hazard ratio: 0.51 [95% CI: 0.43 to 0.61]; P<0.0001) and on HCTZ (adjusted hazard ratio: 0.65 [95% CI: 0.55 to 0.75]; P<0.0001) compared with those who took neither drug. When comparing the 2 drugs, CTD had significantly fewer CVEs compared with HCTZ (P=0.0016). CTD displayed significantly lower SBP (P<0.0001), lower total cholesterol (P<0.0001), lower low-density lipoprotein cholesterol (P=0.0009), lower potassium (P=0.0003), and higher uric acid (P<0.0001) over time compared with HCTZ. In conclusion, both HCTZ and CTD reduce CVEs compared with neither drug. When comparing both drugs, CTD reduces CVEs more than HCTZ, suggesting that CTD may be the preferred thiazide-type diuretic for hypertension in patients at high risk of CVEs.
Article
The purpose of this study was to evaluate the antihypertensive efficacy of hydrochlorothiazide (HCTZ) by ambulatory blood pressure (BP) monitoring. HCTZ is the most commonly prescribed antihypertensive drug worldwide. More than 97% of all HCTZ prescriptions are for 12.5 to 25 mg per day. The antihypertensive efficacy of HCTZ by ambulatory BP monitoring is less well defined. A systematic review was made using Medline, Cochrane, and Embase for all the randomized trials that assessed 24-h BP with HCTZ in comparison with other antihypertensive drugs. Fourteen studies of HCTZ dose 12.5 to 25 mg with 1,234 patients and 5 studies of HCTZ dose 50 mg with 229 patients fulfilled the inclusion criteria. The decrease in 24-h BP with HCTZ dose 12.5 to 25 mg was systolic 6.5 mm Hg (95% confidence interval: 5.3 to 7.7 mm Hg) and diastolic 4.5 mm Hg (95% confidence interval: 3.1 to 6.0 mm Hg) and was inferior compared with the 24-h BP reduction of angiotensin-converting enzyme inhibitors (mean BP reduction 12.9/7.7 mm Hg; p < 0.003), angiotensin-receptor blockers (mean BP reduction 13.3/7.8 mm Hg; p < 0.001), beta-blockers (mean BP reduction 11.2/8.5 mm Hg; p < 0.00001), and calcium antagonists (mean BP reduction 11.0/8.1 mm Hg; p < 0.05). There was no significant difference in both systolic (p = 0.30) and diastolic (p = 0.15) 24-h BP reduction between HCTZ 12.5 mg (5.7/3.3 mm Hg) and HCTZ 25 mg (7.6/5.4 mm Hg). However, with HCTZ 50 mg, the reduction in 24-h BP was significantly higher (12.0/5.4 mm Hg) and was comparable to that of other agents. The antihypertensive efficacy of HCTZ in its daily dose of 12.5 to 25 mg as measured in head-to-head studies by ambulatory BP measurement is consistently inferior to that of all other drug classes. Because outcome data at this dose are lacking, HCTZ is an inappropriate first-line drug for the treatment of hypertension.