Losartan hydrochlorothiazide

Losartan hydrochlorothiazide DEFAULT

Fixed combination of losartan and hydrochlorothiazide and reduction of risk of stroke

Vasc Health Risk Manag. 2007 Jun; 3(3): 299–305.

Published online 2007 Jun.

Sverre E Kjeldsen,1Paulette A Lyle,2Jorge R Kizer,3Suzanne Oparil,4Aud Høieggen,1 and Ingrid Os1

Sverre E Kjeldsen

1Ullevaal University Hospital, Oslo, Norway

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Paulette A Lyle

2Merck Research Laboratories, Horsham, PA, USA

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Jorge R Kizer

3Weill Medical College of Cornell University, New York, NY, USA

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Suzanne Oparil

4University of Alabama Birmingham, Birmingham, AL, USA

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Aud Høieggen

1Ullevaal University Hospital, Oslo, Norway

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Ingrid Os

1Ullevaal University Hospital, Oslo, Norway

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Author informationCopyright and License informationDisclaimer

1Ullevaal University Hospital, Oslo, Norway

2Merck Research Laboratories, Horsham, PA, USA

3Weill Medical College of Cornell University, New York, NY, USA

4University of Alabama Birmingham, Birmingham, AL, USA

Correspondence: Sverre E Kjeldsen Department of Cardiology, Ullevaal University Hospital, N-0407 Oslo, Norway Tel +47 22 11 91 00 Fax +47 22 11 91 81 Email [email protected] .e.s

Copyright © 2007 Dove Medical Press Limited. All rights reserved

This article has been cited by other articles in PMC.

Abstract

A fixed-dose combination of losartan/hydrochlorothiazide (HCTZ) therapy may be a logical choice for antihypertensive treatment, including for initial therapy in patients with blood pressure elevation >20/10 mmHg above treatment target. The renin–angiotensin– aldosterone–system-activating effect of hydrochlorothiazide augments the efficacy of blocking the angiotensin II type 1 (AT1) receptor with losartan. Some adverse effects associated with hydrochlorothiazide, including increased risk for new-onset diabetes mellitus, may be offset by losartan. Losartan was frequently administered with hydrochlorothiazide in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, in which there was a 25% risk reduction for stroke in the losartan-based compared with the atenolol-based treatment group. The efficacy, tolerability, and convenience of losartan/HCTZ combination therapy may increase patient compliance and lower risk for stroke, a devastating outcome in patients with hypertension.

Keywords: angiotensin receptor blocker, combination therapy, hydrochlorothiazide, hypertension, stroke

Introduction to management of stroke risk in hypertension

Stroke has enormous consequences for patients and healthcare systems worldwide (Goldstein et al 2006). Stroke has been reported to be the most common cardiovascular outcome in many (Kjeldsen et al 2001), but not all (ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group 2002), hypertension clinical trials. Stroke is the third leading cause of death in the US, with a yearly incidence of 700,000 in 2004 and a 1-month fatality rate of about 12% (Rosamond et al 2007). Approximately one third of survivors of stroke who have lived for at least 6 months post-stroke are dependent on others for activities of daily living (Warlow 1998). The estimated direct and indirect cost of stroke in the US in 2007 is US$62.7 billion (Rosamond et al 2007).

The predominant modifiable risk factor for stroke is hypertension (Wolf et al 1991; Straus et al 2002). Data from the National Health and Nutrition Examination Survey for 1999–2000 (NHANES, n = 4531) showed that the prevalence of hypertension in the US is increasing (Fields et al 2004). In 1999–2000, 31.3% of the NHANES population had hypertension (blood pressure ≥140/90 mmHg or treated with antihypertensive therapy) (Fields et al 2004), an increase from the 23.4% prevalence reported for 1989–1994 (Wolz et al 2000). This trend was attributed to increased obesity and an aging population (Fields et al 2004). In a report from the 1999–2000 NHANES population (n = 5448), 58.4% of the participants were treated (an increase of 6.0% from 1988–1991), and hypertension was controlled in 31.0% (an increase of 6.4% from 1988–1991) (Hajjar and Kotchen 2003). In European countries, the age- and sex-adjusted prevalence of hypertension (≥140/90 mmHg) is 44.2% (vs 27.6% in North America), with an average of 8% of patients with controlled hypertension (vs 23% in North America) (Wolf-Maier et al 2003).

Current guidelines recommend treatment goals of less than 140/90 mmHg for patients with uncomplicated hypertension and less than 130/80 mmHg for patients with diabetes, cardiac disease, or chronic kidney disease (Guidelines Committee 2003; Chobanian et al 2003). In clinical trials (ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group 2002) and clinical practice (Amer 2002), most patients require at least two medications to achieve goal blood pressure. Treatment guidelines for hypertension suggest the use of low-dose combination agents for the initial treatment of hypertension in some circumstances, such as blood pressure elevation greater than 20/10 mmHg over goal (Guidelines Committee 2003; Chobanian et al 2003).

Here we review the stroke results and losartan plus hydrochlorothiazide (HCTZ) use from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study and discuss the potential advantages of fixed-dose losartan/HCTZ therapy for stroke risk reduction.

The LIFE study

Thiazide diuretics and beta-blockers reduce stroke risk in patients with hypertension (Mulrow et al 2000; Psaty et al 2003). In the LIFE study, 9193 patients aged 55–80 with hypertension (160–200/95–110 mmHg) and electrocardiographic left ventricular hypertrophy were treated for a mean duration of 4.8 years with diuretics for 72% of the time in the losartan group and 70% of the time in the atenolol group (mean dose of HCTZ in each group was 20 mg) (Dahlöf et al 1997, 1998, 2004). An independent Endpoint Classification Committee adjudicated endpoints. Stroke (a component of the primary composite endpoint that also included cardiovascular death and myocardial infarction) was defined as a new-onset neurologic deficit of vascular origin lasting ≥24 hours or until death (Kizer et al 2005). Stroke classification was based on categories developed in the Framingham Study (Wolf et al 1992). Ischemic stroke was assigned in the absence of evidence of primary intracranial bleeding, whereas hemorrhagic stroke required evidence of hemorrhage (ie, bloody spinal fluid and/or blood on computed tomography), excluding cases of vessel rupture due to traumatic, neoplastic, or infectious processes. Ischemic stroke was further classified as embolic or athero-thrombotic. The diagnosis of embolic stroke was based on the presence of a source of embolus (eg, chronic or paroxysmal atrial fibrillation, rheumatic mitral stenosis, recent myocardial infarction, prosthetic heart valve, ulcerated carotid plaque) and consistent clinical features (eg, rapid onset and partial clearing, slightly bloody spinal fluid) or the occurrence of associated peripheral emboli. Atherothrombotic stroke was assigned when no evidence of an embolic etiology was present. Strokes for which a distinct etiology could not be ascertained were classified as other. Neurologic deficits were classified as depression of consciousness, disturbance of vision, paresis or paralysis of one or more extremities, sensory impairment, speech impairment, central cranial nerve dysfunction, memory defect, ataxia, and movement disorder.

The primary composite endpoint of cardiovascular death, stroke, or myocardial infarction was reduced by 13% (p = 0.021) in the losartan group, due primarily to a 25% reduction (p = 0.001) in stroke. Kizer et al (2005) examined the stroke results in the LIFE study in detail (Table 1). Losartan-based compared with atenolol-based treatment significantly lowered the risk of fatal stroke by 35% (hazard ratio [HR] = 0.65, 95% confidence interval [CI] 0.43–0.96, p = 0.032) and of atherothrombotic stroke by 27% (HR = 0.73, 95% CI 0.60–0.89, p = 0.002). The risk reductions for hemorrhagic and embolic stroke were 20% and 24%, respectively, but these were not statistically significant, possibly due to low numbers. The effect of losartan-based therapy on stroke incidence was independent of degree of electrocardiographic left ventricular hypertrophy, Framingham risk score, systolic blood pressure during follow-up, prevalent and incident atrial fibrillation or coronary heart disease, and treatment with aspirin, warfarin, or statins. The risk of recurrent stroke was significantly reduced in the losartan compared with the atenolol group (26 versus 46 patients with ≥2 incident strokes, p = 0.017) despite comparable use of antiplatelet and/or anticoagulant medications 30 days after the first stroke by 78% of patients in both groups. The number of neurologic deficits per stroke was similar in both treatment groups, but there were fewer strokes in the losartan group for virtually every level of stroke severity. The number needed to treat for 5 years to prevent one stroke in the losartan group as a whole was 54. The numbers needed to treat for 5 years to prevent one stroke for patients with cerebrovascular disease, isolated systolic hypertension, and atrial fibrillation who were treated with losartan were 25, 24, and 9, respectively.

Table 1

Stroke subtypes by treatment in the LIFE study

Stroke typeLosartan
(n = 4605)
Atenolol
(n = 4588)
Adjustedb hazard ratio
(95% Cl)
p-valueUnadjusted hazard ratio
(95% Cl)
p-value

n (%)Ratean (%)Ratea
Any stroke232 (5.0)10.8309 (6.7)14.50.75 (0.63–0.89)0.0010.74 (0.63–0.88)<0.001
Ischemic203 (4.4)9.2277 (6.0)12.60.73 (0.61–0.88)0.0010.73 (0.61–0.87)<0.001
Athero-thrombotic170 (3.7)7.9233 (5.1)10.90.73 (0.60–0.89)0.0020.72 (0.59–0.88)0.001
Embolic36 (0.8)1.648 (1.0)2.20.76 (0.50–1.18)0.220.75 (0.48–1.15)0.19
Hemorrhagic27 (0.6)1.234 (0.7)1.60.80 (0.48–1.32)0.380.79 (0.48–1.31)0.36
Other/Unclassifi ed5 (0.1)0.25 (0.1)0.21.02 (0.30–3.53)0.971.00 (0.29–3.44)0.99
Any fatal stroke40 (0.9)1.862 (1.4)2.80.65 (0.43–0.96)0.0320.64 (0.43–0.95)0.028

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Among black patients, greater stroke risk was observed in the losartan-based compared with the atenolol-based treatment group, which approached statistical significance (unadjusted HR = 1.99, 95% CI 1.00–3.98, p = 0.051) (Julius et al 2004a; Kizer et al 2005). Many American blacks appear to have low-renin, salt-sensitive hypertension (Wright 1988) and respond less to renin–angiotensin–aldosterone–system (RAAS) antihypertensive agents (Hall 1987). However, losartan-based and atenolol-based therapy resulted in comparable blood-pressure lowering in black and non-black subgroups in the LIFE study, and losartan was associated with greater left ventricular hypertrophy regression than was atenolol in both black and non-black patients (Julius et al 2004a). Adjustment for racial differences in baseline characteristics did not affect the endpoint results, and changes in laboratory measures during the trial were similar in the black and non-black subgroups (Julius et al 2004a). Thus, there is no apparent explanation for the endpoint results in black patients in the LIFE study (Julius et al 2004a).

Discussion

As early as 1993, it was shown that treatment with losartan at doses that did not affect systolic blood pressure decreased the risk of stroke in stroke-prone spontaneously hypertensive rats, suggesting that angiotensin II affects the pathophysiology of stroke and that losartan has a direct stroke benefit that is independent of blood pressure reduction (Stier et al 1993). These findings were tested in humans in the large, well-conducted LIFE study in which losartan-based antihypertensive therapy significantly decreased risk for stroke when compared with atenolol-based therapy in the context of comparable blood pressure reductions in both treatment groups (Dahlöf et al 2002). Several potential mechanisms that may be responsible for the beneficial effect of losartan in the LIFE study have been suggested (Dahlöf et al 2002; Mancia 2004; Devereux and Dahlöf 2007a): attenuation of arterial stiffness; inhibition of angiotensin II-induced endothelial dysfunction (Schiffrin et al 2000); inhibition of hypertrophy, fibrosis, and remodeling of cerebral arteries; beneficial effects on concomitant risk factors (albuminuria [Ibsen et al 2004], left ventricular hypertrophy [Devereux et al 2004; Kizer and Devereux 2006; Okin et al 2003], atrial fibrillation [Wachtell et al 2005], new-onset diabetes [Lindholm et al 2002]); inhibition of platelet aggregation; unique molecule-specific effects (eg, uric acid [Hoieggen et al 2004]); metabolite-specific anti-inflammatory activity; and neuro-protective effects (Sadoshima 2002).

Many patients require more than one antihypertensive agent for blood pressure control (ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group 2002; Amer 2002). Very frequently this includes HCTZ because of its antihypertensive efficacy, beneficial effects on stroke (Mulrow et al 2000; Psaty et al 2003), and low cost (Chobanian et al 2003). Combining two antihypertensive agents, such as HCTZ and an angiotensin receptor blocker (ARB), usually produces additive antihypertensive effects. In a meta-analysis of ARB monotherapy and combination therapy with HCTZ (Conlin et al 2000), decreases in systolic and diastolic blood pressures were comparable for the therapies studied (candesartan, irbesartan, losartan, valsartan). The antihypertensive efficacy of losartan plus HCTZ has been demonstrated in studies of initial/first-line use (Gradman et al 2002; Salerno et al 2004), in patients with inadequate blood pressure lowering with losartan monotherapy (Gleim et al 2006), and in the LIFE study (Devereux et al 2007). A fixed-dose combination of losartan/HCTZ therapy may be a logical choice for initial therapy in patients with blood pressure elevation <20/10 mmHg above treatment target (Chobanian et al 2003); this is the only fixed-dose combination therapy currently approved in the US for the treatment of severe hypertension.

Fixed-dose combinations of HCTZ with ARBs orangiotensin-converting enzyme inhibitors (ACEIs) have enhanced tolerability (Kjeldsen et al 2005a; Waeber 2003). Thiazide diuretics are most effective in patients who have salt- or volume-sensitive hypertension. Most patients respond to the salt depletion and volume contraction induced by a thiazide diuretic by releasing renin (Sassano et al 1989). Blood pressure is then more dependent on angiotensin II, and the blood pressure effect of diuretics is blunted. Addition of an agent that inhibits the RAAS further decreases blood pressure and generally has an additive antihypertensive effect. In order for any drug that blocks the RAAS to work optimally, high background activity of the system is necessary, a situation not typical in salt-sensitive hypertension and one that is enhanced by treatment with thiazide diuretics (Brunner et al 1980; Sassano et al 1989) and/or a low-salt diet (Anderson and Morgan 1990; MacGregor et al 1987; Navis et al 1987; Singer et al 1995).

There may be better tolerability with a 2-drug combination of higher doses of ARB/HCTZ compared with a multi-drug regimen of lower doses of less well-tolerated antihypertensive agents, leading to better patient compliance. Many of the undesirable side-effects of thiazide diuretics may be lessened by combination with a RAAS agent (Table 2). Most importantly, the tendency for thiazides to increase the risk for new-onset diabetes during long-term treatment may be offset by RAAS antihypertensive agents. Reductions in new-onset diabetes with ARBs have been noted with candesartan-based versus placebo-based therapy in the Study on Cognition and Prognosis in the Elderly (SCOPE) (Lithell et al 2003), losartan-based versus atenolol-based therapy in the LIFE study (Dahlöf et al 2002), and valsartan-based versus amlodipine-based therapy in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study (Julius et al 2004b). Reductions in new-onset diabetes with ACEIs have been noted with captopril versus diuretics and/or beta-blockers in the Captopril Prevention Project (CAPPP) (Hansson et al 1999) and ramipril versus placebo therapy in the Heart Outcomes Prevention Evaluation (HOPE) study (The Heart Outcomes Prevention Evaluation Study Investigators 2000).

Table 2

Actions of angiotensin receptor blockers and diuretics

ARBsDiureticsARBs+Diuretics
Antihypertensive effects↓↓
Renin-angiotensin system↓↓
Sympathetic nervous system↓↓
Potassium balance=
Uric acid↓ ==
Left ventricular hypertrophy↓↓↓ =↓↓

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Because of the tendency of RAAS antihypertensive agents to increase serum potassium, hypokalemia is likely to be less of a problem with diuretics when they are combined with RAAS agents (Weinberger 1985). The ARB candesartan did not produce the unfavorable lipid changes of HCTZ administered with or without beta-blocker therapy in the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE) study (Lindholm et al 2003). A unique quality of one ARB, losartan, is that it lowers serum uric acid (Elliott et al 2001). The increase in uric acid that was noted over the course of the LIFE study, perhaps partially due to concomitant HCTZ treatment, was ameliorated in the losartan-treated group (Hoieggen et al 2004). This appeared to explain 29% of the beneficial treatment effect of losartan on the primary composite endpoint of cardiovascular death, stroke, and myocardial infarction, raising the possibility that some of the beneficial effects of losartan in the LIFE study may not be generalizable to the ARB class. Uric acid level was an independent predictor of stroke in the LIFE study (Kizer et al 2004).

Reducing pill burden has been shown to enhance patient’s quality of life and satisfaction and acceptability, adherence, and uptake of medications (Dezii 2000; Wald and Law 2003; Chapman et al 2005; Sleight et al 2006). Increasing patient compliance with antihypertensive therapy is particularly important in patients at higher risk, such as those with diabetes, higher levels of blood pressure, and the metabolic syndrome. These patients need multiple medications for treatment of concurrent risk factors and conditions (Wald and Law 2003; Sleight et al 2006). Furthermore, combination therapy may be cost effective because of the potential for reduced drug costs (eg, fewer co-payments), better blood pressure control, improved compliance, and fewer discontinuations and switches between therapies (Ambrosioni 2001).

We believe that ARB/HCTZ combinations, such as losartan/HCTZ, may be superior to ACEI/HCTZ and other antihypertensive agent/HCTZ combinations because of 1) the better tolerability of ARBs and 2) available outcomes data. Although ramipril compared with placebo therapy significantly lowered the risk for stroke in patients with history of cardiovascular disease with or without hypertension in the HOPE study (The Heart Outcomes Prevention Evaluation Study Investigators 2000), these results that may have been influenced by blood pressure differences between the groups favoring ramipril as shown in an ambulatory blood pressure substudy (Svensson et al 2001). Data from clinical trials with ACEIs suggest a neutral effect on outcomes compared with traditional antihypertensive treatment for the same degree of blood-pressure lowering in patients with hypertension and high risk for cardiovascular disease (Kjeldsen et al 2005b; Williams 2005). Interestingly, in the perindopril protection against recurrent stroke study (PROGRESS), which compared single therapy with perindopril versus placebo or dual therapy with perindopril plus indapamide versus placebo in patients with a history of cerebrovascular disease, only combination treatment, not the ACEI alone, significantly reduced stroke incidence (PROGRESS Collaborative Group 2001). Data from clinical trials suggest that ARBs have benefits on non-coronary outcomes compared with traditional treatment; however, there have been some inconsistencies in the results of ARB trials due to problems with equalizing blood pressures in the treatment groups (Kjeldsen et al 2005b). Treatment with losartan in the LIFE study was associated with a significant risk reduction for stroke in the context of blood pressure reductions similar to those achieved in the active comparator (atenolol) group. Similar results were observed for stroke or transient ischemic attack in the Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention (MOSES) study of eprosartan-based or nitrendipine-based therapy (Schrader et al 2005). It remains to be seen whether comparable advantages will be seen with other ARBs compared with other classes of antihypertensive drugs in long-term outcome studies.

Stroke is a devastating outcome in patients with hypertension. The efficacy, tolerability, and convenience of losartan/HCTZ combination therapy may increase patient compliance and reduce risk for stroke.

References

  • The ALLHAT Officers and Coordinators 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 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) JAMA. 2002;288:2981–97. [PubMed] [Google Scholar]
  • Ambrosioni E. Pharmacoeconomics of hypertension management: the place of combination therapy. Pharmacoeconomics. 2001;19:337–47. [PubMed] [Google Scholar]
  • Amer J. Hypertension in high-risk patients: beware of the underuse of effective combination therapy (results of the PRATIK study) J Hypertens. 2002;20:779–84. [PubMed] [Google Scholar]
  • Anderson A, Morgan TO. Interaction of enalapril with sodium restriction, diuretics, and slow-channel calcium-blocking drugs. Nephron. 1990;55(Suppl 1):70–2. [PubMed] [Google Scholar]
  • Brunner HR, Gavras H, Waeber B. Enhancement of diuretics of the antihypertensive action of long-term angiotensin converting enzyme blockade. Clin Exp Hypertens. 1980;2:639–57. [PubMed] [Google Scholar]
  • Chapman RH, Benner JS, Petrilla AA, et al. Predictors of adherence with antihypertensive and lipid-lowering therapy. Arch Intern Med. 2005;165:1147–52. [PubMed] [Google Scholar]
  • Chobanian AV, Bakris GL, Black HR, et al. The JNC 7 Report. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA. 2003;289:2560–71. [PubMed] [Google Scholar]
  • Conlin PR, Spence JD, Williams B, et al. Angiotensin II antagonists for hypertension: are there differences in efficacy? Am J Hypertens. 2000;13:418–26. [PubMed] [Google Scholar]
  • Dahlöf B, Devereux R, de Faire U, et al. The Losartan Intervention For Endpoint Reduction (LIFE) in Hypertension Study. Rationale, design, and methods. Am J Hypertens. 1997;10:705–13. [PubMed] [Google Scholar]
  • Dahlöf B, Devereux RB, Julius S, et al. Characteristics of 9194 patients with left ventricular hypertrophy: The LIFE Study. Hypertension. 1998;32:989–97. [PubMed] [Google Scholar]
  • Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995–1003. [PubMed] [Google Scholar]
  • Dahlöf B, Devereux RB, Kjeldsen SE. Diuretics in the LIFE study. Lancet. 2004;364:413–4. [PubMed] [Google Scholar]
  • Devereux RB, Dahlöf B, Gerdts E, et al. Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Trial. Circulation. 2004;110:1456–62. [PubMed] [Google Scholar]
  • Devereux RB, de Faire U, Fyhrquist F, et al. Blood pressure reduction and antihypertensive medication use in the losartan intervention for endpoint reduction in hypertension (LIFE) study in patients with hypertension and left ventricular hypertrophy. Curr Med Res Opin. 2007;23:259–70. [PubMed] [Google Scholar]
  • Devereux RB, Dahlof B. Potential mechanisms of stroke benefit favoring losartan in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Curr Med Res Opin. 2007;23:443–457. [PubMed] [Google Scholar]
  • Dezii CM. A retrospective study of persistence with single-pill combination therapy vs. concurrent two-pill therapy in patients with hypertension. Manag Care. 2000;9(Suppl 9):2–6. [PubMed] [Google Scholar]
  • Elliott WJ, Calhoun DA, DeLucca PT, et al. Losartan versus valsartan in the treatment of patients with mild to moderate essential hypertension: data from a multicenter, randomized, double-blind, 12-week trial. Clin Ther. 2001;23:1166–79. [PubMed] [Google Scholar]
  • Fields LE, Burt VL, Cutler JA, et al. The burden of adult hypertension in the United States 1999 to 2000: A rising tide. Hypertension. 2004;44:398–404. [PubMed] [Google Scholar]
  • Gleim GW, Rubino J, Zhang H, et al. A randomized, double-blind trial of the antihypertensive efficacy and tolerability of once-daily losartan 100 mg/hydrochlorothiazide 12.5 mg combination compared with losartan 100 mg monotherapy in the treatment of mild-to-severe essential hypertension. Clin Ther. 2006;28:1639–48. [PubMed] [Google Scholar]
  • Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Stroke. 2006;37:1583–633. [PubMed] [Google Scholar]
  • Gradman AH, Brady WE, Gazdick LP, et al. A multicenter, randomized, double-blind, placebo-controlled, 8-week trial of the efficacy and tolerability of once-daily losartan 100 mg/hydrochlorothiazide 25 mg and losartan 50 mg/hydrochlorothiazide 12.5 mg in the treatment of moderate-to-severe essential hypertension. Clin Ther. 2002;24:1049–61. [PubMed] [Google Scholar]
  • Guidelines Committee. 2003 European Society of Hypertension- European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens. 2003;6:1011–53. [PubMed] [Google Scholar]
  • Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. JAMA. 2003;290:199–206. [PubMed] [Google Scholar]
  • Hall WD. Pharmacologic therapy of hypertension in blacks. J Clin Hypertens. 1987;3(Suppl 3):108S–113S. [PubMed] [Google Scholar]
  • Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999;353:611–6. [PubMed] [Google Scholar]
  • The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145–53. [PubMed] [Google Scholar]
  • Hoieggen A, Alderman MH, Kjeldsen SE, et al. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int. 2004;65:1041–9. [PubMed] [Google Scholar]
  • Ibsen H, Wachtell K, Olsen MH, et al. Does albuminuria predict cardiovascular outcome on treatment with losartan versus atenolol in hypertension with left ventricular hypertrophy? A LIFE substudy. J Hypertens. 2004;22:1805–11. [PubMed] [Google Scholar]
  • Julius S, Alderman MH, Beevers G, et al. Cardiovascular risk reduction in hypertensive black patients with left ventricular hypertrophy. The LIFE study. J Am Coll Cardiol. 2004a;43:1047–55. [PubMed] [Google Scholar]
  • Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004b;363:2022–31. [PubMed] [Google Scholar]
  • Kizer JR, Hoieggen A, Alderman MH, et al. Serum uric acid and ischemic stroke risk among hypertensive patients with left ventricular hypertrophy: The losartan intervention for endpoint reduction in hypertension (LIFE) study. J Am Coll Cardiol. 2004;43(5 suppl A):475A.[Google Scholar]
  • Kizer JR, Dahlöf B, Kjeldsen SE, et al. Stroke reduction in hypertensive adults with cardiac hypertrophy randomized to losartan versus atenolol: the Losartan Intervention For Endpoint reduction in hypertension study. Hypertension. 2005;45:46–52. [PubMed] [Google Scholar]
  • Kizer JR, Devereux RB. Regression of left ventricular hypertrophy: lodestar to stroke prevention in the treatment of hypertension? Am J Hypertens. 2006;19:439–444. [PubMed] [Google Scholar]
  • Kjeldsen SE, Julius S, Hedner T, et al. Stroke is more common than myocardial infarction in hypertension: analysis based on 11 major randomized intervention trials. Blood Press. 2001;10:190–2. [PubMed] [Google Scholar]
  • Kjeldsen SE, Os I, Hoieggen A, et al. Fixed-dose combinations in the management of hypertension: defining the place of angiotensin receptor antagonists and hydrochlorothiazide. Am J Cardiovasc Drugs. 2005a;5:17–22. [PubMed] [Google Scholar]
  • Kjeldsen SE, Lyle PA, Tershakovec AM, et al. Targeting the renin-angiotensin system for the reduction of cardiovascular outcomes in hypertension: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Expert Opin Emerging Drugs. 2005b;10:729–45. [PubMed] [Google Scholar]
  • Lindholm LH, Ibsen H, Borch-Johnsen K, et al. Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study. J Hypertens. 2002;20:1879–86. [PubMed] [Google Scholar]
  • Lindholm LH, Persson M, Alaupovic P, et al. Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study) J Hypertens. 2003;21:1563–74. [PubMed] [Google Scholar]
  • Lithell H, Hansson L, Skoog I, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003;21:875–86. [PubMed] [Google Scholar]
  • MacGregor GA, Markandu ND, Singer DR, et al. Moderate sodium restriction with angiotensin converting enzyme inhibitor in essential hypertension: a double blind study. BMJ. 1987;294:531–4.[PMC free article] [PubMed] [Google Scholar]
  • Mancia G. Prevention and treatment of stroke in patients with hypertension. Clin Ther. 2004;26:631–48. [PubMed] [Google Scholar]
  • Mulrow C, Lau J, Cornell J, et al. Pharmacotherapy for hypertension in the elderly. Cochrane Database Syst Rev. 2000:CD000028. [PubMed] [Google Scholar]
  • Navis G, de Jong PE, Donker A, et al. Moderate sodium restriction in hypertensive subjects: renal effects of ACE-inhibition. Kidney Int. 1987;31:815–9. [PubMed] [Google Scholar]
  • Okin PM, Devereux RB, Jern S, et al. Regression of electrocardiographic left ventricular hypertrophy by losartan versus atenolol: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Circulation. 2003;108:684–90. [PubMed] [Google Scholar]
  • PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:1033–41. [PubMed] [Google Scholar]
  • Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA. 2003;289:2534–44. [PubMed] [Google Scholar]
  • Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115:e69–171. [PubMed] [Google Scholar]
  • Sadoshima J. Novel AT(1)-receptor-independent functions of losartan. Circ Res. 2002;90:754–6. [PubMed] [Google Scholar]
  • Salerno CM, Demopoulos L, Mukherjee R, et al. Combination angiotensin receptor blocker/hydrochlorothiazide as initial therapy in the treatment of patients with severe hypertension. J Clin Hypertens (Greenwich) 2004;6:614–20.[PMC free article] [PubMed] [Google Scholar]
  • Sassano P, Chatellier G, Billaud E, et al. Comparison of increase in the enalapril dose and addition of hydrochlorothiazide as second-step treatment of hypertensive patients not controlled by enalapril alone. J Cardiovasc Pharmacol. 1989;13:314–9. [PubMed] [Google Scholar]
  • Schiffrin EL, Park JB, Intengan HD, et al. Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan. Circulation. 2000;101:1653–9. [PubMed] [Google Scholar]
  • Schrader J, Luders S, Kulschewski A, et al. Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention: principal results of a prospective randomized controlled study (MOSES) Stroke. 2005;36:1218–26. [PubMed] [Google Scholar]
  • Singer DR, Markandu ND, Cappuccio FP, et al. Reduction of salt intake during converting enzyme inhibitor treatment compared with addition of a thiazide. Hypertension. 1995;25:1042–4. [PubMed] [Google Scholar]
  • Sleight P, Pouleur H, Zannad F. Benefits, challenges, and registerability of the polypill. Eur Heart J. 2006;27:1651–6. [PubMed] [Google Scholar]
  • Stier CT, Adler LA, Levine S, et al. Stroke prevention by losartan in stroke-prone spontaneously hypertensive rats. J Hypertens. 1993;11:S37–42. [PubMed] [Google Scholar]
  • Straus SE, Majumdar SR, McAlister FA. New evidence for stroke prevention: scientific review. JAMA. 2002;288:1388–95. [PubMed] [Google Scholar]
  • Svensson P, de Faire U, Sleight P, Yusuf S, Ostergren J. Comparative effects of ramipril on ambulatory and office blood pressure: a HOPE substudy. Hypertension. 2001;38:E28–32. [PubMed] [Google Scholar]
  • Wachtell K, Hornestam B, Lehto M, et al. Cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation: The Losartan Intervention for End Point Reduction in Hypertension (LIFE) Study. J Am Coll Cardiol. 2005;45:705–11. [PubMed] [Google Scholar]
  • Waeber B. Combination therapy with ACE inhibitors/angiotensin II receptor antagonists and diuretics in hypertension. Expert Rev Cardiovasc Ther. 2003;1:43–50. [PubMed] [Google Scholar]
  • Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80% BMJ. 2003 326:1419. Erratum in BMJ, 2003. 327:586 and BMJ, 2006. 60:823. [PMC free article] [PubMed] [Google Scholar]
  • Warlow CP. Epidemiology of stroke. Lancet. 1998;352:S1–4. [PubMed] [Google Scholar]
  • Weinberger MH. Blood pressure and metabolic responses to hydrochlorothiazide, captopril, and the combination in black and white mild-to-moderate hypertensive patients. J Cardiovasc Pharmacol. 1985;7(Suppl 1):S52–5. [PubMed] [Google Scholar]
  • Williams B. Recent hypertension trials: implications and controversies. J Am Coll Cardiol. 2005;45:813–27. [PubMed] [Google Scholar]
  • Wolf PA, D’Agostino RB, Belanger AJ, et al. Probability of stroke: a risk profile from the Framingham Study. Stroke. 1991;22:312–8. [PubMed] [Google Scholar]
  • Wolf PA, D’Agostino RB, O’Neal A, et al. Secular trends in stroke incidence and mortality. The Framingham Study. Stroke. 1992;23:1551–5. [PubMed] [Google Scholar]
  • Wolf-Maier K, Cooper RS, Banegas JR, et al. Hypertension prevalence and blood pressure levels in 6 European countries, Canada, and the United States. JAMA. 2003;289:2363–9. [PubMed] [Google Scholar]
  • Wolz M, Cutler J, Roccella EJ, et al. Statement from the National High Blood Pressure Education Program: prevalence of hypertension. Am J Hypertens. 2000;13:103–4. [PubMed] [Google Scholar]
  • Wright JT., Jr Profile of systemic hypertension in black patients. Am J Cardiol. 1988;61:41H–45H. [PubMed] [Google Scholar]

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hydrochlorothiazide and losartan

Pronunciation: HYE droe KLOR oh THYE a zide and loe SAR tan

Brand: Hyzaar

Hyzaar

12.5 mg-100 mg, oval, white, imprinted with 745

Image of Hyzaar

Hyzaar

25 mg-100 mg, oval, yellow, imprinted with 747

Image of Hyzaar

Hydrochlorothiazide-Losartan

slide 3 of 25, Hydrochlorothiazide-Losartan,

12.5 mg-50 mg, oval, yellow, imprinted with 93, 7367

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Hydrochlorothiazide-Losartan

slide 4 of 25, Hydrochlorothiazide-Losartan,

25 mg-100 mg, oval, yellow, imprinted with 93, 7368

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Hydrochlorothiazide-Losartan

slide 5 of 25, Hydrochlorothiazide-Losartan,

12.5 mg-100 mg, oval, white, imprinted with 93, 7369

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Hydrochlorothiazide-Losartan

slide 6 of 25, Hydrochlorothiazide-Losartan,

12.5 mg-100 mg, round, white, imprinted with SZ 309

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Hydrochlorothiazide-Losartan

slide 7 of 25, Hydrochlorothiazide-Losartan,

12.5 mg-50 mg, round, white, imprinted with SZ 349

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Hydrochlorothiazide-Losartan

slide 8 of 25, Hydrochlorothiazide-Losartan,

25 mg-100 mg, round, white, imprinted with SZ 390

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Hydrochlorothiazide-Losartan

slide 9 of 25, Hydrochlorothiazide-Losartan,

12.5 mg-50 mg, oval, yellow, imprinted with 717

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Hydrochlorothiazide-Losartan

slide 10 of 25, Hydrochlorothiazide-Losartan,

12.5 mg-100 mg, oval, white, imprinted with 745

Image of Hydrochlorothiazide-Losartan

Hydrochlorothiazide-Losartan

slide 11 of 25, Hydrochlorothiazide-Losartan,

25 mg-100 mg, oval, yellow, imprinted with 747

Image of Hydrochlorothiazide-Losartan

Hydrochlorothiazide-Losartan

slide 12 of 25, Hydrochlorothiazide-Losartan,

12.5 mg-50 mg, oval, yellow, imprinted with 116

Image of Hydrochlorothiazide-Losartan

Hydrochlorothiazide-Losartan

slide 13 of 25, Hydrochlorothiazide-Losartan,

25 mg-100 mg, oval, yellow, imprinted with 1118

Image of Hydrochlorothiazide-Losartan

Hydrochlorothiazide-Losartan

slide 14 of 25, Hydrochlorothiazide-Losartan,

12.5 mg-100 mg, oval, white, imprinted with F, 74

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Hydrochlorothiazide-Losartan

slide 15 of 25, Hydrochlorothiazide-Losartan,

25 mg-100 mg, oval, yellow, imprinted with E, 49

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Hydrochlorothiazide-Losartan

slide 16 of 25, Hydrochlorothiazide-Losartan,

12.5 mg-50 mg, oval, yellow, imprinted with E, 48

Image of Hydrochlorothiazide-Losartan

Hydrochlorothiazide-Losartan

slide 17 of 25, Hydrochlorothiazide-Losartan,

12.5 mg-100 mg, oval, white, imprinted with LU, M42

Image of Hydrochlorothiazide-Losartan

Hydrochlorothiazide-Losartan

slide 18 of 25, Hydrochlorothiazide-Losartan,

12.5 mg-50 mg, oblong, white, imprinted with ZD18

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Hydrochlorothiazide-Losartan

slide 19 of 25, Hydrochlorothiazide-Losartan,

25 mg-100 mg, oblong, white, imprinted with ZD19

Image of Hydrochlorothiazide-Losartan

Hyzaar

12.5 mg-50 mg, oval, yellow, imprinted with 717

Image of Hyzaar

Hyzaar

12.5 mg-100 mg, oval, white, imprinted with 745

Image of Hyzaar

Hyzaar

25 mg-100 mg, oval, yellow, imprinted with 747

Image of Hyzaar

Hydrochlorothiazide-Losartan

slide 23 of 25, Hydrochlorothiazide-Losartan,

12.5 mg-100 mg, round, white, imprinted with 54, 931

Image of Hydrochlorothiazide-Losartan

Hydrochlorothiazide-Losartan

slide 24 of 25, Hydrochlorothiazide-Losartan,

25 mg-100 mg, round, yellow, imprinted with 54 557

Image of Hydrochlorothiazide-Losartan

Hydrochlorothiazide-Losartan

slide 25 of 25, Hydrochlorothiazide-Losartan,

12.5 mg-50 mg, round, yellow, imprinted with 54 717

Image of Hydrochlorothiazide-Losartan
Sours: https://www.cigna.com/individuals-families/health-wellness/hw/medications/hydrochlorothiazide-and-losartan-d03830a1
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hydrochlorothiazide and losartan

What is the most important information I should know about hydrochlorothiazide and losartan?

You should not use this medicine if you are unable to urinate.

Do not use if you are pregnant. Stop using the medicine and tell your doctor right away if you become pregnant.

If you have diabetes, do not use hydrochlorothiazide and losartan together with any medication that contains aliskiren (a blood pressure medicine).

What is hydrochlorothiazide and losartan?

Hydrochlorothiazide is a diuretic (water pill). Losartan is an angiotensin II receptor antagonist (sometimes called an ARB blocker).

Hydrochlorothiazide and losartan is a combination medicine used to treat high blood pressure (hypertension). It is also used to lower the risk of stroke in certain people with heart disease.

Hydrochlorothiazide and losartan may also be used for purposes not listed in this medication guide.

What should I discuss with my healthcare provider before taking hydrochlorothiazide and losartan?

You should not use this medicine if you are allergic to hydrochlorothiazide or losartan, if you are unable to urinate.

If you have diabetes, do not use hydrochlorothiazide and losartan together with any medication that contains aliskiren (a blood pressure medicine).

You may also need to avoid taking hydrochlorothiazide and losartan with aliskiren if you have kidney disease.

Tell your doctor if you have ever had:

  • lupus;
  • liver or kidney disease;
  • asthma or allergies;
  • diabetes;
  • gout;
  • congestive heart failure;
  • glaucoma;
  • low or high levels of potassium in your blood;
  • high cholesterol or triglyceride levels; or
  • an allergy to penicillin or sulfa drugs.

Do not use if you are pregnant. Stop using the medicine and tell your doctor right away if you become pregnant. Hydrochlorothiazide and losartan can cause injury or death to the unborn baby if you take the medicine during your second or third trimester.

You should not breastfeed while using this medicine.

Hydrochlorothiazide and losartan is not approved for use by anyone younger than 18 years old.

How should I take hydrochlorothiazide and losartan?

Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose. Use the medicine exactly as directed.

Your blood pressure will need to be checked often.

Call your doctor if you are sick with vomiting or diarrhea, or if you are sweating more than usual. You can easily become dehydrated while taking this medicine. This can lead to very low blood pressure, a serious electrolyte imbalance, or kidney failure.

If you need surgery or medical tests, tell the surgeon ahead of time that you are using hydrochlorothiazide and losartan.

If you have high blood pressure, keep using this medicine even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medicine for the rest of your life.

Store at room temperature away from moisture, heat, and light.

What happens if I miss a dose?

Take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking hydrochlorothiazide and losartan?

Do not use potassium supplements or salt substitutes, unless your doctor has told you to.

Drinking alcohol can further lower your blood pressure and may cause side effects.

Avoid becoming overheated or dehydrated during exercise, in hot weather, or by not drinking enough fluids.

What other drugs will affect hydrochlorothiazide and losartan?

If you also take cholestyramine or colestipol, take your hydrochlorothiazide and losartan dose 4 hours before or 4 to 6 hours after you take the other medicine.

Tell your doctor about all your other medicines, especially:

  • a diuretic or "water pill";
  • other blood pressure medications;
  • lithium; or
  • NSAIDs (nonsteroidal anti-inflammatory drugs) --aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others.

This list is not complete. Other drugs may affect hydrochlorothiazide and losartan, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible drug interactions are listed here.

Where can I get more information?

Your pharmacist can provide more information about hydrochlorothiazide and losartan.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

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Blood pressure medication recalled

Losartan/hydrochlorothiazide combination vs. high-dose losartan in patients with morning hypertension—a prospective, randomized, open-labeled, parallel-group, multicenter trial

Abstract

The treatment of morning hypertension has not been established. We compared the efficacy and safety of a losartan/hydrochlorothiazide (HCTZ) combination and high-dose losartan in patients with morning hypertension. A prospective, randomized, open-labeled, parallel-group, multicenter trial enrolled 216 treated outpatients with morning hypertension evaluated by home blood pressure (BP) self-measurement. Patients were randomly assigned to receive a combination therapy of 50 mg losartan and 12.5 mg HCTZ (n=109) or a high-dose therapy with 100 mg losartan (n=107), each of which were administered once every morning. Primary efficacy end points were morning systolic BP (SBP) level and target BP achievement rate after 3 months of treatment. At baseline, BP levels were similar between the two therapy groups. Morning SBP was reduced from 150.3±10.1 to 131.5±11.5 mm Hg by combination therapy (P<0.001) and from 151.0±9.3 to 142.5±13.6 mm Hg by high-dose therapy (P<0.001). The morning SBP reduction was greater in the combination therapy group than in the high-dose therapy group (P<0.001). Combination therapy decreased evening SBP from 141.6±13.3 to 125.3±13.1 mm Hg (P<0.001), and high-dose therapy decreased evening SBP from 138.9±9.9 to 131.4±13.2 mm Hg (P<0.01). Although both therapies improved target BP achievement rates in the morning and evening (P<0.001 for both), combination therapy increased the achievement rates more than high-dose therapy (P<0.001 and P<0.05, respectively). In clinic measurements, combination therapy was superior to high-dose therapy in reducing SBP and improving the achievement rate (P<0.001 and P<0.01, respectively). Combination therapy decreased urine albumin excretion (P<0.05) whereas high-dose therapy reduced serum uric acid. Both therapies indicated strong adherence and few adverse effects (P<0.001). In conclusion, losartan/HCTZ combination therapy was more effective for controlling morning hypertension and reducing urine albumin than high-dose losartan.

Introduction

Cardiovascular events, such as stroke and myocardial infarction, occur most frequently in the morning.1, 2 Elevation of blood pressure (BP) in the early morning (morning hypertension) is a risk factor for cardiovascular events in the morning.3, 4, 5, 6 A recent study using home-based BP self-measurement revealed that morning hypertension exists in ∼65% of patients receiving antihypertensive medications.7 Currently, the treatment of morning hypertension has not been established.

Current guidelines for the management of hypertension recommend a combination therapy of antihypertensive agents when an antihypertensive monotherapy cannot achieve target BP levels.8, 9 Among various combinations, an angiotensin II type-1 receptor blocker (ARB) combined with a small dose of thiazide diuretic is desirable because the two drugs have complementary mechanisms of action, effectively reduce BP, and are generally well tolerated.10, 11 A high-dose regimen of ARB is another treatment option. At present, however, little or no information is available on the efficacy of the ARB/thiazide diuretic combination for controlling morning hypertension.

Therefore, we conducted a prospective, randomized, open-labeled, multicenter trial to determine the efficacy and safety of a fixed-dose combination of losartan and hydrochlorothiazide (HCTZ) and a high dose of losartan in the treatment of patients with morning hypertension. For this purpose, outpatients experiencing morning hypertension despite antihypertensive medications were randomly assigned to receive a ‘combination therapy’ with a combination of 50 mg losartan and 12.5 mg HCTZ or a ‘high-dose therapy’ with 100 mg losartan. The primary efficacy end points were morning systolic BP (SBP) level and target BP achievement rate after 3 months of treatment on the basis of home BP self-measurement.

Methods

The design of this study was a 3-month prospective, randomized, open-labeled, parallel-group, multicenter trial, with a blinded end-point assessment. This study was performed by the Morning Hypertension and Angiotensin Receptor Blocker/Hydrochlorothiazide Combination Therapy Study investigators in Japan (listed in Supplementary Data). The Institutional Review Boards or Ethics Committees of all participating institutions approved the study protocol. All patients provided written informed consent.

Study population

Outpatients who had morning hypertension despite antihypertensive medications were enrolled in the study. Morning hypertension was defined as a morning SBP⩾135 mm Hg, diastolic BP (DBP)⩾85 mm Hg or both9 on 7 different days of home BP self-measurements during the run-in period (at least 1 month). Exclusion criteria included secondary hypertension, malignant hypertension or uncontrolled hypertension (for example, DBP⩾120 mm Hg), uncontrolled diabetes mellitus with HbA1c ⩾9.0%, a history of gout or serum uric acid ⩾8.0 mg dl−1, serum creatinine ⩾2.0 mg dl−1, serum potassium ⩾5.5 mmol l−1, liver damage (for example, alanine aminotransferase or γ-GTP level >3 × the upper normal limit), administration of a thiazide diuretic, administration of an ARB or angiotensin-converting enzyme inhibitor (ACEI) exceeding the standard doses approved in Japan, and the presence of contraindications for thiazides or ARBs.

Study design

Patients were randomly assigned to receive a combination of 50 mg losartan and 12.5 mg. HCTZ (combination therapy) or 100 mg losartan (high-dose therapy), each of which were administered once every morning. A 50-mg losartan/12.5-mg HCTZ combination tablet was used for the combination therapy. The envelope method was used for randomization. If patients had been administered an ARB or ACEI, the ARB or ACEI was switched to the losartan/HCTZ combination or 100 mg losartan. If an ARB or ACEI had not been prescribed, one of the prescribed antihypertensives was changed to either of the test drugs. There was no washout period before the randomization. The prescription of antihypertensive agents was not changed during the observation period.

On the day of the randomization, the initial evaluation (that is, medical history, medications) and laboratory tests were performed after written informed consent was obtained. Clinic BP values, adherence and information about adverse events were routinely recorded at each hospital visit every 4 weeks. After the 3-month treatment, the follow-up evaluation and laboratory tests were repeated. Adherence was semi-quantitatively evaluated: 1, 80% or more; 2, 50–80%; 3, <50%. The adverse events included intractable high BP (for example, DBP >120 mm Hg), intractable hypotension symptoms (for example, fainting or dizziness), hyperkalemia (potassium >6.0 mmol l−1), laboratory data abnormalities (for example, doubling increase of serum creatinine or transaminases) and any other conditions that the attending physicians considered to be medically necessary to protect the patients’ best interests.

Measurements

Patients were instructed to perform BP self-measurements at home in the early morning (within 1 h after waking up, after urination, before dosing in the morning, before breakfast and after resting for 1–2 min in a sitting position) and in the evening (before bedtime, after resting for 1–2 min in a sitting position) every day, according to the Japanese Society of Hypertension Guidelines for the Management of Hypertension 2009 (JSH2009 guidelines).9 Cuff oscillometry was applied using electronic upper arm-cuff devices. The type of devices is unknown, but the devices used were certified to comply with the Association for the Advancement of Medical Instrumentation standards. Each patient used the same type of home BP monitoring device throughout the study. The values of the first measurements taken each morning and evening were recorded. The measurements of the last 7 days preceding each clinic visit were averaged for the morning and evening BP values. BP was measured in the clinic using a sphygmomanometer after 5 min resting in a seated position at 1- to 2-min intervals. At least two measurements were averaged for the clinic BP values.9

Circulating biochemical parameters and urinary albumin excretion were measured in the morning in a fasting state at baseline and after 3 months of treatment. All assays were performed using a commercially available laboratory. Estimated glomerular filtration rates (eGFR) were calculated with the Cockcroft-Gault equation.12 Urine albumin levels were determined from a spot urine sample using a turbidimetric immunoassay and expressed as the urine albumin/creatinine ratio (urine albumin/creatinine ratio (UACR), mg g−1 creatinine).13

Study outcomes

The primary efficacy end points were morning SBP level and target BP achievement rate in the morning (SBP <135 mm Hg and DBP <85 mm Hg) after the 3-month-treatment period. The secondary efficacy end points included (1) evening SBP level and the achievement rate of evening target BP (SBP <135 mm Hg and DBP <85 mm Hg), (2) clinic SBP level and target BP achievement ratio in the clinic (SBP <140 mm Hg and DBP <90 mm Hg) and (3) changes in serum potassium, uric acid, plasma type-B natriuretic peptide, eGFR and urinary albumin secretion after the 3-month-treatment period. The safety end points were adherence to medications and the prevalence of adverse events during the 3-month-treatment period.

Statistical analysis

Statistical analysis was performed using commercially available software (IBM SPSS Statistics 18.0J, IBM, Tokyo, Japan). Data are expressed as mean±s.d. Because of skewed distributions, natural logarithmic transformations were performed for triglycerides, B-type natriuretic peptide and UACR before the data analyses. Paired Student's t-test and the χ2 test were applied to determine the significance of differences between baseline and post-treatment values. Unpaired Student's t-test and the χ2 test were used for detecting the significance of differences between the two treatment groups. A repeated measures analysis of variance followed by the Bonferroni/Dunn test was performed to evaluate the differences in the time-dependent changes between the two therapy groups. Differences were considered statistically significant at P<0.05. To detect a 5-mm Hg between-group BP difference with a power of 90% and a minimum significance level of P<0.05, given a s.d. of 10 mm Hg, 86 patients per group were necessary.

Results

Baseline characteristics and demographics

A total of 216 patients were randomly assigned to the combination therapy (n=107) and high-dose therapy (n=109) groups (Table 1). The mean age of participants was 67.8 years (ranging from 37 to 92 years; 50% male). Morning BP was significantly higher than evening BP (P<0.001). At baseline, BP levels and target BP achievement rates were similar between the combination therapy and high-dose therapy groups. The groups had similar characteristics, with the exception of male gender prevalence, low-density lipoprotein cholesterol level and β-blocker use, which were slightly greater in the combination therapy group. During the run-in period, the average number of antihypertensive medications was 1.63±0.81 and 1.57±0.67 per patient in the combination therapy and high-dose therapy groups, respectively (no significance (NS)). An ACEI or ARB was prescribed to 93.6% in combination therapy and 94.4% in high-dose therapy (NS).

Full size table

Follow-up and safety end points

During the follow-up period, 53.2% of patients in the combination therapy group and 52.3% of patients in the high-dose therapy group had no co-administered antihypertensive drugs (NS; Table 1). The frequency of co-administration of Ca channel blockers, α-blockers, β-blockers, loop diuretics and aldosterone blockers was similar between the two groups.

Six (5.5%) patients receiving combination therapy and five (4.7%) patients receiving high-dose therapy were withdrawn or lost to follow-up, primarily because of these patients relocated (NS; Figure 1). Table 2 illustrates that the adherence to medications was high in both groups throughout the observation period. The follow-up was discontinued because of adverse effects in four (3.7%) patients receiving combination therapy and five (4.7%) patients receiving high-dose therapy (NS). However, no serious adverse effects were reported in either group (Table 2).

Enrollment and follow-up.

Full size image

Full size table

As shown in Figure 1, 97 patients receiving combination therapy and 99 receiving high-dose therapy completed the 3-month treatment and were included in the efficacy analyses.

Primary efficacy end points

Combination therapy reduced morning SBP from 150.3±10.1 to 131.5±11.5 mm Hg (P<0.001), and high-dose therapy reduced morning SBP from 151.0±9.3 to 142.5±13.6 mm Hg (P<0.001) after 3 months of treatment (Figure 2a). Post-treatment morning SBP levels were lower in the combination therapy group than in the high-dose therapy group (P<0.001). Combination therapy increased the target achievement rate of morning BP to 58.7%, and high-dose therapy increased it to 27.0% (Figure 3). Combination therapy indicated a twofold greater target BP achievement rate for morning BP than high-dose therapy (P<0.001).

Effects of combination therapy (n=99, open column) and high-dose therapy (n=97, closed column) on systolic blood pressure (SBP) in the morning (a), evening (b) and clinic (c). Left, absolute values; right, changes. Bar=1 × s.d. *P<0.05, **P<0.01 and ***P<0.001 vs. baseline. ###P<0.001 vs. high-dose therapy.

Full size image

Target blood pressure (BP) achievement rates in the morning, evening and clinic. Open column, combination therapy (n=99); closed column, high-dose therapy (n=97). ***P<0.001 vs. baseline. #P<0.05, ##P<0.01 and ###P<0.001 vs. high-dose therapy.

Full size image

Secondary efficacy end points

Evening SBP was reduced from 141.6±13.3 to 125.3±13.1 mm Hg by combination therapy (P<0.001) and from 138.9±9.9 to 131.4±13.2 mm Hg by high-dose therapy (P<0.01; Figure 2b). Although the achieved SBP levels were similar between the two groups, combination therapy induced a greater evening SBP reduction than high-dose therapy (P<0.001). The target BP achievement rate of evening BP was improved from 24.2 to 79.0% by combination therapy and from 28.3 to 61.7% by high-dose therapy (P<0.001 for both; Figure 3). After treatment, the target BP achievement rate of evening BP was greater in the combination therapy group than in the high-dose therapy group (P<0.05).

Combination therapy reduced clinic SBP from 147.0±14.3 to 128.6±14.7 mm Hg (P<0.001), and high-dose therapy reduced clinic SBP from 147.5±13.8 to 140.0±15.2 mm Hg (P<0.05; Figure 2c). Post-treatment clinic SBP levels were lower from combination therapy than from high-dose therapy (P<0.001). Target BP achievement rates in the clinic were increased from 25.6 to 75.6% by combination therapy and from 22.8 to 51.3% by high-dose therapy (P<0.001 for both; Figure 3). Combination therapy improved the post-treatment target achievement rates of clinic BP more than high-dose therapy (P<0.01).

Changes in UACR, uric acid, eGFR and HbA1c

UACR was reduced by combination therapy (P<0.05) but was not changed by high-dose therapy after the 3-month-treatment period (Figure 4a). The serum uric acid levels were decreased by high-dose therapy (P<0.001), but it was not changed by combination therapy (Figure 4b). There were no differences in eGFR and HbA1c levels between combination therapy and high-dose therapy groups after the 3-month-treatment period (Figures 4c and d). Neither therapy affected other biochemical parameters, such as serum potassium and B-type natriuretic peptide, after the 3-month-treatment period (Supplementary Table).

Effects of combination therapy (open column) and high-dose therapy (closed column) on urine albumin/creatinine ratio (UACR; a), serum uric acid (b), estimated glomerular filtration rate (eGFR; c) and HbA1c (d). Right panels of (a, b) represent the percent changes in UACR and uric acid, respectively. Bar=1 × s.d. ***P<0.001 vs. baseline. #P<0.05 and ###P<0.001 vs. high-dose therapy.

Full size image

Discussion

This study indicated that among patients with morning hypertension undergoing treatment, combination therapy with 50 mg losartan and 12.5 mg HCTZ and high-dose therapy with 100 mg losartan decreased SBP levels and improved target BP achievement rates. Combination therapy reduced morning and clinic SBP more than high-dose therapy, and the improvement of target BP achievement rates in the morning, evening and the clinic were greater with combination therapy than with high-dose therapy. Combination therapy reduced urine albumin excretion whereas high-dose therapy reduced serum uric acid levels. Both therapies were safe and well tolerated. This study provides the first evidence for the efficacy and safety of losartan/HCTZ combination therapy for patients with uncontrolled morning hypertension on the basis of home BP self-measurements.

Home-based BP measurements have been indicated to be superior to office BP measurements in the prediction of hypertensive organ damage and prognosis.14, 15, 16, 17 Self-measurement of home BP is now popular in clinical practice for hypertension treatment in Japan.18, 19 A recent study has confirmed that morning BP taken by BP self-measurements at home is similar to that by 24-h ambulatory BP monitoring.20 Thus, the recent Japanese guidelines appreciate its use in the diagnosis and management of hypertension.9 In middle-aged and elderly populations, SBP is more closely associated with cardiovascular prognosis than DBP.21, 22 Of the patients participating in this study, the mean age was 67.8 years, and 98% were >45 years. We therefore primarily evaluated SBP levels. More than 90% of the enrolled patients had been administered an ARB before this study was initiated. Thus, the current observations mostly reflect the switching effects from a standard dose of ARB to the combination therapy with losartan and HCTZ or to a high dose of losartan.

Although combination therapy and high-dose therapy reduced morning SBP and improved the target BP achievement rate, combination therapy was superior in controlling morning hypertension through a greater SBP reduction and a greater improvement of target BP achievement rates (Figures 2 and 3). The superiority of combination therapy to high-dose therapy was also documented for the evening and clinic BP measurements. There are several possible reasons for the superiority of combination therapy. First, the combination of ARB and thiazide diuretic exerts a synergistic BP-lowering effect through complementary mechanisms of action whereas the antihypertensive effect of ARBs is not dose dependent.10, 11, 23 Second, 50 mg of losartan combined with 12.5 mg of HCTZ has a longer duration and a greater trough-to-peak ratio of BP-lowering effect than once daily 100 mg losartan.24 Next, increased salt sensitivity is associated with a non-dipper pattern of circadian BP rhythm.25, 26 A non-dipper pattern contributes to morning hypertension in some patients.27, 28, 29 Thiazide diuretics have been indicated to not only improve salt sensitivity but also shift the circadian BP rhythm from non-dipper to dipper in hypertensive patients.25, 30 Thus, combination therapy has an advantage over high-dose therapy for controlling morning hypertension.

The urinary albumin secretion is an established prognostic risk factor for cardiovascular and renal outcomes.31, 32, 33 Long-term trials have indicated an antiproteinuric effect of losartan.33, 34, 35, 36 In this study, the 3-month treatment with 100 mg losartan failed to show a significant UACR reduction in patients with morning hypertension (Figure 4a). This negative result may be explained by the fact that most patients had already been administered a standard dose of ARB or ACEI before the randomization. In contrast, UACR was significantly reduced by combination therapy (Figure 4a). The use of diuretics may have affected the UACR reduction by reducing the GFR. However, eGFR was not changed by the 3-month treatment with combination therapy (Figure 4c). Thus, the UACR reduction may be attributable to a greater BP-lowering effect by combination therapy.

Serum uric acid elevation is one of the clinical concerns regarding the use of thiazide diuretics because diuretic-induced elevation of uric acid to >1.0 mg dl−1 may be a risk factor for coronary events independent from achieved BP control.37 Note that a high dose of losartan brought a further uric acid reduction in the patients studied, most of whom had received a standard dose of ARB during the run-in period (Figure 4b). This finding supports the notion that losartan is a unique ARB, which reduces serum uric acid levels through the cis-inhibitory effects on the reabsorption of uric acid by the renal uric acid transporter 1.38 In this study, combination therapy did not increase uric acid levels (Figure 4b), suggesting that losartan minimized the HCTZ-induced uric acid elevation in combination therapy. This beneficial effect is a characteristic feature distinguishing losartan from other ARBs.39

In this study, adherence was substantially high in both therapy groups throughout the observation period (Table 2), which is in line with previous studies demonstrating that losartan and a combination of losartan and a small dose of HCTZ were well tolerated in hypertensive patients.40, 41, 42 In addition, BP self-measurements at home might be useful in raising the adherence to hypertensive medications by improving patient motivation.43

Combination therapy included more male subjects than high-dose therapy (Table 1). Thus, the imbalance of gender may have affected the results of this study. However, as shown in the Supplementary Figure, there were no gender differences in the effects of combination therapy or high-dose therapy on the primary end points (morning SBP levels and target BP achievement rates after the 3-month-treatment period).

Study limitations

From this study, it remains unknown whether combination therapy would provide a greater reduction in future cardiovascular events in patients with morning hypertension than high-dose therapy. A large-scale, long-term, randomized trial is necessary to address this issue. Second, adverse effects of diuretics, such as glucose intolerance, are major concerns in the clinical setting. Therefore, a longer observation period is required to examine adverse metabolic effects, such as electrolyte imbalance, glucose intolerance and hyperuricemia. Next, bedtime administration of antihypertensives was reported to improve BP control more than morning administration.44, 45 The feasibility of bedtime administration of combination therapy and high-dose therapy for morning hypertension should be determined in future studies.

In conclusion, combination therapy with a standard dose of losartan and a low dose of HCTZ is more effective for controlling morning hypertension and reducing urine albumin excretion than high-dose therapy with losartan. These beneficial effects may be attributable to the consistent and well-maintained BP-lowering effects of the combination therapy.

References

  1. 1

    Goldberg RJ, Brady P, Muller JE, Chen ZY, de Groot M, Zonneveld P, Dalen JE . Time of onset of symptoms of acute myocardial infarction. Am J Cardiol 1990; 66: 140–144.

    CASArticle Google Scholar

  2. 2

    Kelly-Hayes M, Wolf PA, Kase CS, Brand FN, McGuirk JM, D’Agostino RB . Temporal patterns of stroke onset. The Framingham Study. Stroke 1995; 26: 1343–1347.

    CASArticle Google Scholar

  3. 3

    Muller JE, Tofler GH, Stone PH . Circadian variation and triggers of onset of acute cardiovascular disease. Circulation 1989; 79: 733–743.

    CASArticle Google Scholar

  4. 4

    Kario K, Pickering TG, Umeda Y, Hoshide S, Hoshide Y, Morinari M, Murata M, Kuroda T, Schwartz JE, Shimada K . Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives: a prospective study. Circulation 2003; 107: 1401–1406.

    Article Google Scholar

  5. 5

    Asayama K, Ohkubo T, Kikuya M, Obara T, Metoki H, Inoue R, Hara A, Hirose T, Hoshi H, Hashimoto J, Totsune K, Satoh H, Imai Y . Prediction of stroke by home ‘morning’ versus ‘evening’ blood pressure values: the Ohasama study. Hypertension 2006; 48: 737–743.

    CASArticle Google Scholar

  6. 6

    Metoki H, Ohkubo T, Imai Y . Diurnal variations in blood pressure: clinical implications and pathogenesis. Hypertens Res 2010; 33: 652–656.

    Article Google Scholar

  7. 7

    Obara T, Ito K, Ohkubo T, Shibamiya T, Shinki T, Nakashita M, Hara A, Metoki H, Inoue R, Asayama K, Kikuya M, Mano N, Imai Y . Uncontrolled hypertension based on morning and evening home blood pressure measurements from the J-HOME study. Hypertens Res 2009; 32: 1072–1078.

    Article Google Scholar

  8. 8

    Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Boudier HA, Zanchetti A, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Erdine S, Kiowski W, Agabiti-Rosei E, Ambrosioni E, Lindholm LH, Viigimaa M, Adamopoulos S, Agabiti-Rosei E, Ambrosioni E, Bertomeu V, Clement D, Erdine S, Farsang C, Gaita D, Lip G, Mallion JM, Manolis AJ, Nilsson PM, O’Brien E, Ponikowski P, Redon J, Ruschitzka F, Tamargo J, van Zwieten P, Waeber B, Williams B . Management of arterial hypertension of the European Society of Hypertension; European Society of Cardiology 2007 Guidelines for the Management of Arterial Hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25: 1105–1187.

    CASArticle Google Scholar

  9. 9

    Ogihara T, Kikuchi K, Matsuoka H, Fujita T, Higaki J, Horiuchi M, Imai Y, Imaizumi T, Ito S, Iwao H, Kario K, Kawano Y, Kim-Mitsuyama S, Kimura G, Matsubara H, Matsuura H, Naruse M, Saito I, Shimada K, Shimamoto K, Suzuki H, Takishita S, Tanahashi N, Tsuchihashi T, Uchiyama M, Ueda S, Ueshima H, Umemura S, Ishimitsu T, Rakugi H . The Japanese Society of Hypertension guidelines for the management of hypertension (JSH 2009). Hypertens Res 2009; 32: 3–107.

    CASPubMedPubMed Central Google Scholar

  10. 10

    MacKay JH, Arcuri KE, Goldberg AI, Snapinn SM, Sweet CS . Losartan and low-dose hydrochlorothiazide in patients with essential hypertension. A double-blind, placebo-controlled trial of concomitant administration compared with individual components. Arch Intern Med 1996; 156: 278–285.

    CASArticle Google Scholar

  11. 11

    Yamada Y, Tsuboi K, Hattori T, Murase T, Ohtake M, Furukawa M, Ueyama J, Nishiyama A, Murohara T, Nagata K . Mechanism underlying the efficacy of combination therapy with losartan and hydrochlorothiazide in rats with salt-sensitive hypertension. Hypertens Res 2011; 34: 809–816.

    CASArticle Google Scholar

  12. 12

    Cockcroft DW, Gault MH . Prediction of creatinine clearance from serum creatinine. Nephron 1975; 13: 31–41.

    Google Scholar

  13. 13

    Ewald B, Attia J . Which test to detect microalbuminuria in diabetic patients? A systematic review. Aust Fam Physician 2004; 33: 565–567.

    PubMed Google Scholar

  14. 14

    Tsuji I, Imai Y, Nagai K, Ohkubo T, Watanabe N, Minami N, Itoh O, Bando T, Sakuma M, Fukao A, Satoh H, Hisamichi S, Abe K . Proposal of reference values for home blood pressure measurement: prognostic criteria based on a prospective observation of the general population in Ohasama, Japan. Am J Hypertens 1997; 10: 409–418.

    CASPubMed Google Scholar

  15. 15

    Ohkubo T, Imai Y, Tsuji I, Nagai K, Kato J, Kikuchi N, Nishiyama A, Aihara A, Sekino M, Kikuya M, Ito S, Satoh H, Hisamichi S . Home blood pressure measurement has a stronger predictive power than does screening blood pressure measurement: a propulation-based observation in Ohasama, Japan. J Hypertens 1998; 16: 971–975.

    CASArticle Google Scholar

  16. 16

    Bobrie G, Chatellier G, Genes N, Clerson P, Vaur L, Vaisse B, Menard J, Mallion JM . Cardiovascular prognosis of ‘masked hypertension’ detected by blood pressure self-measurement in elderly treated hypertensive patients. JAMA 2004; 291: 1342–1349.

    CASArticle Google Scholar

  17. 17

    Sega R, Facchetti R, Bombelli M, Cesana G, Corrao G, Grassi G, Mancia G . Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population: Follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. Circulation 2005; 111: 1777–1783.

    Article Google Scholar

  18. 18

    Obara T, Ohkubo T, Fukunaga H, Kobayashi M, Satoh M, Metoki H, Asayama K, Inoue R, Kikuya M, Mano N, Miyakawa M, Imai Y . Practice and awareness of physicians regarding home blood pressure measurement in Japan. Hypertens Res 2010; 33: 428–434.

    Article Google Scholar

  19. 19

    Sato A, Watanabe S, Okubo S, Toi T, Doi T, Nakano H, Tada J, Aonuma K . The therapeutic importance of home blood pressure assessment and combination antihypertensive therapy for achieving target blood pressure control: Ibaraki hypertension assessment trial. Hypertens Res 2010; 33: 1264–1271.

    Article Google Scholar

  20. 20

    Stergiou GS, Nasothimiou EG . Does dosing antihypertensive drugs at night alter renal or cardiovascular outcome: do we have the evidence? Curr Opin Nephrol Hypertens 2008; 17: 464–469.

    CASArticle Google Scholar

  21. 21

    Stamler J, Stamler R, Neaton JD . Blood pressure, systolic and diastolic, and cardiovascular risks. US population data. Arch Intern Med 1993; 153: 598–615.

    CASArticle Google Scholar

  22. 22

    Psaty BM, Furberg CD, Kuller LH, Cushman M, Savage PJ, Levine D, O’Leary DH, Bryan RN, Anderson M, Lumley T . Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study. Arch Intern Med 2001; 161: 1183–1192.

    CASArticle Google Scholar

  23. 23

    Fenton C, Keating GM, Scott LJ . Telmisartan/hydrochlorothiazide: in the treatment of essential hypertension. Drugs 2003; 63: 2013–2026.

    CASArticle Google Scholar

  24. 24

    Elliot HL, Meredith PA . Clinical implications of the trough: peak ratio. Blood Press Monit 1996; 1 (Suppl 1): S47–S51.

    Google Scholar

  25. 25

    Uzu T, Kimura G . Diuretics shift circadian rhythm of blood pressure from nondipper to dipper in essential hypertension. Circulation 1999; 100: 1635–1638.

    CASArticle Google Scholar

  26. 26

    Kimura G, Dohi Y, Fukuda M . Salt sensitivity and circadian rhythm of blood pressure: the keys to connect CKD with cardiovasucular events. Hypertens Res 2010; 33: 515–520.

    Article Google Scholar

  27. 27

    White WB, Mansoor GA, Tendler BE, Anwar YA . Nocturnal blood pressure epidemiology, determinants, and effects of antihypertensive therapy. Blood Press Monit 1998; 3: 43–51.

    CASPubMed Google Scholar

  28. 28

    Eguchi K, Hoshide S, Kabutoya T, Shimada K, Kario K . Is very low dose hydrochlorothiazide combined with candesartan effective in uncontrolled hypertensive patients? Blood Press Monit 2010; 15: 308–311.

    Article Google Scholar

  29. 29

    de la Sierra A, Segura J, Gorostidi M, Banegas JR, de la Cruz JJ, Ruilope LM . Diurnal blood pressure variation, risk categories and antihypertensive treatment. Hypertens Res 2010; 33: 767–771.

    CASArticle Google Scholar

  30. 30

    Burnier M, Brunner HR . Neurohormonal consequences of diuretics in different cardiovascular syndromes. Eur Heart J 1992; 13 (Suppl G): 28–33.

    Article Google Scholar

  31. 31

    Culleton BF, Larson MG, Parfrey PS, Kannel WB, Levy D . Proteinuria as a risk factor for cardiovascular disease and mortality in older people: a prospective study. Am J Med 2000; 109: 1–8.

    CASArticle Google Scholar

  32. 32

    Tanihara S, Hayakawa T, Oki I, Nakamura Y, Sakata K, Okayama A, Fujita Y, Ueshima H, NIPPON DATA Research Group. Proteinuria is a prognostic marker for cardiovascular mortality: NIPPON DATA 80, 1980–1999. J Epidemiol 2005; 15: 146–153.

    Article Google Scholar

  33. 33

    Cerasola G, Cottone S, Mulè G . The progressive pathway of microalbuminuria: from early marker of renal damage to strong cardiovascular risk predictor. J Hypertens 2010; 28: 2357–2369.

    CASPubMed Google Scholar

  34. 34

    Iino Y, Hayashi M, Kawamura T, Shiigai T, Tomino Y, Yamada K, Kitajima T, Ideura T, Koyama A, Sugisaki T, Suzuki H, Umemura S, Kawaguchii Y, Uchida S, Kuwahara M, Yamazaki T . Renoprotective effect of losartan in comparison to amlodipine in patients with chronic kidney disease and hypertension—A report of the Japanese Losartan Therapy Intended for the Global Renal Protection in Hypertensive Patients (JLIGHT) study. Hypertens Res 2004; 27: 21–30.

    CASArticle Google Scholar

  35. 35

    de Zeeuw D, Lewis EJ, Remuzzi G, Brenner BM, Cooper ME . Renoprotective effects of renin-angiotensin-system inhibitors. Lancet 2006; 367: 899–900.

    Article Google Scholar

  36. 36

    Eijkelkamp WB, Zhang Z, Brenner BM, Cooper ME, Devereux RB, Dahlöf B, Ibsen H, Keane WF, Lindholm LH, Olsen MH, Parving HH, Remuzzi G, Shahinfar S, Snapinn SM, Wachtell K, de Zeeuw D . Renal function and risk for cardiovascular events in type 2 diabetic patients with hypertension: the RENAAL and LIFE studies. J Hypertens 2007; 25: 871–876.

    CASArticle Google Scholar

  37. 37

    Franse LV, Pahor M, Di Bari M, Shorr RI, Wan JY, Somes GW, Applegate WB . Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP). J Hypertens 2000; 18: 1149–1154.

    CASArticle Google Scholar

  38. 38

    Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, Hosoyamada M, Takeda M, Sekine T, Igarashi T, Matsuo H, Kikuchi Y, Oda T, Ichida K, Hosoya T, Shimokata K, Niwa T, Kanai Y, Endou H . Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002; 417: 447–452.

    CASArticle Google Scholar

  39. 39

    Iwanaga T, Sato M, Maeda T, Ogihara T, Tamai I . Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter. J Pharmacol Exp Ther 2007; 320: 211–217.

    CASArticle Google Scholar

  40. 40

    Saruta T, Ogihara T, Matsuoka H, Suzuki H, Toki M, Hirayama Y, Nonaka K, Takahashi K . Antihypertensive efficacy and safety of fixed-dose combination therapy with losartan plus hydrochlorothiazide in Japanese patients with essential hypertension. Hypertens Res 2007; 30: 729–739.

    CASArticle Google Scholar

  41. 41

    Shimosawa T, Gohchi K, Yatomi Y, Fujita T . Effectiveness of add-on low-dose diuretics in combination therapy for hypertension: losartan/hydrochlorothiazide vs candesartan/amlodipine. Hypertens Res 2007; 30: 831–837.

    CASArticle Google Scholar

  42. 42

    Naritomi H, Fujita T, Ito S, Ogihara T, Shimada K, Shimamoto K, Tanaka H, Yoshiike N . Efficacy and safety of long-term losartan therapy demonstrated by a prospective observational study in Japanese patients with hypertension: the Japan Hypertension Evaluation with Angiotensin II Antagonist Losartan Therapy (J-HEALTH) study. Hypertens Res 2008; 31: 295–304.

    CASArticle Google Scholar

  43. 43

    Shimada K, Fujita T, Ito S, Naritomi H, Ogihara T, Shimamoto K, Tanaka H, Yoshiike N . The importance of home blood pressure measurement for preventing stroke and cardiovascular disease in hypertensive patients: a sub-analysis of the Japan Hypertension Evaluation with Angiotensin II Antagonist Losartan Therapy (J-HEALTH) study. A prospective nationwide observational study. Hypertens Res 2008; 31: 1903–1911.

    CASArticle Google Scholar

  44. 44

    Hermida RC, Ayala DE . Chronotherapy with the angiotensin-converting enzyme inhibitor ramipril in essential hypertension: improved blood pressure control with bedtime dosing. Hypertension 2009; 54: 40–46.

    CASArticle Google Scholar

  45. 45

    Parati G, Bilo G . Evening administration of antihypertensive drugs: filling a knowledge gap. J Hypertens 2010; 28: 1390–1392.

    CASArticle Google Scholar

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Acknowledgements

We thank Mari Shibata, Naoko Shiotani, Motoko Kakehashi and Midori Ikeda for their secretarial assistance. This study was supported in part by a grant from the Science Frontier Research Promotion Centers from the Ministry of Education, Science, Sports and Culture of Japan.

Author information

Affiliations

  1. Department of Internal Medicine, Division of Cardio-Vascular Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan

    Tamenobu Ueda, Hisashi Kai & Tsutomu Imaizumi

Consortia

on behalf of the MAPPY Study Investigators

Corresponding author

Correspondence to Hisashi Kai.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

This study was presented in the ‘Late-Breaking Clinical Trials session’ at the 34th Annual Scientific Meeting of the Japanese Society of Hypertension on 20 October 2011.

Supplementary Information accompanies the paper on Hypertension Research website

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Ueda, T., Kai, H., Imaizumi, T. et al. Losartan/hydrochlorothiazide combination vs. high-dose losartan in patients with morning hypertension—a prospective, randomized, open-labeled, parallel-group, multicenter trial. Hypertens Res35, 708–714 (2012). https://doi.org/10.1038/hr.2012.27

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Keywords

  • Ang II receptor blockers
  • antihypertensive therapy
  • clinical trial
  • diuretics
  • home blood pressure measurement
Sours: https://www.nature.com/articles/hr201227

Hydrochlorothiazide losartan

Losartan/Hydrochlorothiazide, Oral Tablet

This drug has a boxed warning. This is the most serious warning from the Food and Drug Administration (FDA). A boxed warning alerts doctors and patients about drug effects that may be dangerous.

  • You should not take this drug while pregnant. This drug can harm or end your pregnancy. If you become pregnant, call your doctor and stop taking this drug right away.

Highlights for losartan/hydrochlorothiazide

  1. Losartan/hydrochlorothiazide oral tablet is available as a generic drug and a brand-name drug. Brand name: Hyzaar.
  2. Losartan/hydrochlorothiazide only comes as a tablet you take by mouth.
  3. Losartan/hydrochlorothiazide is a combination of two drugs in a single form. It’s used to treat high blood pressure. It’s also used to reduce the risk of stroke in people with high blood pressure and a heart condition called left ventricular hypertrophy.

What is losartan/hydrochlorothiazide?

Losartan/hydrochlorothiazide is a prescription medication. It comes as an oral tablet.

This drug is available as the brand-name drug Hyzaar and as a generic drug. Generic drugs usually cost less than the brand-name version. In some cases, they may not be available in every strength or form as the brand-name drug.

This is a combination of two drugs in a single form. It’s important to know about all the drugs in the combination because each drug may affect you in a different way.

Losartan/hydrochlorothiazide may be used as part of a combination therapy. That means you need to take it with other drugs.

Why it’s used

Losartan/hydrochlorothiazide is used to treat high blood pressure. It’s given when one drug isn’t enough to lower your blood pressure.

This drug is also used to reduce the risk of stroke in people with high blood pressure and a heart condition called left ventricular hypertrophy. The effectiveness of this drug may be related to your race. Ask your healthcare provider for more information about this topic.

This drug will help control your blood pressure, but it won’t cure high blood pressure.

How it works

Losartan/hydrochlorothiazide contains two drugs that belong in different drug classes. A class of drugs is a group of medications that work in a similar way. These drugs are often used to treat similar conditions.

Losartan is a type of drug called an angiotensin II receptor blocker. It blocks the action of angiotensin II, a chemical in your body that causes your blood vessels to tighten and narrow. Losartan helps to relax and widen your blood vessels, which lowers your blood pressure.

Hydrochlorothiazide is a type of drug called a thiazide diuretic. It’s thought that hydrochlorothiazide works to remove excess salt and water from your body. This keeps your heart from working as hard to pump blood, which lowers your blood pressure.

Losartan/hydrochlorothiazide side effects

Losartan/hydrochlorothiazide can cause mild or serious side effects. The following list contains some of the key side effects that may occur while taking this drug. This list does not include all possible side effects.

For more information on the possible side effects of losartan/hydrochlorothiazide, or tips on how to deal with a troubling side effect, talk with your doctor or pharmacist.

More common side effects

The more common side effects that occur with losartan/hydrochlorothiazide include:

  • upper respiratory infection, such as the common cold
  • dizziness
  • cough
  • back pain

These effects may go away within a few days or a couple of weeks. If they’re more severe or don’t go away, talk to your doctor or pharmacist.

Serious side effects

Call your doctor right away if you have serious side effects. Call 911 if your symptoms feel life-threatening or if you think you’re having a medical emergency. Serious side effects and their symptoms can include the following:

  • Serious allergic reaction. Symptoms can include:
    • swelling of your face, lips, throat, or tongue
    • trouble breathing
  • Low blood pressure (hypotension). Symptoms can include:
    • dizziness
    • feeling like you’re going to faint
  • Lupus. Symptoms can include:
    • joint pain
    • stiffness
    • weight loss
    • fatigue
    • skin rash
  • Kidney problems. Symptoms can include:
    • swelling of your feet, ankles, or hands
    • weight gain
  • Eye problems. Symptoms can include:
  • High or low potassium blood levels. Symptoms can include:
    • heart rhythm problems
    • muscle weakness
    • slow heart rate

Losartan/hydrochlorothiazide may interact with other medications

Losartan/hydrochlorothiazide oral tablet can interact with several other medications. Different interactions can cause different effects. For instance, some can interfere with how well a drug works, while others can cause increased side effects.

Below is a list of medications that can interact with this drug. This list does not contain all drugs that may interact with losartan/hydrochlorothiazide.

Before taking losartan/hydrochlorothiazide, be sure to tell your doctor and pharmacist about all prescription, over-the-counter, and other drugs you take. Also tell them about any vitamins, herbs, and supplements you use. Sharing this information can help you avoid potential interactions.

If you have questions about drug interactions that may affect you, ask your doctor or pharmacist.

Drugs or supplements that contain potassium

Losartan/hydrochlorothiazide can increase the levels of a substance called potassium in your blood. Taking losartan with drugs that contain potassium, potassium supplements, or salt substitutes with potassium, can increase your risk of hyperkalemia (high levels of potassium).

Examples of drugs that contain potassium include:

  • potassium chloride (Klor-Con, Klor-Con M, K-Tab, Micro-K)
  • potassium gluconate
  • potassium bicarbonate (Klor-Con EF)

Lithium

Taking losartan/hydrochlorothiazide with lithium, a drug used to treat bipolar disorder, may increase the levels of lithium in your body. This can increase your risk of dangerous side effects.

If you need to take these drugs together, your doctor may reduce your lithium dosage.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Using this drug with NSAIDs raises your risk of kidney damage. Your risk may be higher if you have poor kidney function, are a senior, take a water pill, or are dehydrated.

NSAIDs may also reduce the blood pressure-lowering effects of losartan/hydrochlorothiazide. This means that losartan may not work as well.

Examples of NSAIDs include:

Blood pressure drugs

Taking losartan/hydrochlorothiazide with other drugs that work in the same way may increase your chance of low blood pressure, high potassium levels in your blood, and kidney damage.

Examples of these drugs include:

  • angiotensin receptor blockers (ARBs), such as:
    • irbesartan
    • candesartan
    • valsartan
  • angiotensin-converting enzyme (ACE) inhibitors, such as:
    • lisinopril
    • fosinopril
    • enalapril
    • aliskiren

Diabetes drugs

Losartan/hydrochlorothiazide can make your blood sugar levels increase. If you’re taking diabetes medications with losartan/hydrochlorothiazide, your doctor may adjust the dosage of your diabetes medications. Examples of diabetes drugs include:

  • insulin
  • glipizide
  • glyburide
  • pioglitazone
  • rosiglitazone
  • acarbose
  • miglitol

Cholesterol-lowering drugs

Taking losartan/hydrochlorothiazide with certain cholesterol-lowering drugs can decrease the amount of losartan/hydrochlorothiazide in your body. This means it may not work as well.

Your doctor may recommend that you take losartan/hydrochlorothiazide at least 4 hours before you take these drugs, or 4 to 6 hours after you take them.

Examples of these cholesterol-lowering drugs include:

Stopping losartan/hydrochlorothiazide

Do not stop taking losartan/hydrochlorothiazide without talking to your doctor. Stopping it suddenly can cause your blood pressure to increase quickly. This raises your risk of a heart attack or stroke. If you want to stop taking this drug, talk with your doctor. They will slowly taper your dosage so that you can stop using the drug safely.

How to take losartan/hydrochlorothiazide

The losartan/hydrochlorothiazide dosage your doctor prescribes will depend on several factors. These include:

  • the type of the condition you’re using losartan/hydrochlorothiazide to treat
  • your age
  • other medical conditions you may have, such as kidney damage

Typically, your doctor will start you on a low dosage and adjust it over time to reach the dosage that’s right for you. They’ll ultimately prescribe the smallest dosage that provides the desired effect.

The following information describes dosages that are commonly used or recommended. However, be sure to take the dosage your doctor prescribes for you. Your doctor will determine the best dosage to suit your needs.

Drug forms and strengths

Generic: Losartan/hydrochlorothiazide

  • Form: oral tablet
  • Strengths:
    • 50 mg losartan/12.5 mg hydrochlorothiazide
    • 100 mg losartan/12.5 mg hydrochlorothiazide
    • 100 mg losartan/25 mg hydrochlorothiazide

Brand: Hyzaar

  • Form: oral tablet
  • Strengths:
    • 50 mg losartan/12.5 mg hydrochlorothiazide
    • 100 mg losartan/12.5 mg hydrochlorothiazide
    • 100 mg losartan/25 mg hydrochlorothiazide

Dosage for high blood pressure (hypertension)

Adult dosage (ages 18 to 64 years)

The starting dose is 50 mg losartan/12.5 mg hydrochlorothiazide or 100 mg losartan/12.5 mg hydrochlorothiazide, taken once per day.

Your dosage may depend on the dosage of the blood pressure drug you were taking before. If needed, your doctor may increase your dosage up to 100 mg losartan/25 mg hydrochlorothiazide taken once per day.

The maximum dosage is 100 mg losartan/25 mg hydrochlorothiazide taken once per day.

Child dosage (ages 0 to 17 years)

This drug hasn’t been studied in children and shouldn’t be used in people younger than 18 years.

Senior dosage (ages 65 years and older)

There are no specific recommendations for senior dosing. Older adults may process drugs more slowly. As a result, a normal adult dosage may cause levels of this drug to be higher than normal in your body. If you’re a senior, you may need a lower dosage, or a different dosing schedule.

Dosage for high blood pressure (hypertension) and left ventricular hypertrophy

Adult dosage (ages 18 to 64 years)

The starting dosage is 50 mg losartan/12.5 mg hydrochlorothiazide once daily.

If this doesn’t control your blood pressure enough, your doctor may increase your dosage to 100 mg losartan/12.5 mg hydrochlorothiazide once daily, followed by 100 mg losartan/25 mg hydrochlorothiazide once daily.

Child dosage (ages 0 to 17 years)

This drug hasn’t been studied in children and shouldn’t be used in people younger than 18 years.

Senior dosage (ages 65 years and older)

There are no specific recommendations for senior dosing. Older adults may process drugs more slowly. As a result, a normal adult dosage may cause levels of this drug to be higher than normal in your body. If you’re a senior, you may need a lower dosage, or a different dosing schedule.

Special dosage considerations

  • For people with kidney disease: You shouldn’t take this drug if your creatinine clearance (CrCl) is less than 30 ml/min.
  • For people with liver disease: You shouldn’t take this drug if you have liver damage. A lower starting dose of losartan is needed for people with liver disease, but the lower dose is not available in this combination drug.

Losartan/hydrochlorothiazide warnings

Low blood pressure (hypotension)

Using this drug may cause low blood pressure. You’re more likely to have low blood pressure with this drug if you also take diuretics, are on a low-salt diet, have heart problems, or get sick with vomiting or diarrhea. If you have any of these medical problems, your doctor may monitor you closely when you receive your first dose.

Sensitivity reaction

If you have a history of allergies or asthma, you may get a sensitivity reaction when you first start taking this drug. Symptoms include skin rash, hives, shortness of breath or wheezing, itching, and fever.

Eye problems

This drug may cause eye conditions called myopias and glaucoma. If you have trouble seeing or pain in your eyes, call your doctor and stop taking the drug right away.

Allergy warning

This drug can cause a severe allergic reaction. Symptoms include:

  • trouble breathing
  • swelling of your throat or tongue
  • hives

If you develop these symptoms, call 911 or go to the nearest emergency room.

Don’t take this drug again if you’ve ever had an allergic reaction to it before. Taking it a second time after an allergic reaction could be fatal.

Alcohol interaction warning

Consuming drinks that contain alcohol can increase your risk of dizziness or lightheadedness from losartan/hydrochlorothiazide. If you drink alcohol, talk to your doctor about whether alcohol use is safe for you while you take this drug.

Warnings for people with certain health conditions

For people with a sulfonamide allergy: If you’re allergic to sulfonamides, don’t take this drug. Be sure to tell your doctor about all of your allergies.

For people with kidney disease: You have a higher risk of serious side effects from this drug. If you have kidney disease and no longer make any urine, you shouldn’t take this drug. Your doctor will monitor your kidney function and adjust your medication as needed.

For people with liver disease: If you have liver disease, you shouldn’t take this drug.

For people with lupus: This drug can cause new or worsening lupus symptoms. Call your doctor right away if this occurs.

For people with diabetes: Your doctor may adjust the dosage of your diabetes drugs while you’re taking this drug. They’ll tell you how often to test your blood sugar levels.

For people with glaucoma: This drug may make your glaucoma worse.

Warnings for other groups

For pregnant women: This drug is a pregnancy category D drug. That means two things:

  1. Research in humans has shown adverse effects to the fetus when the mother takes the drug.
  2. This drug should only be used during pregnancy in serious cases where it’s needed to treat a dangerous condition in the mother.

Talk to your doctor if you’re pregnant or planning to become pregnant. Ask your doctor to tell you about the specific harm that may be done to the fetus. This drug should only be used if the potential risk to the fetus is acceptable given the drug’s potential benefit.

Call your doctor right away if you become pregnant while taking this drug.

For women who are breastfeeding: It isn’t known if this drug passes into breast milk. If it does, it may cause side effects in a child who is breastfed.

Talk to your doctor if you breastfeed your child. You may need to decide whether to stop breastfeeding or stop taking this medication.

For seniors: Older adults may process drugs more slowly. As a result, a normal adult dosage may cause levels of this drug to be higher than normal in your body. If you’re a senior, you may need a lower dosage, or a different dosing schedule.

For children: This drug hasn’t been studied in children and shouldn’t be used in people younger than 18 years.

Take as directed

Losartan/hydrochlorothiazide is used for long-term treatment. It comes with serious risks if you don’t take it as prescribed.

If you don’t take it at all: This drug reduces high blood pressure. If this condition isn’t treated, it can lead to stroke, heart attack, heart failure, kidney failure, and vision problems. It can even be fatal.

If you stop taking it suddenly: Don’t stop taking this drug without talking to your doctor. High blood pressure can occur if you stop taking this drug too suddenly. This may increase your chance for a heart attack or stroke. If you need to stop taking this drug, your doctor will slowly decrease your dose.

If you don’t take it on schedule: Your blood pressure may not improve or may get worse. You may have a higher chance of a heart attack or stroke.

What to do if you miss a dose: If you forget to take your dose, take it as soon as you remember. If it’s just a few hours until the time for your next dose, then wait and only take one dose at that time. Never try to catch up by taking two doses at once. This could cause dangerous side effects.

If you take too much: If you take too much of this drug, you may have changes in the amount of electrolytes in your blood. Also, you may have symptoms such as:

  • feeling like your heart is pounding
  • weakness
  • dizziness

If you think you’ve taken too much of this drug, call your doctor or seek guidance from the American Association of Poison Control Centers at 800-222-1222 or through their online tool. But if your symptoms are severe, call 911 or go to the nearest emergency room right away.

How to tell this drug is working: Your blood pressure should be lower. Your doctor will monitor your blood pressure at your checkups. You can also check your blood pressure at home. Keep a log with the date, time of day, and your blood pressure readings. Bring this diary with you to your doctor appointments.

Important considerations for taking this drug

Keep these considerations in mind if your doctor prescribes losartan/hydrochlorothiazide for you.

General

You can cut or crush the tablet.

Storage

  • Store this drug at room temperature close to 77°F (25°C). It may be stored briefly at a temperature between 59°F and 86°F (15°C and 30°C).
  • Don’t freeze this drug. Keep it away from high temperatures.
  • Keep this drug away from light.
  • Don’t store this medication in moist or damp areas, such as bathrooms.

Refills

A prescription for this medication is refillable. You should not need a new prescription for this medication to be refilled. Your doctor will write the number of refills authorized on your prescription.

Travel

When traveling with your medication:

  • Always carry your medication with you. When flying, never put it into a checked bag. Keep it in your carry-on bag.
  • Don’t worry about airport X-ray machines. They won’t damage your medication.
  • You may need to show airport staff the pharmacy label for your medication. Always carry the original prescription-labeled container with you.
  • Don’t put this medication in your car’s glove compartment or leave it in the car. Be sure to avoid doing this when the weather is very hot or very cold.

Self-management

You may need to check your blood pressure at home. You should keep a log with the date, time of day, and your blood pressure readings. Bring this log with you to your doctor appointments.

Shop for blood pressure monitors.

Clinical monitoring

While you’re being treated with this drug, your doctor will check your blood pressure and do blood tests to monitor the following:

  • liver function
  • kidney function
  • blood sugar
  • blood potassium

Your diet

Your doctor may have you follow a special diet, such as a low-salt or a low-potassium diet. You may need to avoid potassium supplements and salt substitutes that contain potassium.

Hidden costs

You may need to purchase a blood pressure monitor to check your blood pressure at home. These are available at most pharmacies.

Are there any alternatives?

There are other drugs available to treat your condition. Some may be more suitable for you than others. Talk to your doctor about possible alternatives.

Disclaimer: Healthline has made every effort to make certain that all information is factually correct, comprehensive, and up-to-date. However, this article should not be used as a substitute for the knowledge and expertise of a licensed healthcare professional. You should always consult your doctor or other healthcare professional before taking any medication. The drug information contained herein is subject to change and is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. The absence of warnings or other information for a given drug does not indicate that the drug or drug combination is safe, effective, or appropriate for all patients or all specific uses.

Sours: https://www.healthline.com/health/drugs/hydrochlorothiazide-losartan-oral-tablet
Blood pressure drug recall Sandozs losartan potassium hydrochlorothiazide

Efficacy and safety of losartan/hydrochlorothiazide in patients with severe hypertension

This 12-week, open-label, multicenter study assessed the efficacy and safety of losartan/hydrochlorothiazide (HCTZ), alone or in combination with other antihypertensive agents, in the treatment of patients with severe systemic hypertension. Treatment began with once-daily losartan/HCTZ 50/12.5 mg. The dose was increased to 100/25 mg, if required, to achieve blood pressure (BP) control (sitting diastolic BP <95 mm Hg); felodipine (extended release) and/or atenolol could be added if target sitting diastolic BP was not achieved with losartan/HCTZ alone. Mean sitting systolic BP of the 131 patients enrolled was 165.3 mm Hg at baseline and 139.8 mm Hg at final visit (reduction -25.4 mm Hg; p < or =0.01). Mean sitting diastolic BP was 111.9 mm Hg at baseline and 93.6 mm Hg at final visit (reduction -18.4 mm Hg; p < or =0.01). After 2 weeks of treatment, 63.8% of patients (83 of 130) were taking losartan/HCTZ 50/12.5 mg alone. By the final visit, one third of patients (35.1%; 46/131) were still only taking losartan/HCTZ. Most patients (48.1%; 63 of 131) were taking losartan/HCTZ 100/25 mg plus felodipine (extended release) at the final visit. Losartan/HCTZ was well tolerated. Drug-related adverse experiences occurred in 30 patients (22.9%). Only 2 patients (1.5%) had a serious adverse experience; 6 patients (4.6%) discontinued the drug because of an adverse experience. In conclusion, losartan/ HCTZ, alone or as part of a regimen with other standard antihypertensive agents, is effective and well tolerated in the treatment of patients with severe hypertension.

Sours: https://pubmed.ncbi.nlm.nih.gov/11249890/

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Uses

This drug is used to treat high blood pressure. It is also used to lower the risk of strokes in patients with high blood pressure and an enlarged heart. Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. This product contains two medications: losartan and hydrochlorothiazide. Losartan is an angiotensin receptor blocker (ARB) and works by relaxing blood vessels so that blood can flow more easily. Hydrochlorothiazide is a "water pill" (diuretic) that causes you to make more urine, which helps your body get rid of extra salt and water.

Other Uses

This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used for heart failure.

How To Use

Read the Patient Information Leaflet if available from your pharmacist before you start taking losartan/hydrochlorothiazide and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth as directed by your doctor, usually once daily with or without food. If this medication causes you to urinate more frequently, it is best to take it at least 4 hours before your bedtime to prevent having to get up to urinate.

If you also take certain drugs to lower your cholesterol (bile acid-binding resins such as cholestyramine or colestipol), take losartan/hydrochlorothiazide at least 4 hours before or at least 4 to 6 hours after these medications.

The dosage is based on your medical condition and response to treatment.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day. It is important to continue taking this medication even if you feel well. Most people with high blood pressure do not feel sick.

Tell your doctor if your condition does not improve or if it worsens (for example, your blood pressure readings increase).

Side Effects

Dizziness or lightheadedness may occur as your body adjusts to the medication. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

To reduce the risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

This product may cause a loss of too much body water (dehydration) and salt/minerals. Tell your doctor right away if you have any symptoms of dehydration or mineral loss, including:

  • extreme thirst
  • very dry mouth
  • muscle cramps/weakness
  • fast/slow/irregular heartbeat
  • confusion

Tell your doctor right away if any of these unlikely but serious side effects occur:

  • fainting
  • decrease in vision
  • eye pain
  • symptoms of a high potassium blood level (such as muscle weakness, slow/irregular heartbeat)
  • signs of kidney problems (such as change in the amount of urine)

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including:

  • rash
  • itching/swelling (especially of the face/tongue/throat)
  • severe dizziness
  • trouble breathing

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Precautions

Before taking this medication, tell your doctor or pharmacist if you are allergic to losartan or hydrochlorothiazide; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of:

  • gout
  • kidney disease
  • liver disease
  • lupus
  • severe loss of body water and minerals (dehydration)
  • skin cancer

This drug may make you dizzy. Alcohol or marijuana (cannabis) can make you more dizzy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Limit alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).

Severe sweating, diarrhea, or vomiting can increase the risk for lightheadedness or a serious loss of body water (dehydration). Report prolonged diarrhea or vomiting to your doctor. To prevent dehydration, drink plenty of fluids unless your doctor directs you otherwise.

If you have diabetes, this product may affect your blood sugar. Check your blood sugar regularly as directed and share the results with your doctor. Your doctor may need to adjust your diabetes medication, exercise program, or diet.

This medication may make you more sensitive to the sun. It may also increase your risk for skin cancer, especially if you take it for a long time. Limit your time in the sun. Avoid tanning booths and sunlamps. Use sunscreen and wear protective clothing when outdoors. Tell your doctor right away if you get sunburned, have skin blisters/redness, or notice new or changed moles/skin lesions.

This product may affect your potassium levels. Before using potassium supplements or salt substitutes that contain potassium, consult your doctor or pharmacist.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

Older adults may be more sensitive to the side effects of this drug, especially dizziness and change in the amount of urine (kidney problems).

This medication is not recommended for use during pregnancy due to the risk for harm to an unborn baby. Consult your doctor for more details. (See also Warning section.)

It is unknown if losartan passes into breast milk. Hydrochlorothiazide passes into breast milk, but is unlikely to harm a nursing infant. Consult your doctor before breast-feeding.

Drug Interactions

See also How to Use and Precautions sections.

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include:

  • aliskiren
  • dofetilide
  • lithium
  • drugs that may increase the level of potassium in the blood (such as ACE inhibitors including benazepril/lisinopril, birth control pills containing drospirenone)

Some products have ingredients that could raise your blood pressure or worsen your heart failure. Tell your pharmacist what products you are using, and ask how to use them safely (especially cough-and-cold products, diet aids, or NSAIDs such as ibuprofen/naproxen).

This medication may interfere with certain laboratory tests (including parathyroid function), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.

Overdose

If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe dizziness, fainting.

Notes

Do not share this medication with others.

Lifestyle changes such as stress reduction programs, exercise, and dietary changes may increase the effectiveness of this medicine. Talk to your doctor or pharmacist about lifestyle changes that might benefit you.

Laboratory and/or medical tests (such as kidney function, potassium levels) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

Check your blood pressure regularly while taking this medication. Learn how to monitor your own blood pressure, and share the results with your doctor.

Missed Dose

If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.

Storage

Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

Sours: https://www.healthlinkbc.ca/medications/fdb3372


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