What Factors Affect a Sufficient Losartan Dose?

Losartan potassium tablet, a prescription drug, is the world's first angiotensin II receptor antagonist (AIIA) for the treatment of hypertension ^[1] . It was officially launched in China in 1998 with the approval of the State Food and Drug Administration.

The results of several large-scale clinical studies show that the use of losartan can effectively lower blood pressure, reduce cardiovascular risk, and delay end-stage renal disease. The RENAAL study shows that losartan can significantly reduce the risk of ESRD by 28%; Potassium significantly reduced the primary cardiovascular end point by 13%. ^[2]

Losartan potassium tablets Cited and mentioned in many domestic and foreign guidelines, such as the European Hypertension Guide 2013. The "Guidelines for Blood Pressure Control of Hypertension Complicated with Type 2 Diabetes" issued by the Chinese Medical Association in 2011 states that patients with hypertension and type 2 diabetes must implement a more stringent antihypertensive treatment strategy to effectively control the blood pressure of patients with diabetes. Expert guidance also suggested that angiotensin receptor antagonist (ARB) is the first choice for the treatment of hypertension and diabetes, of which Losartan potassium tablets It has been proven in many classic medical studies that it has a 24-hour potent antihypertensive, long-term stable antihypertensive, improved blood pressure circadian rhythm, and cardiovascular and renal protective effects, with high safety.

Chinese name: Losartan potassium tablets
Foreign name: Losartan Potassium Tablets

product name: COSUYA®
Package: 50mg: Packed in aluminum-plastic board, 7 tablets / box
Specifications: (1) 50mg, (2) 100mg

Losartan potassium tablets drug information

Losartan potassium tablets basic information

[Chinese Pinyin]: Lushatanjia Pian

100mg: Packed in aluminum-plastic board, 7 pieces in a box, 7 pieces × 2 plates / box, 7 pieces × 4 plates / box

[Storage] shading, sealed, and stored in a dry place below 30 ° C.

[Validity] 36 months

[Executive Standard] 50mg JX20120137

100mg JX20120102 ^[3]

[Import Drug Registration Certificate Number]

50mg H20130409

100mg H20130056

100mg H20130057 ^[3]

manufacturer

Company Name: Merck Sharp & Dohme (Australia) Pty. Ltd.

Address: 54-68 Ferndell Street, South Granville, New South Wales 2142, Australia

Factory Name: Merck Sharp & Dohme Limited.

Address: Shotton Lane, Cramlington, Northumberland, NE23 3JU, UK

Packing factory name: Merck Sharp & Dohme (Australia) Pty. Ltd.

Address: 54-68 Ferndell Street, South Granville, New South Wales 2142, Australia ^[3]

[Ingredients]

The main ingredients of this product are: Losartan potassium. Its chemical name is 2-butyl-4-chloro-1-[[2 '-(1H- tetrazol-5-yl) [1,1biphenyl] 4yl] methyl] 1H-imidazole-5-methanol monopotassium salt.

Its structural formula is:

Molecular formula: C ₂₂ H ₂₂ ClKN ₆ O

Molecular weight: 461.01

[Character] 50mg: This product is a white oval film-coated tablet. There is a score on one side of the tablet, and 952 is printed on the other side. After removing the coating, it is white.

100mg: This product is a white teardrop-shaped film-coated tablet. One side of the tablet is engraved with 960 and the other side is not printed. After removing the coating, it is white.

Losartan potassium tablets indications

This product is suitable for the treatment of essential hypertension.

Losartan potassium tablets dosage

This product can be used with other antihypertensive drugs.

This product can be taken with or without food.

For most patients, the starting and maintenance dose is usually 50 mg once daily. Maximum antihypertensive effect can be achieved after 3 to 6 weeks of treatment. In some patients, increasing the dose to 100 mg once daily may produce further hypotensive effects.

For patients with insufficient vascular volume (such as those treated with high-dose diuretics), a starting dose of 25 mg once daily can be considered (see Precautions).

It is not necessary to adjust the starting dose for elderly patients or patients with renal impairment, including patients undergoing hemodialysis. Consider lower doses in patients with a history of liver impairment (see Precautions).

Losartan potassium tablets adverse reactions

Clinical trials have found that this product is well tolerated; side effects are mild and transient, and treatment is generally not required. The overall incidence of adverse reactions with this product was similar to placebo.

In a clinical controlled study of essential hypertension, the only adverse reaction that occurred 1%, was drug-related, and occurred more frequently than placebo was dizziness. In addition, less than 1% of patients develop dose-related orthostatic hypotension. Although the incidence of rashes in controlled clinical trials is lower than placebo, there have been individual reports.

In these clinical double-blind controlled studies of essential hypertension, the adverse reactions occurring at the rate of 1% or more after application of this product, whether or not drug-related, are:

	Losartan potassium tablets (n = 2085)	Blank film (n = 535)
whole body
stomach ache	1.7	1.7
Fatigue / fatigue	3.8	3.9
Chest pain	1.1	2.6
Edema / swelling	1.7	1.9
Cardiovascular System
Palpitations	1.0	0.4
Tachycardia	1.0	1.7
Digestive system
diarrhea	1.9	1.9
indigestion	1.1	1.5
nausea	1.8	2.8
Musculoskeletal system
Back pain	1.6	1.1
Muscle cramps	1.0	1.1
Nervous / mental system
dizziness	4.1	2.4
headache	14.1	17.2
insomnia	1.1	0.7
Respiratory system
cough	3.1	2.6
Nasal congestion	1.3	1.1
pharyngitis	1.5	2.6
Sinus disease	1.0	1.3
Upper respiratory tract infection	6.5	5.6

In addition to the adverse events described above, at least two patients / subjects in the clinical study who had a potential serious adverse event or an incidence of <1% after using losartan are as follows. It is not possible to determine whether these events are related to losartan. Causal relationship:

Whole body: facial edema, fever, orthostatic hypotension, syncope;

Cardiovascular system: angina pectoris, second-degree atrioventricular block, cardiovascular accident, hypotension, myocardial infarction, arrhythmia including atrial fibrillation, palpitations, sinus bradycardia, tachycardia, ventricular tachycardia, ventricle Tremble

Digestive system: loss of appetite, constipation, toothache, dry mouth, flatulence, gastritis, vomiting;

Blood system: anemia;

Metabolism: gout;

Musculoskeletal system: arm pain, hip pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, joint pain, arthritis, fibromyalgia, muscle weakness;

Nervous / mental system: Anxiety, anxiety, ataxia, blurred consciousness, depression, abnormal dreams, dull feelings, decreased libido, memory loss, migraine, nervousness, paresthesia, peripheral neuropathy, phobia, abnormal sleep, lethargy , Tremor, dizziness;

Respiratory system: dyspnea, bronchitis, pharyngeal discomfort, epistaxis, rhinitis, respiratory congestion;

Skin: Hair loss, dermatitis, dry skin, bruising, redness, flushing, light sensitivity, itching, rash, sweating, hives;

Special sensations: blurred vision, burning and tingling eyes, conjunctivitis, wrong taste, tinnitus, decreased visual acuity;

Genitourinary system: impotence, nocturia, frequent urination, urinary tract infection.

This product is generally well tolerated in a controlled clinical trial in patients with hypertension and left ventricular hypertrophy. The most common drug-related adverse reactions are dizziness, fatigue / fatigue, and dizziness.

In the LIFE study, in patients without diabetes at baseline, the incidence of new diabetes in the losartan potassium group was higher than that of atre

The Lore group was lower (242 versus 320, respectively, p <0.001). Because there were no placebo groups in this study, it is unclear whether this result represents the benefit of losartan potassium or the adverse effects of atenolol.

This product is generally well tolerated in a controlled clinical trial in patients with type 2 diabetes with proteinuria. The most common drug-related adverse reactions are fatigue / fatigue, dizziness, hypotension and hyperkalemia (see Precautions, Hypotension and Electrolyte / Body Fluid Imbalance).

Other adverse reactions that have been reported after the listing of this product include:

Allergic reactions: Angioedema (including swelling of the throat and glottis that causes airway obstruction, and / or swelling of the face, lips, pharynx, and / or tongue) has been reported in a very small number of patients taking losartan. Some of these patients have previously experienced angioedema due to taking other drugs, including ACE inhibitors. Vasculitis, including Hennock-Schoenlein (Hen-Sheer) purpura, has been rarely reported.

Gastrointestinal reactions: Hepatitis (rarely reported), abnormal liver function, vomiting.

General disorders and administration site conditions: discomfort.

Blood system: anemia, thrombocytopenia (rarely reported).

Musculoskeletal system: myalgia, joint pain.

Nervous / Mental System: Migraines, Seizures, Taste Disorders.

Reproductive system disorders: erectile dysfunction / impotence.

Respiratory system: Cough.

Skin: hives, pruritus, erythroderma, light sensitivity.

Hyperkalemia and hyponatremia have been reported.

There was one spontaneous report of an unexplained death related to a drug in the country.

Laboratory test results

In clinically controlled trials of essential hypertension, few patients who use this product have clinically significant changes in laboratory parameters. Hyperkalemia occurred in 1.5% of patients (serum potassium> 5.5mEq / L). In a clinical study of patients with type 2 diabetes with proteinuria, 9.9% and 3.4% of patients in the losartan and placebo groups developed hyperkalemia (see Precautions, Hypotension and Electrolyte / Body fluid imbalance). ALT elevations are rare and return to normal after discontinuation.

Creatinine, blood urea nitrogen: In patients with essential hypertension, less than 0.1% of patients using this product alone have observed a slight increase in blood urea nitrogen or serum creatinine.

Hemoglobin and hematocrit: Mild decreases in hemoglobin and hematocrit often occur in patients treated with this product alone (average reductions of about 0.11% g and 0.09% volume, respectively), but rarely of clinical importance, no patients Suspension of medication due to anemia.

Liver function tests: occasionally elevated liver enzymes and / or serum bilirubin. Among patients with essential hypertension treated with this product alone, one patient (<0.1%) discontinued medication due to these laboratory adverse reactions.

Losartan potassium taboo

Patients with diabetes should not use this product in combination with aliskiren (see [Drug Interactions]).

Losartan potassium tablets precautions

Allergic reactions: angioedema. See adverse reactions

Hypotension and electrolyte / body fluid imbalance

Patients with insufficient vascular volume (such as those treated with high-dose diuretics) may develop symptomatic hypotension. These conditions should be corrected before using this product, or a lower starting dose should be used. (See Dosage and Administration).

It should be noted that electrolyte imbalance is common in patients with renal insufficiency, with or without diabetes. In clinical studies in patients with type 2 diabetes with proteinuria, the incidence of hyperkalemia was higher in the losartan potassium treatment group than in the placebo group; however, few patients discontinued treatment due to hyperkalemia (see Adverse Reactions and Laboratory test results).

Liver function impairment

Pharmacokinetic data indicate that the plasma concentration of losartan in patients with liver cirrhosis is significantly increased, so patients with a history of liver impairment should consider using lower doses (see Dosage and Administration).

Impaired renal function

Due to the inhibition of the renin-angiotensin system, changes in renal function, including renal failure, have been reported in sensitive individuals; these changes in renal function can be restored after treatment is discontinued.

For patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system (such as patients with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors can cause oliguria and / or progressive azotemia And (rare) acute renal failure and / or death. Similar reports have been reported with losartan.

For patients with bilateral renal artery stenosis or patients with unilateral kidney and renal artery stenosis, other drugs affecting the renin-angiotensin system can increase their blood urea and serum creatinine levels. There have been similar reports on the use of this product. These changes in kidney function can be restored after stopping treatment.

[Medication for pregnant and lactating women]

Medication for pregnant women

When pregnant women take the drug in the second and third trimester, drugs that directly affect the renin - angiotensin system can cause damage to the developing fetus and even death. When pregnancy is found, this product should be discontinued as soon as possible.

Although there is no experience in using this product in pregnant women, animal studies using losartan potassium have demonstrated fetal and neonatal injury and death, and the mechanism is believed to act on the renin-angiotensin system through drug mediation Caused by. The renal perfusion of human fetus from the second trimester of pregnancy depends on the development of the renin-angiotensin system. Therefore, if this product is applied in the second and third trimester of pregnancy, the risk to the fetus will increase.

Medication for lactating women

It is unknown whether losartan is secreted by human milk. Because many drugs can be secreted by human milk and have an adverse effect on nursing infants, the decision to stop breastfeeding or to discontinue the drug should be based on the importance of the mother.

[Child medication]

The antihypertensive effect of this product has been established in hypertensive children aged> 1 month to 16 years. Evidence from adequate pediatric and adult controlled studies and literature reports on use in children support the use of this product in these age groups.

Fifty children with hypertension, aged> 1 month to <16 years old, were treated with a daily losartan dose of about 0.54-0.77 mg / Kg (average dose). The pharmacokinetics of losartan was studied. Losartan forms active metabolites in all age groups. Overall, the pharmacokinetics of losartan and its active metabolites were similar across the age groups studied, consistent with existing adult pharmacokinetic data.

A clinical study of 177 hypertensive children aged 6-16 years, patients weighing 20Kg to <50Kg, taking 2.5, 25 or 50mg of losartan daily, and patients weighing 50Kg taking 5, 50 or 100 mg of losartan. Taking once daily can reduce trough blood pressure and is dose-dependent. Dose correlation was observed in all subgroups (eg, age, Tanner stage, gender, ethnicity). However, the lowest doses studied, 2.5 mg and 5 mg, corresponded to an average daily dose of 0.7 mg / Kg, and did not show antihypertensive effects consistent with other doses.

In this study, this product is usually well tolerated.

For patients who can swallow tablets, body weights 20Kg to 50Kg, the starting dose is 50mg once a day. The maximum dose can be increased to 100 mg once daily.

For children with insufficient vascular volume, these conditions should be corrected before taking this product.

Adverse events in pediatric patients are similar to those found in adults.

It is not recommended to use this product in children with glomerular filtration rate <30mL / min / 1.73m2, and children with liver damage. Since there is no data for use in neonates, this product is not recommended.

[Medicine for the elderly]

race

Based on the LIFE study, although both treatment groups are effective in lowering blood pressure in black patients, the benefits of losartan in reducing cardiovascular morbidity and mortality compared with atenolol are not applicable to black hypertension with left Ventricular hypertrophy. In all patients participating in the LIFE study (n = 9193), the primary composite endpoint risk of cardiovascular death, stroke, and myocardial infarction was reduced by 13% compared with the atenolol group (p = 0.021). In the LIFE study, compared with atenolol, losartan reduced the risk of cardiovascular disease and death in patients with hypertension other than blacks with left ventricular hypertrophy (n = 8660). And the primary clinical endpoint of myocardial infarction (p = 0.003). However, in this study, black patients in the atenolol group had a lower risk of experiencing a primary composite endpoint compared with the losartan group (p = 0.03). In the subgroup of black patients (n = 533; 6% of patients in the LIFE study), 29 of the 263 patients in the atenolol group (11%, 25.9 per 1,000 patient-years) had a primary endpoint, In contrast, 46 of the 270 patients in the losartan group (17%, 41.8 per 1000 patient-years).

Losartan potassium tablets drug interactions

In clinical pharmacokinetic studies, it has been confirmed that there is no clinically significant drug interaction with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole, and erythromycin. Rifampicin and fluconazole have been reported to reduce active metabolite levels. The clinical outcomes of these interactions have not been evaluated.

As with other drugs that inhibit angiotensin II and its effects, this product is used in combination with potassium-sparing diuretics (such as spironolactone, ampicillin, amiloride), potassium supplements, or potassium-containing salt substitutes. Can lead to elevated potassium.

Like other drugs that affect sodium excretion, excretion of lithium may be reduced. Therefore, if lithium salts are used in combination with angiotensin II receptor antagonists, serum lithium salt levels should be carefully monitored.

Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effects of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effects of angiotensin II receptor antagonists or angiotensin-converting enzyme inhibitors may be impaired by NSAIDs, including COX-2 inhibitors.

For patients with impaired renal function who are taking nonsteroidal anti-inflammatory drugs including selective cyclooxygenase-2 inhibitors (for example, elderly or hypovolemic patients, including patients receiving diuretics), Concomitant administration of angiotensin II receptor antagonists or angiotensin-converting enzyme inhibitors may lead to further renal impairment, including the possibility of acute renal failure. These effects are usually reversible. Therefore, caution should be exercised in combination therapy in patients with renal insufficiency.

Compared to monotherapy, double blockade of renin-angiotensin-aldosterone system (RAAS) with angiotensin receptor resistance, ACE inhibitors or aliskiren increases hypotension, syncope, hyperkalemia, and kidney The risk of functional changes, including acute renal failure. Patients who use losartan potassium in combination with other drugs that affect RAAS closely monitor their blood pressure, renal function, and electrolytes. Diabetics should not use losartan potassium tablets with aliskiren. Patients with renal impairment (GFR <60ml / min) should avoid the combined use of losartan potassium tablets and aliskiren.

Losartan potassium tablets overdose

Little information is available on human overdose. The most likely manifestations of overdose will be hypotension and tachycardia. Bradycardia can occur due to the excitation of the parasympathetic nerve (vagus nerve). If symptomatic hypotension occurs, supportive care should be given.

Neither losartan nor its active metabolites can be cleared by hemodialysis.

Losartan potassium tablets pharmacology and toxicology

Mechanism

Angiotensin II is the main active substance of the renin-angiotensin system. It is a potent vasoconstrictor and plays a major role in the pathophysiology of hypertension. Angiotensin II binds to the AT1 receptor in a variety of tissues (such as vascular smooth muscle, adrenal glands, kidneys, and heart) and produces a number of important biological effects including vasoconstriction and aldosterone release.

At the same time, it can stimulate smooth muscle cell proliferation. Another angiotensin II receptor subtype has been confirmed to be AT2, but its effect on the homeostasis of the cardiovascular system is unclear.

Losartan is a synthetic, potent, orally active drug. Binding tests and pharmacological bioassays have demonstrated that it can selectively bind to the AT1 receptor. In vivo and in vitro studies have shown that losartan and its pharmacologically active carboxylic acid metabolite (E-3174) can block the corresponding physiological effects of angiotensin II synthesized from any source or any pathway. Compared with other peptide angiotensin II antagonists, losartan has no agonistic effect.

Losartan selectively acts on the AT1 receptor, does not affect the function of other hormone receptors or important ion channels in the cardiovascular system, nor inhibits angiotensin converting enzyme (kininase II), which degrades bradykinin. Therefore, effects not directly related to blocking the AT1 receptor, such as bradykinin-mediated effects or edema (losartan 1.7%, placebo 1.9%) were not related to losartan.

Toxicology research

Male mice received losartan potassium orally with an LD50 of 2248 mg / Kg (6744 mg / m ² ) (1124 times the maximum recommended daily dose for adults). The significant minimum lethal doses of this product taken by mice and rats are 1000mg / Kg (3000mg / m ² ) and 2000mg / Kg (11800mg / m ² ), which are the maximum recommended daily doses for adults (calculated based on 50Kg body weight). 500 times and 1000 times.

The potential toxicity of losartan potassium was evaluated by conducting a series of toxicity tests on monkeys for three months, rats and dogs, with multiple oral administrations for one year, and was found not to impede medication at therapeutic dose levels.

The maximum tolerated dose of this product was given to rats and mice. The observation time was 105 weeks and 92 weeks, respectively. No carcinogenic effect of losartan potassium was found.

In vitro alkaline elution tests and chromosomal aberration tests have shown that there is no direct mutagenic effect of losartan potassium using 1700 times the maximum plasma concentration that humans can achieve with the recommended therapeutic dose.

Male and female rats were orally administered losartan potassium at 150 and 300 mg / kg, respectively, and this product was not found to affect reproduction.

Losartan potassium has adverse effects on rat embryos and newborns, including weight loss, death, and / or renal toxicity. In addition, the concentration of losartan potassium and its active metabolites was higher in the milk of the rats.

Losartan potassium tablets pharmacokinetics

Absorption: This product is well absorbed orally, and forms carboxylic acid-type active metabolites and other inactive metabolites after first pass metabolism; bioavailability is about 33%. The plasma concentrations of losartan and its active metabolites peaked at 1 hour and 3-4 hours, respectively. When this product is taken with food, the plasma concentration of losartan does not change significantly.

Distribution: The plasma protein binding rate of losartan and its active metabolites is 99%, which is mainly combined with albumin. Losartan has a distributed volume of 34 liters. Studies in rats have shown that losartan can hardly cross the blood-brain barrier.

Metabolism: After intravenous or oral losartan, approximately 14% of the dose is converted into active metabolites. The 14C-labeled losartan potassium is administered intravenously or orally. The radioactivity in circulating plasma mainly comes from losartan and its active metabolites. In the trial, only a small amount of losartan was converted into active metabolites by about 1% of the individuals.

In addition to the active metabolites, there are also inactive metabolites produced, including the two main metabolites produced by the hydroxylation of the butyl side chain and a small amount of N-2 glucuronide.

Elimination: Loss of plasma of losartan and its active metabolites were 600 ml / min and 50 ml / min, respectively. Renal clearance was 74 ml / min and 26 ml / min, respectively. When losartan potassium is administered orally, about 4% of the dose is excreted in the urine as it is, and 6% of the dose is excreted in the urine as the active metabolite. When oral losartan potassium reaches 200 mg, the pharmacokinetics of losartan and its active metabolites are linear.

After oral administration, the plasma concentrations of losartan and its active metabolites showed a multi-stage exponential decrease with terminal half-life of 2 hours and 6-9 hours, respectively. When 100 mg was administered once a day, neither losartan nor its active metabolite was significantly accumulated in plasma.

Losartan and its metabolites are excreted in bile and urine. When 14C-labeled losartan is orally administered to humans, 35% of radioactivity occurs in urine and 58% occurs in feces. When humans were injected intravenously with 14C-labeled losartan, the radioactivity in urine and feces was 43% and 50%, respectively.

Losartan potassium tablet guide recommendation

As the world's first ARB antihypertensive drug on the market, Kosoy has been cited and mentioned by many domestic and foreign guidelines due to its sufficient evidence-based evidence, such as the European Hypertension Guide 2013 ^[4] . The "Guidelines for Blood Pressure Control of Hypertension Complicated with Type 2 Diabetes" issued by the Chinese Medical Association in 2011 ^[5] states that patients with hypertension and type 2 diabetes must implement a more stringent antihypertensive treatment strategy to effectively control the blood pressure of patients with diabetes. Expert guidance also suggested that angiotensin receptor antagonist (ARB) is the first choice for the treatment of hypertension combined with diabetes. Among them, Kosova has been proven in many classic medical studies to have a 24-hour potent antihypertensive, long-term stable reduction Pressure, improve blood pressure circadian rhythm, and cardiovascular and renal protection, high safety.

Study on Clinical Data of Losartan Potassium Tablets

Hypertension Research

The antihypertensive effect of this product has been proven in 11 controlled studies, of which 1679 patients took this product, 471 patients took placebo, and 488 patients took other various control drugs. Patients with mild and moderate essential hypertension take this product once a day, and the reduction in systolic and diastolic blood pressure is significantly statistically significant; antihypertensive treatment in clinical studies has continued for nearly a year. The blood pressure at the trough (24 hours after taking the medicine) and the peak (5-6 hours after taking the medicine) were measured, which showed that it had a smooth blood pressure lowering effect for 24 hours. The antihypertensive effect is the same as the normal daily circadian rhythm. The blood pressure reduction at the end of the treatment period is about 70% -80% of the 5-6 hours after taking the drug. Maximum hypotensive effect was achieved 3-6 weeks after the first dose. Although it can significantly reduce blood pressure, this product has no significant clinically significant impact on heart rate. There was no sudden rebound in blood pressure after losartan was discontinued.

The daily antihypertensive effect of 50-100mg of this product is significantly stronger than that of captopril 50-100mg once daily. The daily antihypertensive effect of 50mg of this product is similar to that of enalapril 20mg once daily. The daily antihypertensive effect of 50-100mg of this product can be compared with the antihypertensive effect of atenolol 50-100mg once a day. Elderly hypertensive patients (65 years old), after 12 weeks of treatment, the antihypertensive effect of 50-100mg once-daily administration of this product is the same as that of felodipine sustained-release 5-10mg.

For men and women, young (<65 years) and old (65 years) hypertensive patients have the same effect when taking this product. Although this product has antihypertensive effects in all races studied, like other drugs acting on the renin-angiotensin system, the average response of black hypertension patients to losartan monotherapy is slightly lower than that of non-black patients.

When combined with thiazide diuretics, the antihypertensive effect of this product slightly increased.

Because this product selectively blocks the AII receptor, patients are not expected to cause cough when taking this product. An 8-week controlled study was performed on hypertensive patients with a history of cough during the use of ACEI drugs. Taking this product or taking a drug (hydrochlorothiazide) without ACEI cough-causing effects, patients reported similar incidence of cough, which was significant. Lower than patients using ACEIs. In addition, a comprehensive analysis of 4131 patients in 16 double-blind clinical studies reported a spontaneous incidence of cough, similar to taking this product (3.1%) and placebo (2.6%) or hydrochlorothiazide (4.1%) while taking ACEIs. The incidence was 8.8%.

LIFE research

Losartan Hypertensive Patient Survival Study (LIFE Study) is a large, multi-center, multi-national, randomized, three-blind, active drug-controlled study of 9193 patients aged 55-80 years (mean 67 years), ECG (ECG) Hypertensive patients diagnosed with left ventricular hypertrophy (LVH). At baseline, 1195 (13%) patients had diabetes;

1326 (14%) had simple systolic hypertension; 1468 (17%) had coronary heart disease; 728 (8%) had cerebrovascular disease. The purpose of the study was to determine the cardiovascular protective effect of losartan compared to atenolol in terms of the benefits of lowering or exceeding blood pressure (measurement of trough blood pressure). To achieve this goal, the experiment was designed with the same degree of blood pressure control in both treatment groups. Patients were randomized and received either losartan 50 mg or atenolol 50 mg once daily. If the target blood pressure (<140 / 90mmHg) is not reached, hydrochlorothiazide (12.5mg) can be added first. If necessary, the dose of losartan or atenolol can be increased to 100mg once a day. In order to achieve the target blood pressure, other antihypertensive drugs can be added for treatment if necessary (such as increasing the dose of hydrochlorothiazide to 25mg, or adding other diuretics, calcium channel blockers, alpha receptor blockers, or centrally acting drugs, but Do not add ACE inhibitors, angiotensin II receptor antagonists or beta blockers).

Blood pressure in both treatment groups was significantly reduced to similar levels, and blood pressure in similar proportions of patients decreased to ideal levels. The average follow-up time was 4.8 years.

The primary clinical endpoint was cardiovascular morbidity and mortality, and the observed indicators were the decline in the combined incidence of cardiovascular death, stroke, and myocardial infarction. The results showed a 13% reduction in the risk of the primary composite endpoint in the losartan group compared with the atenolol group (p = 0.021) (see Figure 1).

Figure 1. Kaplan-Meier curve for the primary composite endpoint of cardiovascular death, stroke, or myocardial infarction adjusted for baseline Framingham risk factor scores and ECG LVH levels in the losartan and atenolol-treated groups.

Compared with the atenolol group, the losartan treatment group reduced the risk of stroke by 25% (p = 0.001). There was no significant difference between the two groups in reducing cardiovascular death and myocardial infarction. Losartan has shown benefits beyond blood pressure control in reducing the incidence of primary composite endpoints (see table below).

Other clinical endpoints of the LIFE study: total mortality, heart failure or angina requiring hospitalization, coronary or peripheral vascular reconstruction surgery, and cardiac arrest and resuscitation. There was no significant difference between the two treatment groups in reducing the incidence of these clinical endpoints. Compared with the atenolol group, the LVH index of losartan group was significantly reduced.

In the subgroup of patients with a history of diabetes (n = 1195) or a history of simple systolic hypertension (ISH) (n = 1326) at baseline, atenolol was used as a control to evaluate the cardiovascular prevalence of losartan And mortality. In terms of reducing the primary comprehensive clinical endpoint, the results obtained in the subgroup were consistent with the therapeutic benefits of losartan in the entire study population: a 24% reduction in the risk of the primary comprehensive endpoint was observed in patients with diabetes (p = 0.03), and For patients with isolated systolic hypertension, the risk was reduced by 25% (p = 0.06). Consistent with the results obtained in the entire study population, reducing the risk of stroke has important clinical benefits for patients with diabetes or patients with isolated systolic hypertension.

In this study, losartan was well tolerated, and due to the significantly lower incidence of adverse reactions interruption, it was better tolerated than atenolol.

RENAAL research

Losartan Renal Protection Study (RENAAL Study) is a large, multicenter, randomized, placebo-controlled, double-blind clinical study that globally enrolled 1513 patients with type 2 diabetes with proteinuria (of which 751 were treated with losartan ), With or without history of hypertension. The purpose of the study was to determine the renal protective effect of losartan in reducing blood pressure and its benefits beyond blood pressure. To achieve this goal, the experiment was designed to achieve the same blood pressure control in both treatment groups. Based on conventional antihypertensive therapy (except ACE inhibitors and angiotensin II receptor antagonists), patients with proteinuria and serum creatinine 1.3-3.0mg / dL were randomly assigned to the losartan 50mg group Once a day, the dose of losartan can be adjusted according to the antihypertensive effect, or the placebo group.

When appropriate, researchers were instructed to adjust the study drug dose to 100 mg once daily; 72% of patients took losartan at a dose of 100 mg once daily for most of the study period. Other antihypertensive drugs can be added to both study groups as needed: diuretics, calcium channel blockers, alpha- or beta-blockers, and centrally acting drugs. Patients were followed for up to 4.6 years (mean 3.4 years).

The primary end point of the study was the combined end point of doubling serum creatinine, end-stage renal disease (dialysis or kidney transplantation required), or death. The results showed that compared with the placebo group (359 patients), the losartan group (327 patients) reduced the risk of the primary comprehensive endpoint by 16.1% (p = 0.022). The losartan group also showed a significant reduction in risk with respect to the following primary and composite primary endpoints: a 25.3% reduction in the risk of doubling serum creatinine concentration (p = 0.006); a 28.6% reduction in the risk of end-stage renal disease (p = 0.002) ); The risk of end-stage renal disease or death decreased by 19.9% (p = 0.009); the serum creatinine concentration doubled or the risk of end-stage renal disease decreased by 21.0% (p = 0.010). In both treatment groups, mortality from all causes was not Significant differences.

The secondary endpoints of the study were the combined endpoints of changes in proteinuria, rate of renal disease progression, morbidity and mortality of cardiovascular disease (including heart failure, myocardial infarction, vascular reconstruction, and hospitalization due to stroke, and unstable angina) Hospitalization or cardiovascular death). The results showed that the proteinuria level of patients in the losartan group decreased by an average of 34.3% (p <0.001). In long-term studies, the reciprocal of serum creatinine concentration was used to evaluate the rate of reduction of renal function in the losartan group by 13.9% (p = 0.003) (median rate of decreasing renal function was 18.5%, p = 0.01 ). Regarding the composite end point of cardiovascular disease morbidity and mortality, although there was not enough efficacy to test this composite end point in this study, there was no significant difference between the losartan group (247 patients) and the placebo group (268 patients).

In this study, losartan was well tolerated. The incidence of discontinuation of studies due to adverse events was similar in both groups.