Download low-dose diuretics for first-line and combined treatment of

LOW-TO-MODERATE DOSE DIURETICS FOR FIRST-LINE
AND COMBINED TREATMENT OF HYPERTENSION
June 22, 2005
The ALLHAT Dissemination Committee
And The National High Blood Pressure Education Program
Prepared by:
Curt D. Furberg, MD, PhD
Department of Public Health Sciences
Wake Forest University School of Medicine
Winston-Salem, NC 27157-1063
Phone: (336) 716-3730; FAX: (336) 716-0395
E-mail: [email protected]
Jeffrey Cutler, MD, MPH
National Heart, Lung, and Blood Institute Project Office
National Institutes of Health
Bethesda, Md 20892-7936
Phone: (301) 435-0413; FAX: (301) 480-1773
E-mail: [email protected]
Barry R. Davis, MD, PhD
Coordinating Center for Clinical Trials
University of Texas Houston Health Science Center, School of Public Health
Houston, TX 77030
Phone: 713-500-9515; FAX: 713-500-9530
E-mail: [email protected]
Jackson T. Wright, Jr., MD, PhD
General Clinical Research Center
University Hospitals of Cleveland
Cleveland OH 44106-6041
Phone: (216) 844-5174; FAX (216) 844-1522
E-mail: [email protected]
William Cushman, MD
Preventive Medicine
Memphis VAMC
Memphis TN 38104-2193
Phone: (901) 577-7357; FAX: (901) 577-7457
E-mail: [email protected]
-1-
The purpose of this document is to provide information documenting the superior efficacy and
safety of the use of low-to-moderate dose1 diuretics for the treatment of hypertension. The
Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure states (1):
“Thiazide-type diuretics should be used as initial therapy for most patients with
hypertension, either alone or in combination with 1 of the other classes (ACE
inhibitors, ARBs, β-blockers, CCBs) demonstrated to be beneficial in randomized
controlled outcome trials.”
Historical Background
Diuretics were introduced in the U.S. in the 1950’s. Two of the three subclasses, thiazide
(including thiazide-like) diuretics and potassium-sparing diuretics, are FDA-approved for
the indication of hypertension.
IMS data on the use of the five major classes of antihypertensive drugs between 1978 and
2002 show interesting trends (Fig. 1). In the late 70s and early 80s, diuretics and betablockers were the main antihypertensives on the market. The use of diuretics peaked in
the early 80s at about 60%. This market share dropped markedly over the next decade
but has largely stayed at around 20% over the past 10 years.
The beta-blockers (BBs) peaked at 30% during the early 80s and fell by half over the next
decade. Their use increased moderately during the latter part of the 90s. The ACE
inhibitors and calcium channel blockers (CCBs), introduced in the mid-80s, did very well
and passed the diuretics in the early 90s (just as ALLHAT was being planned). Since the
mid-90s, ACE inhibitors have seen a small increase, while the CCBs have dropped from
approximately 35% to 25%. Recently, the use of angiotensin receptor blockers (ARBs)
has grown rapidly.
Fig. 1 Hypertension Treatment by Drug Class in the U.S. 1978-2002
60
% of Treated Patients on Medication
1.
50
Calcium Channel Blockers
Beta Blockers
Diuretics
ACE Inhibitors
ARBs
Diuretics
40
30
ß-Blocker
20
ACE Inhibitors
10
CCBs
ARBs
0
1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002
Year
IMS Health NDTI, 1978-2002
1
* For the purposes of this paper, the terms “low-dose” and “low-to-moderate dose” will both
refer to 12.5mg - 25mg chlorthalidone or 25mg - 50mg hydrochlorothiazide. The term “lowdose” was used for this range in past studies; the term “low-to-moderate dose” is more accurately
used for this range today.
-2-
2.
FDA-approved Diuretics
Examples of available diuretic tablets or capsules (excluding the loop diuretics)
according to PDR 2004 (used alone or in combination in large clinical outcome trials):
a.
THIAZIDE & RELATED DIURETICS
• Chlorothiazide
• Chlorthalidone
• Hydrochlorothiazide
• Indapamide
b.
COMBINATION DIURETIC AND OTHER ANTIHYPERTENSIVE DRUG
• Combinations of thiazides and an ACE inhibitor, ARB, BB or CCB
c.
POTASSIUM-SPARING DIURETICS
• triamterene
• amiloride
d.
COMBINATION DIURETICS
• Combinations of HCTZ and a potassium-sparing diuretic
The JNC7 contains a more inclusive list of antihypertensive medications that are
marketed in the United States (1, 2).
3.
Diuretics and BP Lowering
In their recent review of 354 trials of BP-lowering drugs, Law and co-workers (3)
concluded that the major categories of drugs “gave similar BP reductions.” The mean
placebo-adjusted reduction was 9.1 mm Hg (95% CI 8.8 to 9.3) systolic and 5.5 mm Hg
(CI 5.4 to 5.7) diastolic at standard doses (“usual maintenance doses”)...”
According to available scientific evidence, diuretics are as effective as other classes of
antihypertensive drugs in lowering elevated BP compared to placebo.
The BP results by treatment group in ALLHAT, an active controlled trial, showed that
chlorthalidone (12.5-25 mg) as first-line therapy in a step-up treatment regimen was
superior compared to amlodipine (2.5-10 mg) and lisinopril (10-40 mg/day) in lowering
systolic BP and amlodipine was superior in lowering diastolic BP (Fig 2)(4).
-3-
Fig 2. ALLHAT - BP Results by Treatment Group and Annual Visit
BP Results by Treatment Group
Chlorthalidone
Amlodipine
Lisinopril
150
90
SBP
DBP
85
mm Hg BP
mm Hg BP
145
140
80
75
135
70
130
0
1
2
3
4
5
6
0
1
2
Years
3
Years
4
5
Compared to chlorthalidone:
Compared to chlorthalidone:
SBP significantly higher in the
amlodipine group (~1 mm Hg) and
the lisinopril group (~2 mm Hg).
DBP significantly lower in the
amlodipine group (~1 mm Hg).
6
As first-line drugs, thiazide diuretics are at least as effective in lowering elevated
BP as two of the most commonly used antihypertensive drugs (amlodipine and
lisinopril) in the U.S.
Most patients who are hypertensive will require two or more antihypertensive
medications to achieve their BP goals (1,2).
4.
Diuretics and Event Reduction: Placebo-Controlled Trials
Since the first VA Cooperative trial published in 1967, thiazide-type diuretics have been
the basis of antihypertensive therapy in the majority of placebo-controlled outcome trials
in which CVD events, including strokes, CHD, and HF have been reduced by BP
lowering. (2)
A comprehensive meta-analysis (5) of 18 placebo-controlled trials (one with a usual care
control) reported through 1995 compared three regimens: high-doses diuretics (> 50
mg/day), low-to-moderate dose diuretics and beta-blockers. No large, long-term placebocontrolled clinical trials evaluating CCBs or ACE inhibitors in hypertension had been
completed at that time. The risk reduction for stroke, coronary heart disease, congestive
heart failure and all-cause mortality are shown in Figure 3. Compared to low-tomoderate dose diuretics, high-dose diuretics were more effective in lowering the risks of
stroke and heart failure, but much less effective in reducing CHD risk. The likely
explanation for the difference in effect on CHD is discussed below (section 5). Betablockers were as effective as low-to-moderate dose diuretics in reducing stroke and heart
failure, but also less effective for CHD.
-4-
Risk reduction %
Fig. 3 Meta-analysis: Event Reduction in Placebo-Controlled Trials
Through 1995.
0
Stroke
CHD
Death
CHF
*
-20
-40
-60
*
*
*
*
*
*
*p<0.05
-80
low dose
diuretics
high dose
diuretics
Betablockers
*
Psaty et al., JAMA 1997;277:739
Placebo-controlled trials of a variety of diuretics demonstrated that this class of
drug is very effective in reducing the risk of cardiovascular complications. The
risk-benefit balance favors low-dose over high-dose diuretics.
An updated review published in the JAMA in May, 2003 used a new technique called
network meta-analysis (6). This review included both placebo-controlled and actively
controlled trials. The findings comparing low-to-moderate dose diuretics to placebo are
remarkable (Fig.4). The variety of diuretics tested markedly reduced the risk of all
cardiovascular complications - heart failure by 50%, stroke by 30%, combined
cardiovascular (CV) events by 25% and CHD and CV mortality each by 20%.
Fig 4. Network Meta-analysis - Major Outcomes: Low-Dose Diuretics vs. Placebo
Outcome
RR
95% CI
p
CHD
0.79
0.69-0.92
0.002
Heart failure
0.51
0.42-0.62
<0.001
Stroke
0.71
0.63-0.81
<0.001
CVD events
0.76
0.69-0.83
<0.001
CVD mortality 0.81
0.73-0.92
0.001
Total mortality 0.90
0.84-0.96
0.002
0.40
0.65
0.90
Low-dose diuretics better
1.15
1.40
Low-dose diuretics worse
Psaty et al., JAMA 2003;289:2534-2544
-5-
The findings from the network meta-analysis of the chlorthalidone trials and those of the
non-chlorthalidone trials are shown in Fig 5. (7)
Fig. 5. Comparisons of Low-Dose Chlorthalidone vs. Placebo (left panel) and
Low-Dose “Non-Chlorthalidone” vs. Placebo (right panel)
Clinical Effects of Diuretics by Type in
Placebo-Controlled Trials
Low-dose Chlorthalidone
Other Thiazide Diuretics
Direct Comparisons
Direct Comparisons
Outcome
RR (95% CI)
CHD
0.74 (0.58 - 0.95)
CHD
Stroke
0.64 (0.51 - 0.80)
Stroke
CHF
0.53 (0.39 - 0.73)
CHF
CVD events
0.70 (0.61 - 0.80)
CVD events
0.76 (0.66 - 0.87)
CVD mortality
0.80 (0.61 - 1.04)
CVD mortality
0.79 (0.65 - 0.94)
Total mortality
0.89 (0.75 - 1.06)
Total mortality
0.91 (0.79 - 1.03)
0.40
0.60
Low-dose chlorthalidone
better
0.80
1.00
1.20
Low-dose chlorthalidone
worse
Outcome
RR (95% CI)
0.72 (0.54 - 0.95)
0.71 (0.60 - 0.85)
No Data
0.40
0.60
0.80
Other thiazide diuretic
better
1.00
1.20
Other thiazide diuretic
worse
Psaty et al., JAMA 2004;292:43-4
The health benefit of low-dose diuretics is substantial and applies to thiazide
diuretics as a class.
5.
Diuretics and Event Reduction: Active-Controlled Trials
In the network meta-analysis (6), low-to-moderate dose diuretics were also compared to 5
other classes of antihypertensive drugs (Fig. 6). With 6 outcomes, there were a total of
30 comparisons and the conclusions are striking:
“...none of the other first-line treatment strategies -- -blockers, ACE
inhibitors, CCBs, α-blockers, and ARBs -- was significantly better than
low-dose diuretics for any major cardiovascular disease outcome. In 8 of
the 30 between-drug comparisons, however, low-dose diuretics were
significantly better than other treatments for the prevention of
cardiovascular disease health outcomes. Among nonsignificant, betweendrug comparisons, 13 favored low-dose diuretics, 5 favored other
therapies, and 4 were indifferent.” (6)
The asterisks placed after the specific outcomes in Figs. 6A-D indicate that the
comparator drugs were significantly better than placebo for that outcome.
-6-
Fig. 6A. Low-Dose Diuretics vs. Beta-Blockers
Outcome
RR
95% CI
p
CHD
0.87
0.74-1.03
0.10
Heart failure*
0.83
0.68-1.01
0.07
Stroke*
0.90
0.76-1.06
0.20
CVD events*
0.89
0.80-0.98
0.02
CVD mortality* 0.93
0.81-1.07
0.34
Total mortality* 0.99
0.91-1.07
0.73
0.40
0.65
0.90
1.15
Low-dose diuretics better
1.40
Low-dose diuretics worse
Fig. 6B. Low-Dose Diuretics vs. ACE Inhibitors
Outcome
RR
95% CI
p
CHD*
1.00
0.88-1.14
0.99
Heart failure*
0.88
0.80-0.96
0.01
Stroke*
0.86
0.77-0.97
0.01
CVD events*
0.94
0.89-1.00
0.04
CVD mortality* 0.93
0.85-1.02
0.13
Total mortality* 1.00
0.95-1.05
0.86
0.40
0.65
0.90
Low-dose diuretics better
1.15
1.40
Low-dose diuretics worse
Fig. 6C. Low-Dose Diuretics vs. CCBs
Outcome
RR
95% CI
p
CHD
0.89
0.76-1.01
0.07
Heart failure*
0.74
0.67-0.81
<0.001
Stroke*
1.02
0.91-1.14
0.74
CVD events*
0.94
0.89-1.00
0.045
CVD mortality* 0.95
0.87-1.04
0.29
Total mortality* 1.03
0.98-1.08
0.30
0.40
0.65
0.90
Low-dose diuretics better
-7-
1.15
1.40
Low-dose diuretics worse
Fig. 6D. Low-Dose Diuretics vs. ARBs
Outcome
RR
95% CI
p
CHD
0.83
0.59-1.16
0.28
Heart failure*
0.88
0.66-1.16
0.36
Stroke*
1.20
0.93-1.55
0.16
CVD events*
1.00
0.85-1.18
0.98
CVD mortality* 1.07
0.85-1.36
0.55
Total mortality* 1.09
0.96-1.22
0.18
0.40
0.65
0.90
Low-dose diuretics better
1.15
1.40
Low-dose diuretics worse
Fig. 6E. Low-Dose Diuretics vs. α-Blockers
Outcome
RR
95% CI
p
CHD
0.99
0.75-1.31
0.97
Heart failure
0.51
0.43-0.60
<0.001
Stroke
0.85
0.66-1.10
0.22
CVD events
0.84
0.75-0.93
0.001
CVD mortality 1.00
0.75-1.34
1.00
Total mortality 0.98
0.88-1.10
0.79
0.40
0.65
0.90
Low-dose diuretics better
1.15
1.40
Low-dose diuretics worse
“This network meta-analysis provides compelling evidence that low-dose
diuretics are the most effective first-line treatment for preventing the occurrence
of cardiovascular disease morbidity and mortality.”
6.
Diuretics and Event Reduction by Subgroup
The prevalence, severity, and impact of hypertension are increased in Blacks, who also
demonstrate somewhat reduced BP responses to monotherapy with β-blockers, ACE
inhibitors, or ARBs compared with diuretics or CCBs. These differential responses are
largely eliminated by drug combinations that include adequate doses of a diuretic.(1)
Four subgroup analyses were pre-specified in the ALLHAT protocol. For age (< 65 and
> 65), gender and diabetes status at baseline, there were no statistically significant
interactions. Thus, the overall amlodipine/chlorthalidone and lisinopril/chlorthalidone
-8-
findings also applied to these subgroups. In contrast, statistically significant interactions
were observed for two outcomes, stroke and combined CVD, when the data were
analyzed by race, black vs. non-black (Fig. 7). Chlorthalidone was superior to lisinopril
for the prevention of HF and combined CVD in non-blacks, and of stroke, HF, combined
CHD, and combined CVD in blacks. Only part of the excess risk in blacks can be
explained by a difference in achieved systolic BP. The chlorthalidone-lisinopril
difference in mean systolic BP at 5 years was > 4 mm Hg for blacks and < 1 mm Hg for
non-blacks.
Fig. 7. Clinical Outcomes - Blacks and Non-Blacks, Lisinopril vs.
Chlorthalidone
Clinical Outcomes –
Blacks and Non-Blacks
Lisinopril/Chlorthalidone
Blacks
Non-Blacks
NFMI + CHD Death
1.10 (0.94 - 1.28)
0.94 (0.85 - 1.05)
All-Cause Mortality
1.06 (0.95 - 1.18)
0.97 (0.89 - 1.06)
Combined CHD
1.15 (1.02 - 1.30)
1.01 (0.93 - 1.09)
Combined CVD *
1.19 (1.09 - 1.30)
1.06 (1.00 - 1.13)
Stroke *
1.40 (1.17 - 1.68)
1.00 (0.85 - 1.17)
Heart Failure
1.32 (1.11 - 1.58)
1.15 (1.01 - 1.30)
ESRD
1.29 (0.94 - 1.75)
0.93 (0.67 - 1.30)
0.50
Favors
Lisinopril
1
2
Favors
Chlorthalidone
0.50
Favors
Lisinopril
1
2
Favors
Chlorthalidone
* p for interaction <.05
Diuretics are more effective than ACE inhibitors in reducing the risk of HF and
combined CVD in non-black hypertensives and markedly more effective than ACE
inhibitors in reducing systolic BP and the risk of stroke, HF and combined CVD
and modestly more effective in reducing combined CHD in black hypertensives.
7.
Adverse Events
a.
Hypokalemia
Until the early 90s, thiazide diuretics were often prescribed in high doses, e.g.,
>50-100 mg/day of hydrochlorothiazide or chlorthalidone. Adverse drug
reactions, for example hypokalemia, were more common with these dosages.
Ventricular arrhythmias were also reported with high doses of diuretics.
Siscovick et al. (8) documented in a lead article in the New England Journal of
Medicine, a strong association between high doses of thiazide diuretics and
primary cardiac arrest. The addition of potassium-sparing diuretics or lower
doses of thiazide diuretics reduced the risk of cardiac arrest. This article
contributed to the shift from higher to lower doses of diuretics in the mid-90s, and
-9-
it may explain the findings that overall high-dose diuretics were not associated
with a reduced risk of CHD in the clinical trials. There are also other possible
explanations.
Hyperglycemia
It has been known for decades that thiazide diuretics are associated with an
increased risk of the development of diabetes. At lower doses of chlorthalidone
(12.5-25 mg/day), this effect is modest. Fig. 8 shows mean fasting glucose levels
among three subgroups of ALLHAT patients - non-diabetic, those with impaired
fasting glucose (IFG) and diabetics by treatment. The mean levels at baseline
were similar in all three subgroups. Among the non-diabetic participants, fasting
glucose increased in all treatment groups (Fig. 8A), probably due to weight gain
as well as aging. The increase was slightly higher (2-4 mg/dL) in the diuretic
group. In the IFG group, increases were seen in both the chlorthalidone and
amlodipine groups (Fig. 8B). No changes were observed in the lisinopril group.
Among the diabetics, fasting glucose decrease was slower in the chlorthalidone
group (Fig. 8C). At 4 years, there was no significant difference between the three
groups.
Fig. 8. Fasting Glucose Among Non-diabetics, Participants with IFG and
Diabetics by Treatment Group
A.
Fasting Glucose Among
Nondiabetic Participants
Fasting Glucose (mg/dL)
b.
140
130
120
110
* *
100
* *
Chlor
Amlod
Lisin
90
80
Baseline
2 Years
4 Years
Chlor
90.8
99.3
102.2
Amlod
90.7
96.3
99.5
Lisin
90.8
95.1
98.4
* p<.05 compared to chlorthalidone
1
- 10 -
B.
Fasting Glucose (mg/dL)
Fasting Glucose Among
Participants with IFG at Baseline
140.0
130.0
*
120.0
*
*
110.0
100.0
Chlor
Amlod
Lisin
90.0
80.0
Baseline
2 Years
4 Years
Chlor
116.0
129.7
129.2
Amlod
115.6
122.6
130.5
Lisin
116.2
115.8
116.7
* p<.05 compared to chlorthalidone
2
C.
Fasting Glucose (mg/dL)
Fasting Glucose Among
Diabetic Participants
180.0
170.0
160.0
150.0
140.0
130.0
120.0
110.0
100.0
90.0
80.0
* *
Chlor
Amlod
Lisin
Baseline
2 Years
4 Years
Chlor
169.0
170.6
163.8
Amlod
167.3
161.2
160.5
Lisin
168.3
161.2
159.0
* p<.05 compared to chlorthalidone
3
Thiazide diuretics have a modest diabetogenic effect. Metabolic ward studies in
the U.S. and long-term clinical studies reported mainly from Europe suggest that
the drug effect on fasting glucose is linked to the potassium level. Patients who
maintain normal plasma and body levels of potassium rarely develop diabetes.
Additionally, restoration of low potassium levels through supplementation or
withdrawal of the diuretic often leads to normalization of the glucose level. Thus,
drug-induced diabetes appears to be more reversible than “naturally occurring”
diabetes; sustained weight loss will probably reverse any early Type 2 diabetes.
- 11 -
c.
Outcomes by Diabetes Status
Thiazide diuretics, β-blociers, ACE inhibitors, ARBs, and CCBs are beneficial in
reducing CVD and stroke incidence in patients with diabetes.(1)
Stratified analysis of the ALLHAT database by diabetes status - Lisinopril vs.
chlorthalidone is shown in Fig. 9.
Fig. 9. Outcomes by Diabetes Status - Lisinopril vs. Chlorthalidone
Diabetics & Nondiabetics (History)
Lisinopril/Chlorthalidone
Relative Risk and 95% Confidence Intervals
Nondiabetics
Diabetics
CHD
1.00 (0.87, 1.14)
0.99 (0.88, 1.11)
Mortality
1.02 (0.91, 1.13)
1.00 (0.91, 1.09)
Stroke
1.07 (0.90, 1.28)
1.23 (1.05, 1.44)
Heart Failure
1.22 (1.05, 1.42)
1.20 (1.04, 1.38)
Combined CVD
1.08 (1.00, 1.17)
1.12 (1.04, 1.19)
ESRD
1.17 (0.87, 1.57)
1.05 (0.74, 1.48)
0.50
Favors
Lisinopril
1
2
Favors
Chlorthal
0.50
Favors
Lisinopril
1
There is no difference in treatment group effect by baseline history of diabetes.
2
Favors
Chlorthal
1
JAMA 2002;288:2981-2997
There is no evidence in ALLHAT that diuretics are less effective in diabetic than
non-diabetic hypertensives during an average follow-up of approximately 5 years.
d.
Effect of incident diabetes and changes in fasting glucose on endpoints
A recent paper from the SHEP study, in which mortality data were
evaluated for those with diabetes at baseline, those who developed
diabetes during the trial, and those who did not develop diabetes, indicated
that:
•
•
•
Chlorthalidone based treatment of hypertension results in
improved long-term outcomes.
The diabetes related to chlorthalidone therapy has better
prognosis than diabetes at baseline.
The benefit of chlorthalidone-based therapy on long-term total
and CV mortality is most pronounced in hypertensive patients
with diabetes.(10)
- 12 -
In addition, unpublished ALLHAT data show that change in fasting
glucose among those without baseline diabetes is not associated with CVD
outcomes during the trial.
8.
Diuretics and Drug Adherence
It is often stated that drug adherence with diuretics is a major issue. The source of this
claim is not known. It may be a carry-over from the time when high doses of thiazide
diuretics (>50-100 mg) were used. With low-to-moderate dose diuretics (initial doses of
12.5 or 25 mg), drug adherence is comparable to that of other classes of antihypertensive
drugs (2).
The drug adherence data from ALLHAT are robust. 15,255 high-risk hypertensives were
randomized to chlorthalidone and were followed for an average of almost 5 years. After
5 years, more than 80% of the patients stayed on chlorthalidone and/or a non-study
diuretic (Fig. 10). Adherence was not different than with amlodipine, but adherence was
better in the diuretic group than among those assigned to lisinopril.
Fig. 10. ALLHAT - Drug Adherence by Treatment Group and Annual Visit
Drug Adherence* by Treatment
100.0
80.0
60.0
%
40.0
20.0
0.0
1 Year
2 Years
3 Years
4 Years
5 Years
Chlor
87.1
84.7
82.7
80.8
80.5
Aml
87.6
85.2
83.2
80.5
80.4
Lis
82.4
78.4
77.1
74.8
72.6
*Step 1 or equivalent treatment
Long-term adherence to low-dose diuretics is as good as or better than for the
other commonly used antihypertensive agents.
- 13 -
9.
Drug Cost
The drug costs for thiazide diuretics to the patient (Costco, a large volume retailer) and
the average wholesale prices (AWP) are much lower compared to branded Norvasc and
generic lisinopril. Since chlorthalidone is approximately twice as potent as
hydrochlorothiazide, 25 mg chlorthalidone is equivalent to 50 mg hydrochlorothiazide.
(7)
Chlorthalidone (25 mg)
Hydrochlorothiazide (50 mg)
Norvasc (10 mg)
Zestril (40 mg)
Generic Lisinopril (40 mg)**
Patient cost / 30 tablets
(Costco.com 6/22/2005)(11)
$5.99 (MYL)*
$5.79 (QUA)
$60.47 (PFI)
$52.49 (ZEN)
$24.99
AWP / 100 tablets
(Redbook 2004 – lowest)(12)
$6.75 (Consol. Midland)
$2.75 (Consol. Midland)
$217.62 (PFI)
$178.03 (ZEN)
$77.00 (Major)
*Manufacturer listed in parentheses.
**Not available at Costco.com. Patient cost is from Drugstore.com, where the manufacturer is
not available.
Higher cost is justified if a drug offers added value. Chlorthalidone was unsurpassed as
first-line therapy by amlodipine and lisinopril in terms of BP reduction and drug
adherence over 5 years and compared favorably for reduction in risk of at least one
major CV complication of hypertension.
The cost of care is among the barriers that must be overcome to achieve goal BP.(1)
10.
ALLHAT Recommendations
Thiazide-type diuretics should be considered for nearly all patients with hypertension (2):
 Untreated patients
 Inadequately controlled patients on non-diuretic agent(s)
11.
JNC 7 (2003) (1,2)
“Thiazide-type diuretics should be used in drug treatment for most patients with
hypertension, either alone or combined with other drugs from other classes.” (8,9)


Most patients require two or more drugs to achieve BP control
Almost half of the patients have a compelling indication. These include heart failure,
post myocardial infarction, high CAD risk, diabetes, chronic kidney disease, and
recurrent stroke prevention.
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12.
References
1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr. JL, Jones
DW, Materson BJ, Oparil S, Wright Jr. JT, Roccella EJ and the National High Blood
Pressure Education Program Coordinating Committee. The Seventh Report of the
Joint National Committee on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure. The JNC 7 Report. JAMA 2003;289:2560-2572.
2. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr. JL, Jones
DW, Materson BJ, Oparil S, Wright Jr. JT, Roccella EJ and the National High Blood
Pressure Education Program Coordinating Committee. Seventh Report of the Joint
National Committee on Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure. Hypertension 2003;42:1206-1252.
3. Law MR, Wald NJ, Morris R, Jordan RE. Value of low dose combination treatment
with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ
2003;326:1427-1434.
4. The ALLHAT Officers and Coordinating for the ALLHAT Collaborative Research
Group. Major outcomes in high-risk hypertensive patients randomized to
angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic. The
ALLHAT and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
JAMA 2002;288:2981-2997.
5. Psaty BM, Smith NL, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR, Lemitre
RN, Wagner EH, Furberg CD. Health outcomes associated with antihypertensive
therapies used as first-line agents. JAMA 1997;277:739-745.
6. Psaty BM, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alderman MH, Weiss
NS. Health outcomes associated with various antihypertensive therapies used as firstline agents. A network meta-analysis. JAMA 2003;289:2534-2544.
7. Psaty BM, Lumley T, Furberg CD. Meta-analysis of health outcomes of
chlorthalidone-based versus non-chlorthalidone-based low-dose diuretic therapies.
[Research Letter]. JAMA 2004;292:43-44.
8. Siscovick DS, Raghunathan TE, Psaty BM, Koepsell TD, Wicklund KG, Lin X, Cobb
L, Rautaharju PM, Copass MK, Wagner EH. Diuretic therapy for hypertension and
the risk of primary cardiac arrest. N Engl J Med 1994;330;1852-1857.
9. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone.
Evidence supporting their interchangeability. Hypertension 2004;43:4-9.
10. Kostis JB, Wilson AC, Freudenberger RS, Cosgrove NM, Pressel SL, Davis BR for
the SHEP Collaborative Research Group. The Long-Term Effect of Diuretic-Based
Therapy on Fatal Outcomes in Subjects with Isolated Systolic Hypertension With and
Without Diabetes. Am J Cardiol 2005;95:29-35.
11. Costco.com, referenced June 22, 2005.
12. Drug Topics Red Book. Medical Economics Co., Inc., Montvale, NJ, 2004.
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