Jackson T. Wright, Jr. MD, PhD
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1 DIFFERENTIAL EFFECTS OF BLOOD PRESSURE MEDICATIONS IN BLACK PATIENTS Jackson T. Wright, Jr. MD, PhD Professor of Medicine Program Director, WT Dahms MD Clinical Research Unit Clinical and Translational Science Collaborative Director, Clinical Hypertension Program University Hospitals Case Medical Center
2 Presenter Disclosure Information Jackson T. Wright, Jr, MD, PhD FINANCIAL DISCLOSURE: Research support: NIH Consulting: Novartis, Takada, Sanofi-Aventis, CVRx, NIH UNLABELED / UNAPPROVED USES DISCLOSURE: None
3 RACE IN MEDICINE Definition not standardized Usually defined by self-identification in research studies Unless participant questionnaire utilized or telephone survey, often have little assurance that all participants are actually asked the question Especially a problem for retrospective studies where method of ascertainment often not defined Racial differences usually confounded by SES which usually cannot be adequately adjusted for statistically However, racial differences are often sufficiently large that ambiguity in the definition of race is unlikely to account for these differences
4 RACE IN MEDICINE Some have suggested that race is a social construct, BUT it does have biological consequences Blacks have a higher rate of complications all of the major causes of death and hospitalization, including CVD, many cancers, infectious diseases, etc. A Black child born today has the life-expectancy of a White child born yrs ago and is twice as likely to die in the first year of life Racial differences often confused with genetic differences; however genetics is only one (and probably least important explanation)
5 RACE IN MEDICINE Clinically significant differences in disease presentation, pathophysiologic characteristics and response to treatment are evident by race and ethnicity Evaluation of disease differences in subsegments of the population is essential to understand the variation in pathophysiological mechanisms The study of population differences may provide valuable information on the disease in the affected population but is also likely to benefit the overall population
6 Increased Complications in Black Hypertensive Patients Cause of death in 30% African American males and 20% Black females Nonfatal strokes 30% than in whites Fatal strokes 80% than in whites Heart disease deaths 50% than in whites and occurs at younger age Kidney failure 400% than in whites (HTNrelated up to 2000% greater)
7 Prevalence of Hypertension, % Prevalence of HTN in African- and European- Origin Populations* *Age-adjusted. Cooper RS et al. BMC Medicine. 2005;3:2.
8 Percentage of Population Prevalence of HTN Among the African Diaspora St. Lucia Jamaica Maywood, IL Barbados Cameroon (rural) Nigeria Cameroon (urban) Average BMI Adapted from Cooper R, et al. Am J Public Health. 1997;87:166.
9 Development of Antihypertensive Therapies Effectiveness Tolerability 1940 s s 1970 s 1980 s 1990 s 2002 Peripheral sympatholytics Ganglion blockers Veratrum alkaloids Direct vasodilators Thiazide diuretics Central 2 agonists Calcium antagonistsnon DHPs -blockers -blockers Calcium antagonists- DHPs ACE inhibitors ARBs DRIs
10 % of Treated Patients on Medication Hypertension Treatment by Drug Class Diuretics ß-Blocker ACE Inhibitors CCBs ARBs Year IMS Health NDTI,
11 The reason to prescribe a treatment is that there is good evidence that it provides benefit NOT that there is insufficient evidence that it does not THIS IS PARTICULARLY TRUE IN POPULATIONS (LIKE BLACKS) AT HIGHEST RISK
12 RENIN ANGIOTENSIN SYSTEM (RAS) INHIBITORS Angiotensin converting enzyme (ACE)- Inhibitors Angiotensin Receptor Blockers (ARBs) Direct Renin Inhibitors (DRIs) (Beta Blockers)
13
14 HISTORY OF RAS INHIBITOR USE IN US RAS inhibitors leading class of CV medications since the early 80 s (> $7 billion/yr market) During much of their history on the market, industry avoided studies containing significant numbers of Blacks It more commonly generously supported programs and speakers aimed at promoting their use Lessened efficacy of β-blockers and ACEIs lowering BP in Black hypertensives not appreciated for 10 yrs after introduction Efficacy of ACEI on renal disease not available in Blacks for 8 yrs after proven effective in non-blks A-level evidence still missing for both β-blockers and ACEIs in Blacks for CHF
15 Patients with Response (%) Patients with Response (%) BP Response Rates in VA Trial by Race Older Blacks Older Whites DILT HCTZ CLON PRAZ ATEN PLAC CAPT ATEN DILT CAPT CLON HCTZ PRAZ PLAC Materson, B. J. et. al. N Engl J Med 1993;328:
16 Frequency Distribution SBP in Response to Quinapril in Black and White Participants (E. Mokwe et. al., HTN 2004;43:1) White s n = 2046 Black s n = 533
17 Decrement in Blood Pressure Mean Black-White Difference in mmhg (CI) 4.6 ( )/3.0 ( ) Ashwini R. Sehgal, Hypertension 2004; 43;
18 HOPE Trial Heart Outcomes Prevention Evaluation Ramipril Vs Placebo in 9,541 High CV Risk Participants Event(s) Risk Reduction CV deaths + MI + stroke 22% CV death 25% Nonfatal MI 20% Nonfatal stroke 32% Revascularization 15% CHF hospitalizations (#) 16% New-onset diabetes 30% HOPE Investigators. NEJM 2000; 342:145
19 Representation of Blacks in Major CVD/DM/Renal Clinical Trials Trial Year # Blacks (%) Trial Year # Blacks (%) ALLHAT ,133 (35.6%) SOLVD/Rx (15.3%) AASK ,094 (100%) TONE (24.0%) A-HeFT ,050 (100%) IDNT (14%) HDFP ,846 (44.3%) RENAAL (15%) SHEP (13.9%) HOPE 2000 ~175 (1.8%) VA Coop (53.8%) UKPDS (7.6%) VA Coop (41.3%) MDRD (7.9%) ACCOMPL ,416 (12%) ABCD (13.8%) HOT (3.1%) MRFIT (7.2%) LIFE (5.8%) ELITE (4.7%) VALUE (2.7%) CAPT-DM (7.3%) ASCOT 2005 ~960 (5%)* DREAM 2006 <5%
20 AASK Clinical Endpoint Analysis ACEI vs. CCB ACEI vs. BB Outcome % Risk 95 % Reduction 1 Confidence Interval % Risk Reduction 95 % Confidence Interval GFR event, 38% (+ 14 to + 55) ESRD or Death 2 p< % (+ 1 to + 38) p< GFR event or ESRD 3 40% (+ 13 to + 59) p<0.007 ESRD or Death 4 48% (+ 26 to + 65) p< % (- 1 to + 41) p< % (- 5 to + 40) p< 0.11 ESRD alone 5 59% (+ 34 to + 74) p< % (- 10 to + 45) p< ) Adjusted for baseline proteinuria, MAP,gender, Hx CHF and age; 2) 179 declining GFR, 84 ESRD, 77 death; 3) 170 declining GFR, 84 ESRD; 4) 171 ESRD, 79 deaths; events, deaths censored. Wright et al 2002; JAMA, 288:2421
21 Blood Pressure During Follow-up Ramipril Amlodipine Metoprolol Low MAP Goal Usual MAP Goal SBP (mm Hg) DBP (mm Hg) MAP (mm Hg) * * * 104 *Significantly different between two blood pressure goals P<0.01 Wright et al. JAMA. 2002;288:2421.
22 Cumulative Incidence (%) AASK Grp. Arch Intern Med 2008;168:832 Cumulative Incidence of Events (Doubling SCr, ESRD, or Death) Only Trial Mixed Trial and Post-Trial Composite Follow-up Time (Years) Only Post-Trial ESRD or Doubling SCr Death Number at Risk:
23 Cumulative Incidence (%) 60 Cumulative Incidence of Events in (1) ACEI with Low BP Group and (2) Non-ACEI with Usual BP Groups Only Trial Mixed Trial and Post-Trial Only Post-Trial Non-ACEI with Usual BP ACEI with Low BP 0 Number At Risk Usual BP & non-acei: Low BP and ACEI: Follow-Up Time (Years)
24 ALLHAT Hypertension Trial 42,418 high-risk hypertensive patients 90% previously treated 10% untreated STEP 1 AGENTS Chlorthalidone mg Amlodipine mg Lisinopril mg Doxazosin 1-8 mg Non-Blacks: 9,886 Blacks: 5,369 Non-Blacks: 5,844 Blacks: 3,210 Atenolol 28.0% STEP 2 AND 3 AGENTS (5 years) Clonidine 10.6% Reserpine 4.3% Hydralazine 10.9%
25 ALLHAT Blood Pressure at 5 Years by Race Chlorthalidone Amlodipine Lisinopril SBP mean (sd) DBP mean (sd) BP compared with chlorthalidone Black (15.8) (15.3) (19.7) (14.8) (14.6) (16.7) Black 77.4 (10.0) 76.3 (10.1) 78.0 (11.4) 74.4 (9.5) 73.6 (9.6) 74.1 (10.1) Black / -1.1* +4.1* / +0.6 Nonblack Nonblack Nonblack / -0.8* +0.9 / -0.3 Wright JT et al. JAMA 2005; 293:1593 *P<0.005
26 ALLHAT Black vs. Non-Black Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Intervals Nonfatal MI + CHD Death All-Cause Mortality Combined CHD Combined CVD Stroke End Stage Renal Disease Heart Failure Black 1.10 ( ) 1.06 ( ) 1.15 ( ) 1.19 ( ) 1.40 ( ) 1.30 ( ) 1.30 ( ) Non-Black 0.94 ( ) 0.97 ( ) 1.01 ( ) 1.06 ( ) 1.00 ( ) 0.93 ( ) 1.13 ( ) right JT et al JAMA 2005; Favors Lisinopril Favors Chlorthalidone Favors Lisinopril Favors Chlorthalidone
27 ALLHAT Summary Lisinopril vs. Amlodipine Non-Blacks Blacks SBP Control <+0.5 mmhg mmhg # antihypertensive drugs similar Combined CHD, Mortality, ESRD, cancer Stroke Combined CVD HF hospitalized angina PAD similar similar but men -11%, women +46% similar - 15% similar + 18% similar + 45% + 13% - 11% + 26% + 22% GI Bleed + 16% + 28% Angioedema > >> +favors amlodipine - favors lisinopril Leenen F,et.al. Hypertens 2006;48:1
28 ALLHAT ANGIOEDEMA Total Chlorthalidone 8 / 15, % Lisinopril 38 / 9, % Blacks 2 / 5,369 <0.1% 23 / 3, % Nonblacks 6 / 9, % 15 / 5, % P<0.001 P<0.001 P=0.002 There were 3 cases (<0.1%) of angioedema in the amlodipine group (comparison to chlorthalidone not significant).
29 Endpoint Rate LIFE: Primary Composite Endpoint Intention-to-Treat Atenolol Losartan Adjusted Risk Reduction 13 0%, p=0 021 Unadjusted Risk Reduction 14 6%, p= Study Day Study Month Losartan (n) Atenolol (n) B Dahlof et al. Lancet 2002;359:
30 Results of Primary Composite Endpoint in LIFE by Ethnic Group Results of primary composite end point by ethnic group. The dots represent the hazard ratio; dot size is proportional to the number of patients for each ethnic group, as shown to the left. The line through each dot corresponds to the 95% confidence interval. Results of primary composite end point by ethnic group in the U.s.: blacks versus nonblacks. Julius et al. J Am Coll Cardiol. 2004;43:
31 Figure 2 J Hypertens 2006;24:2163
32 ALLHAT Biochemical Results Fasting Glucose mg/dl Chlorthalidone Amlodipine Lisinopril Total mean (SD) Baseline (58.3) (57.0) (56.1) 4 Years (55.6) (52.0) (51.3)* Among baseline nondiabetics with baseline <126 mg/dl mean (SD) Baseline 93.1 (11.7) 93.0 (11.4) 93.3 (11.8) 4 Years (28.5) (27.7) (19.5)* Diabetes incidence (follow-up fasting glucose 126 mg/dl) 4 Years 11.6% 9.8%* 8.1%* *P<0.05 compared to chlorthalidone
33 DREAM RAS Blockade & New Diabetes (Diabetes - Not Primary Outcome) Study N (no DM) Active Control RRR ACE Inhibitors HOPE 5720 Ramipril 10 OD Placebo 34% PEACE 6174 Trandolapril Placebo 17% Overall Effect (HOPE, EUROPA, PEACE): 0.86 ( ) EUROPA 10716Dagenais Perindopril et al. Lancet 8 mg 2006;368:581 Placebo 3% D-SOLVD 291 Enalapril Placebo 74% Angiotensin Receptor Blockers SCOPE 4368 Candesartan 16/d Placebo 20% CHARM 5436 Candesartan 4-32/d Placebo 24%
34 Cardiovascular Mortality Rate per 10,000 Patient-Years Elevated SBP in Type 2 Diabetes Increases Cardiovascular Risk Elevated SBP increases risk of CV death almost twofold in diabetic vs nondiabetic patients Nondiabetic patients Diabetic patients < Stamler J et al. Diabetes Care. 1993;16: SBP (mm Hg) MRFIT 20
35 DREAM Metabolic Changes Baseline 4 Years A B A B Serum cholesterol, mg/dl Serum potassium, mmol/l Fasting serum glucose, mg/dl Serum creatinine, mg/dl
36 DREAM Summary of Chlorthalidone / Doxazosin Comparisons from ALLHAT Outcome RR (95% CI) p value CVD 1.20 ( ) <0.001 Heart failure 1.80 ( ) <0.001 Stroke 1.26 ( ) CHD 1.03 ( ) 0.62 All-cause mortality 1.03 ( ) 0.50 ALLHAT Collab Res Grp. Hypertens 2003; 42:239
37 ALLHAT Effect of Incident Diabetes on ALLHAT Endpoints* (Cox Regressions Beginning at 2 Years) Incident Diabetes / No Diabetes HR (95% CI) CHD 1.64 ( ) Stroke 1.61 ( ) CCVD 1.04 ( ) Heart failure 1.37 ( ) ESRD 2.86 ( ) Total mortality 1.31 ( ) * In patients without diabetes at baseline. Adjusted for age, treatment group, race, gender, smoking, baseline FG, baseline BMI, 2-year BP, 2- year serum potassium, 2-year atenolol & statin treatment. Barzilay J et al: Arch Intern Med. 2006;166:2191
38 ALLHAT Effect of Change in Fasting Glucose on ALLHAT Endpoints* (Cox Regressions Beginning at 2 Years) ΔFG to 2 Yr (per 10 mg/dl) HR (95% CI) CHD 1.02 ( ) Stroke 1.00 ( ) CCVD 1.00 ( ) Heart failure 1.02 ( ) ESRD 1.06 ( ) Total mortality 1.01 ( ) * In patients without diabetes at baseline. Adjusted for age, treatment group, race, gender, smoking, baseline FG, baseline BMI, 2-year serum potassium, 2-year atenolol atenolol & statin treatment. Barzilay J et al: Arch Intern Med. 2006;166:2191
39 ALLHAT Effect of Change in Fasting Glucose on ALLHAT Endpoints* (Cox Regressions Beginning at 2 Years) ΔFG to 2 Yr (per 10 mg/dl) HR (95% CI) P compared with chlorthalidone CHD Total 1.02 ( ) 0.44 Chlorthalidone 1.00 ( ) 0.94 Amlodipine 0.99 ( ) 0.87 Lisinopril 1.09 ( ) 0.03 CCVD Total 1.00 ( ) 0.84 Chlorthalidone 0.99 ( ) 0.56 Amlodipine 1.00 ( ) 0.95 Lisinopril 1.06 ( ) 0.04 * In patients without diabetes at baseline. Adjusted for age, treatment group, race, gender, smoking, baseline FG, baseline BMI, 2-year serum potassium, 2-year atenolol atenolol & statin treatment.
40 ALLHAT CHD Black With Metabolic Syndrome Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Intervals 6-year Rate per 100 Black 1.17 ( ) Without Metabolic Syndrome 1.07 ( ) All-cause Mortality 1.14 ( ) 1.02 ( ) Stroke 1.37 ( ) 1.31 ( ) Heart Failure 1.49 ( ) 1.09 ( ) Combined CVD 1.23 ( ) 1.09 ( ) ESRD 1.70 ( ) 0.75 ( ) Wright et al. Arch Int Med 2008; 168: Favors Lisinopril Favors Chlorthalidone Favors Lisinopril Favors Chlorthalidone
41 2010 Consensus Recommendations from the International Society of Hypertension in Blacks (ISHIB) A major recommendation of this consensus panel was the preference of the combination of a RAS-inhibitor with a calcium channel blocker over a RASinhibitor + a diuretic in Black hypertensives Flack J et al. Hypertens 2010; online
42 ACCOMPLISH Preliminary Results: Primary* and Secondary End Points End point Hazard ratio (95% CI) *Cardiovascular morbidity/mortality 0.80 ( ) Cardiovascular morbidity/mortality (excluding coronary revascularization) 0.79 ( ) Cardiovascular mortality 0.81 ( ) Nonfatal MI 0.81 ( ) Nonfatal stroke 0.87 ( ) Hospitalization for unstable angina 0.74 ( ) Coronary revascularization 0.85 ( ) Resuscitation for sudden death 1.75 ( ) Jamerson KA, et al. NEJM 2008;359:2117
43 Randomization ACCOMPLISH: Design Amlodipine 10 + benazepril 40 mg Free add-on antihypertensive agents* Amlodipine 5 mg + benazepril 40 mg Screening Amlodipine 5 mg + benazepril 20 mg Benazepril 20 mg + HCTZ 12.5 mg Benazepril 40 mg + HCTZ 12.5 mg Titrated to achieve BP<140/90 mmhg; <130/80 mmhg in patients with diabetes or renal insufficiency Benazepril 40 mg + HCTZ 25 mg Free add-on antihypertensive agents* 14 Days Day 1 Month 1 Month 2 Month 3 Year 5 *Beta blockers; alpha blockers; clonidine; (loop diuretics). Jamerson KA et al. Am J Hypertens. 2003;16(part2)193A
44 Thiazide-type Diuretic Doses in Hypertension Morbidity Trials Trial Drug Dose of Thiazide (mg/d) VA CSP M&M HCTZ 100 HDFP chlorthalidone MRC I bendroflumethiazide 10 HAPPHY bendroflumethiazide 5-10 HCTZ EWPHE HCTZ/triamterine MRC Elderly HCTZ/amiloride SHEP chlorthalidone ALLHAT chlorthalidone PATS indapamide 2.5 PROGRESS indapamide (+ACEI) 2.5 HYVET indapamide 1.5 ADVANCE BP indapamide (+ACEI) 1.25
45 Reduction in SBP (mmhg) Chlorthalidone vs HCTZ Estimated Dosing Equivalence based on Estimated Equivalent BP Reduction Current dosing of mg can be viewed as compromise between antihypertensive efficacy and kaliuresis HCTZ Chlor. 50 mg HCTZ ~ 25 to 37.5 mg chlorthalidone Carter BL, Ernst ME, Cohen JD. Hypertension 2004;43:4-9.
46 Pharmacokinetics HCTZ Chlorthalidone Vd 3-4 L/kg 40% protein bound 3-13 L/kg 75% protein bound 98% distribution into RBC Relative Potency* Oral Bioavail Onset (h) Peak (h) Half-life (h) 1 ~70% (single dose) 8-15 (longterm dosing) 1 ~65% (single dose) (longterm dosing) Duration (h) 12 (single dose) (longterm dosing) (single dose) (longterm dosing) Indapamide 20 ~93% 1-2 <2 14 Up to 36 * per most pharmacology texts; research suggests otherwise Carter BL, Ernst ME, Cohen JD. Hypertension 2004;43:4-9.
47 Perspective May be promoted by some to encourage use of CCBs over thiazide-type diuretics (each with RAS inhibitors). Calls for guidelines changes are premature. Dose of thiazide-type diuretic Doses of thiazide-type diuretics equivalent to <25-50 mg/day HCTZ have not been evaluated in clinical outcome trials demonstrating the benefits of HCTZ on CVD outcomes In ALLHAT, adequate dosage of diuretic was superior to both the CCB and ACE-inhibitor in preventing HF and unsurpassed for other CVDrenal outcomes, esp in Black patients 8/20/2008
48 Combination Therapy Needed to Achieve Target SBP Goals Trial/SBP Achieved UKPDS (144 mm Hg) RENAAL (141 mm Hg) ALLHAT (135 mm Hg) IDNT HOT (138 mm Hg) (138 mm Hg) INVEST (133 mm Hg) ABCD MDRD AASK (132 mm Hg) (132 mm Hg) (128 mm Hg) Updated from Bakris GL et al. Am J Kidney Dis. 2000;36: Number of BP meds
49 If most hypertensives (especially Black hypertensives) need 2-3 meds, which medications would these include CCB, DIURETICS, RAASI
50 RAS INHIBITOR USE IN HYPERTENSIVE BLACKS ACEIs/ARBs should be considered first in patients (including Blacks) with nephropathy (esp with proteinuria) and/or heart failure Available data suggest that RAS inhibitors are less effective in lowering BP in Black hypertensives in the absence of adequate doses of a diuretic or CCB (and in preventing clinical outcomes) ACEI also carry increased of angioedema, esp in Blacks In the absence of HF or CKD, particularly in Black hypertensives, beta blockers, ACEIs, and ARBs (and presently renin inhibitors) should be prescribed only in combination with thiazide-type diuretics or calcium channel blockers
51 The End
52 2010 Consensus Recommendations from the International Society of Hypertension in Blacks (ISHIB) Flack J et al. Hypertens 2010; online
53 POTENTIAL COSTS/RISKS OF LOWER THAN INDICATED BP TARGETS Increased cost of potentially unnecessary medications Increased risk of medication side effects Increased clinic visits if BP not at lower goal Increased monitoring required More complicated regimen that may jeopardize adherence to evidence-based treatment of other risk factors Potential increased risk of lower BP goals
54 Cumulative Incidence (%) TRIAL AND COHORT ALL PATIENTS Only Trial Mixed Trial and Cohort Only Cohort Low BP Usual BP Low BP vs. Usual BP Goal HR (95%CI) = 0.90 (0.77,1.07) p = Follow-Up Time (Months) AASK. NEJM 2010;363:10
55 Cumulative Incidence (%) TRIAL AND COHORT SUBGROUP WITH UP/Cr > Only Trial Mixed Trial and Cohort Only Cohort Low BP Usual BP Low BP vs. Usual BP Goal HR (95%CI) = 0.72 (0.57,0.92) p = Follow-Up Time (Months) AASK. NEJM 2010;363:10
56 Mean # Meds Intensive: Standard: Average after 1 st year: Standard vs Intensive, Delta = 14.2
57 ACCORD BP-Lowering: Reduction of SBP to <120 mmhg significantly Reduces the Rate of STROKE Outcome Intensive Therapy (n = 2363) Number of Events %/Year Standard Therapy (n = 2371) Number of Events %/Year Hazard Ratio (95% CI) Primary outcome* ( ) 0.20 Prespecified secondary outcomes Nonfatal MI ( ) 0.25 Any stroke ( ) 0.01 Nonfatal stroke ( ) 0.03 Death from any cause ( ) 0.55 Death from CV cause ( ) 0.74 Primary outcome plus revascularization or nonfatal heart disease ( ) 0.40 Major coronary disease event ( ) 0.50 Fatal or nonfatal heart failure ( ) 0.67 *Primary outcome: composite of nonfatal MI, nonfatal stroke, or death from CV causes Major coronary disease events included fatal coronary events, nonfatal MI, and unstable angina ACCORD: Action to Control Cardiovascular Risk in Diabetes Study P Value The ACCORD Study Group. N Engl J. Med. 2010;doi: /NEJMoa
58 Primary Outcome by Pre-defined Subgroups Also examined DBP tertiles (p=0.70) and number of screening meds (p=0.44) The ACCORD Study Group. N Engl J Med 2010;10
59 SUMMARY AND CONCLUSIONS 1/2-2/3 rd of Black hypertensives are above BP goal of 140/90 mmhg The evidence, including that in Black hypertensive patients, does not support BP goals substantially lower than 140/90 mmhg The increased cost in medications, clinic visits, monitoring, and potentially increased risk to achieve lower BP goals remains to be justified More definitive information should be forthcoming from the SPRINT trial In the meantime, efforts to control HTN in Blacks should focus on increasing the number of hypertensives controlled to <140/90 than on getting those already < 140/90 to lower goals
60 DIFFERENTIATION BETWEEN MARKETING AND EVIDENCE Who are you going to believe - me or the lying data?? Dr. Richard Pryor
61 Reduction in SBP (mmhg) Chlorthalidone vs HCTZ Estimated Dosing Equivalence based on Estimated Equivalent BP Reduction Current dosing of mg can be viewed as compromise between antihypertensive efficacy and kaliuresis HCTZ Chlor. 50 mg HCTZ ~ 25 to 37.5 mg chlorthalidone Carter BL, Ernst ME, Cohen JD. Hypertension 2004;43:4-9.
62 Direct and Indirect Comparisons of Chlorthalidone and Nonchlorthalidone Treatments for 6 Outcomes Based on Placebo-Controlled Trials RR (95% CI) Indirect Outcome Chlorthalidone Nonchlorthalidone Comparison, SI (95% Cl)* Coronary disease 0.74 ( ) 0.72 ( ) 1.03 ( ) Stroke 0.64 ( ) 0.71 ( ) 0.90 ( ) Heart failure 0.53 ( ) NA NA CVD events 0.70 ( ) 0.76 ( ) 0.92 ( ) CVD mortality 0.80 ( ) 0.79 ( ) 1.01 ( ) Total mortality 0.89 ( ) 0.91 ( ) 0.98 ( ) Psaty BM, JAMA 2004; 292:42
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