Assessment of various efficacy outcomes using ERIVANCE-like criteria in patients with locally advanced basal cell carcinoma receiving sonidegib: results from a preplanned sensitivity analysis.

BACKGROUND: The BOLT study for sonidegib, a Hedgehog pathway inhibitor (HHI) approved for patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy, used modified Response Evaluation Criteria in Solid Tumors (mRECIST) for laBCC tumor evaluation. The ERIVANCE study for vismodegib, another HHI, used a composite RECIST endpoint of ≥30% reduction in externally visible tumor or radiographic dimension, or complete ulceration resolution. This preplanned sensitivity BOLT analysis evaluated efficacy outcomes using ERIVANCE-like criteria in patients with laBCC who received sonidegib 200 mg once daily. METHODS: This phase 2, double-blind study randomized patients 1:2 to sonidegib 200:800 mg daily, respectively. Key endpoints included objective response rate (ORR), duration of response (DOR), complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). laBCC tumors were assessed by both mRECIST and ERIVANCE-like criteria. Per mRECIST, an overall response of CR was based on negative histology; photographic assessment of CR, PR (scar/fibrosis only), SD (scar/fibrosis only), or not available (NA); and a magnetic resonance imaging response of CR or NA. An overall response of CR was primarily based on negative histology using ERIVANCE-like criteria. RESULTS: Per mRECIST criteria, ORR (95% confidence interval [CI]) by central and investigator review for patients with laBCC (n = 66) was 56.1% (43.3-68.3%) and 71.2% (58.7-81.7%), respectively. CR per central review was achieved in 3 (4.5%) patients and PR, SD, and PD occurred in 34 (51.5%), 23 (34.8%), and 1 (1.5%) patient, respectively. Median (95% CI) DOR was 26.1 months (not estimable [NE]). Using ERIVANCE-like criteria, efficacy outcomes per central and investigator review were higher, with an ORR (95% CI) of 60.6% (47.8-72.4%) and 74.2% (62.0-84.2%), respectively. CR per central review was reached in 14 (21.2%) patients and PR, SD, and PD occurred in 26 (39.4%), 20 (30.3%), and 1 (1.5%) patient, respectively. DOR was unchanged with a median (95% CI) of 26.1 months (NE). CONCLUSIONS: Overall, applying ERIVANCE-like criteria to patients with laBCC receiving sonidegib 200 mg daily yielded higher response rates vs mRECIST criteria. TRIAL REGISTRATION: BOLT registration: ClinicalTrials.gov ( NCT01327053 ) on March 30, 2011.

Clinical Effectiveness of Sacubitril/Valsartan Among Patients Hospitalized for Heart Failure With Reduced Ejection Fraction.

Background Sacubitril/Valsartan has been highly efficacious in randomized trials of heart failure with reduced ejection fraction (HFrEF). However, the effectiveness of sacubitril/valsartan in older patients hospitalized for HFrEF in real-world US practice is unclear. Methods and Results This study included Medicare beneficiaries age ≥65 years who were hospitalized for HFrEF ≤40% in the Get With The Guidelines-Heart Failure registry between October 2015 and December 2018, and eligible for sacubitril/valsartan. Associations between discharge prescription of sacubitril/valsartan and clinical outcomes were assessed after inverse probability of treatment weighting and adjustment for other HFrEF medications. Overall, 1551 (10.9%) patients were discharged on sacubitril/valsartan. Of those not prescribed sacubitril/valsartan, 7857 (62.0%) were prescribed an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker. Over 12-month follow-up, compared with a discharge prescription of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, sacubitril/valsartan was independently associated with lower all-cause mortality (adjusted hazard ratio [HR], 0.82; 95% CI, 0.72-0.94; P=0.004) but not all-cause hospitalization (adjusted HR, 0.97; 95% CI, 0.89-1.07; P=0.55) or heart failure hospitalization (adjusted HR, 1.04; 95% CI, 0.91-1.18; P=0.59). Patients prescribed sacubitril/valsartan versus those without a prescription had lower risk of all-cause mortality (adjusted HR, 0.69; 95% CI, 0.60-0.79; P<0.001), all-cause hospitalization (adjusted HR, 0.90; 95% CI, 0.82-0.98; P=0.02), but not heart failure hospitalization (adjusted HR, 0.94; 95% CI, 0.82-1.08; P=0.40). Conclusions Among patients hospitalized for HFrEF, prescription of sacubitril/valsartan at discharge was independently associated with reduced postdischarge mortality compared with angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, and reduced mortality and all-cause hospitalization compared with no sacubitril/valsartan. These findings support the use of sacubitril/valsartan to improve postdischarge outcomes among older patients hospitalized for HFrEF in routine US clinical practice.

Conflicting Perspectives on the Value of Neprilysin Inhibition in Heart Failure Revealed During Development of a Decision Aid Focusing on Patient Costs for Sacubitril/Valsartan.

BACKGROUND: Despite concerns about rising costs in health care, cost is rarely an issue discussed by patients and clinicians when making treatment decisions in a clinical setting. This study aimed to understand stakeholder perspectives on a patient decision aid (PtDA) meant to help patients with heart failure choose between a generic and relatively low-cost heart failure medication (ACE [angiotensin-converting enzyme] inhibitor or angiotensin II receptor blocker) and a newer, but more expensive, heart failure medication (angiotensin II receptor blocker neprilysin inhibitor). METHODS AND RESULTS: Feedback on the PtDA was solicited from 26 stakeholders including patients, clinicians, and the manufacturer. Feedback was recorded and discussed among development team members until consensus regarding both the interpretation of the data and the appropriate changes to the PtDA was reached. Stakeholders found the PtDA sufficient in clarifying the different treatment options for heart failure. However, patients, physicians, and the manufacturer had different opinions on the importance of highlighting cost in a PtDA. Patients indicated issues of cost were crucial to the decision while physicians and manufacturers expressed that the cost issue was secondary and should be de-emphasized. CONCLUSIONS: The stratified perspectives on the role of cost in medical decision-making expressed by our participants underscore the importance and challenge of having clear, frank discussions during clinic visits about treatment cost and perceived value.

Exposure monitoring and risk assessment of biphenyl in the workplace.

This study was performed to assess exposure to and the risk caused by biphenyl in the workplace. Biphenyl is widely used as a heat transfer medium and as an emulsifier and polish in industry. Vapor or high levels of dust inhalation and dermal exposure to biphenyl can cause eye inflammation, irritation of respiratory organs, and permanent lesions in the liver and nervous system. In this study, the workplace environment concentrations were assessed as central tendency exposure and reasonable maximum exposure and were shown to be 0.03 and 0.12 mg/m³, respectively. In addition, the carcinogenic risk of biphenyl as determined by risk assessment was 0.14 × 10⁻4 (central tendency exposure) and 0.56 × 10⁻4 (reasonable maximum exposure), which is below the acceptable risk value of 1.0 × 10⁻4. Furthermore, the central tendency exposure and reasonable maximum exposure hazard quotients were 0.01 and 0.06 for oral toxicity, 0.05 and 0.23 for inhalation toxicity, and 0.08 and 0.39 for reproduction toxicity, respectively, which are all lower than the acceptable hazard quotient of 1.0. Therefore, exposure to biphenyl was found to be safe in current workplace environments. Because occupational exposure limits are based on socioeconomic assessment, they are generally higher than true values seen in toxicity experiments. Based on the results of exposure monitoring of biphenyl, the current occupational exposure limits in Korea could be reviewed.

Comprehensive overview: efficacy, tolerability, and cost-effectiveness of irbesartan.

BACKGROUND: Hypertension represents a major health problem, affecting more than one billion adults worldwide. Irbesartan, an angiotensin II receptor blocker, is considered to be a highly effective treatment in the management of hypertension. The purpose of this review is to evaluate the efficacy, safety and tolerability profile, and cost-effectiveness of treatment with irbesartan in hypertension. METHODS: A review of the literature was conducted using the electronic PubMed and Cochrane Library databases and the Health Economic Evaluations Database of search terms relating to irbesartan efficacy, tolerability, and cost-effectiveness, and the results were utilized. RESULTS: Findings from the present analysis show that irbesartan either as monotherapy or in combination with other antihypertensive agents can achieve significant reductions in blood pressure, both systolic and diastolic, compared with alternative treatment options. Irbesartan was also found to have a renoprotective effect independent of its blood pressure-lowering in patients with type 2 diabetes and nephropathy. Furthermore, irbesartan demonstrated an excellent safety and tolerability profile, with either lower or equal adverse events compared with placebo and other alternative treatments. In terms of economic analyses, compared with other antihypertensive therapy alternatives, irbesartan was found to be a preferred option, that is less costly and more effective. CONCLUSION: The evidence indicates that treating patients with hypertension alone or with type 2 diabetes and nephropathy using irbesartan can control hypertension, prolong life, and reduce costs in relation to existing alternatives.

I-ADD study: assessment of efficacy and safety profile of irbesartan/amlodipine fixed-dose combination therapy compared with irbesartan monotherapy in hypertensive patients uncontrolled with irbesartan 150 mg monotherapy: a multicenter, phase III, prospective, randomized, open-label with blinded-end point evaluation study.

BACKGROUND: Hypertension guidelines recommend the use of 2 agents with synergistic action when >1 agent is needed to achieve blood pressure goals. Newer antihypertensive treatment combinations include fixed-dose combinations of an angiotensin receptor blocker and a calcium channel blocker. OBJECTIVE: The I-ADD study aimed to demonstrate whether the antihypertensive efficacy of fixed-dose combination irbesartan 300 mg/amlodipine 5 mg (I300/A5) was superior to that of irbesartan (I300) monotherapy in lowering home systolic blood pressure after 10 weeks' treatment. METHODS: The I-ADD study was a 10-week, multicenter, Phase III, prospective, randomized, parallel-group, open-label with blinded-end point study. The main inclusion criterion was essential uncontrolled hypertension (systolic blood pressure ≥145 mm Hg at office after at least 4 weeks of irbesartan 150 mg [I150] monotherapy administered once daily). Patients continued to receive I150 for 7 to 10 days and were randomized to either monotherapy with I150 for 5 weeks then I300 for the next 5 weeks, or to a fixed-dose combination therapy (I150/A5, then I300/A5). Safety profile was assessed by recording adverse events reported by patients or observed by the investigator. RESULTS: Following enrollment, 325 patients were randomized to treatment, and 320 (mean [SD] age, 56.7 [11.4] years; 41% male) were included in the intention-to-treat analysis: 155 patients treated with I150/A5 then I300/A5, and 165 patients treated with I150 then I300. At randomization, mean home systolic blood pressure was similar in both groups: 152.7 (11.8) mm Hg in the I150/A5 group and 150.4 (10.1) mm Hg in the I150 group. At week 10, the adjusted mean difference in home systolic blood pressure between groups was -8.8 (1.1) mm Hg (P < 0.001). The percentage of controlled patients (mean home blood pressure <135 and 85 mm Hg) was nearly 2-fold higher in the I300/A5 group versus the I300 group (P < 0.001). Treatment-emergent adverse events were experienced by 10.5% of I300/A5-treated patients and 6.6% of I300-treated patients during the second 5-week period. Three serious adverse events were reported; 2 with monotherapy (1 with I150 and 1 with I300) and 1 with fixed-dose combination I300/A5. All patients affected by serious adverse events made a full recovery. CONCLUSIONS: These 10-week data from this patient population suggest a greater antihypertensive efficacy of the fixed-dose combination I300/A5 over I300 alone in lowering systolic blood pressure. Both treatments were well tolerated throughout the study. ClinicalTrials.gov identifier: NCT00957554.

I-COMBINE study: assessment of efficacy and safety profile of irbesartan/amlodipine fixed-dose combination therapy compared with amlodipine monotherapy in hypertensive patients uncontrolled with amlodipine 5 mg monotherapy: a multicenter, phase III, prospective, randomized, open-label with blinded-end point evaluation study.

BACKGROUND: Hypertension guidelines recommend the use of 2 agents with synergistic action when >1 agent is needed to achieve blood pressure goals. Newer antihypertensive treatment combinations include fixed-dose combinations of an angiotensin receptor blocker and a calcium channel blocker. OBJECTIVE: The I-COMBINE study aimed to determine whether the antihypertensive efficacy of the fixed-dose combination irbesartan 150 mg/amlodipine 5 mg (I150/A5) was superior to that of amlodipine 5 mg (A5) monotherapy in lowering home systolic blood pressure (HSBP) after 5 weeks' treatment. METHODS: The I-COMBINE study was a 10-week, multicenter, Phase III, prospective, randomized, parallel-group, open-label with blinded-endpoint study. The main inclusion criterion was essential uncontrolled hypertension (SBP ≥145 mm Hg at office, after at least 4 weeks of A5 monotherapy administered once daily). Patients continued to receive A5 for 7 to 10 days and were randomized to either monotherapy with A5 for 5 weeks then amlodipine 10 mg (A10) for the next 5 weeks or to a fixed-dose combination therapy (I150/A5 then I150/A10). Safety profile was assessed by recording adverse events reported by patients or observed by the investigator. RESULTS: Following enrollment, 290 patients were randomized to treatment, and 287 (mean [SD] age, 57.3 [11.2] years; 48% male) were included in the intention-to-treat analysis: 144 patients treated with I150/A5 then I150/A10, and 143 patients treated with A5 then A10. At randomization, mean HSBP was similar in both groups: 148.5 (10.3) mm Hg in the I150/A5 group and 149.2 (9.7) mm Hg in the A5 group. At week 5, the adjusted mean difference in HSBP between groups was -6.2 (1.0) mm Hg (P < 0.001). The proportion of controlled patients (mean home blood pressure <135 and 85 mm Hg) was significantly higher in the I150/A5 group than in the A5 group (P < 0.001). Treatment-emergent adverse events were experienced by 13.8% of I150/A5-treated patients and 11.9% of A5-treated patients during the first 5-week period, and by 15.8% of I150/A10-treated patients and 17.0% of A10-treated patients during the second 5-week period. Two serious adverse events were reported with the fixed-dose combination; both patients recovered. CONCLUSIONS: Data from this adult population with essential hypertension suggest greater efficacy with the fixed-dose combination I150/A5 over A5 monotherapy in lowering SBP after 5 weeks. Both treatment regimens were well tolerated throughout the study. ClinicalTrials.gov identifier: NCT00956644.

The role of irbesartan in the treatment of patients with hypertension: a comprehensive and practical review.

Irbesartan is an orally active angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB]) whose pharmacological profile differs significantly from those of many other compounds of the same class. In particular, according to its pharmacokinetic and pharmacodynamic profile, irbesartan has a high bioavailability, a long duration of action and a small potential for pharmacological interactions due to the nature of the enzymatic pathway involved in its metabolic process. Morbidity data with irbesartan have been mainly accumulated in patients with renal impairment where the drug has demonstrated the most remarkable evidence of efficacy among the ARBs class, regardless of the stage of the renal disease (from early to late) and the length of the observational period. The efficacy of irbesartan has also been demonstrated in patients with left ventricular hypertrophy and congestive heart failure. The drug is indicated for the treatment of hypertension and renal impairment in patients with type 2 diabetes mellitus (T2D) and hypertension, and its tolerability and safety profile have been extensively investigated and reported to be similar to placebo. From the pharmacoeconomic point of view, treating patients with T2D, hypertension and overt nephropathy using irbesartan was both a cost- and life-saving procedure compared with the use of amlodipine and standard antihypertensive treatment in an Italian setting. The role of irbesartan in the management of hypertension with or without T2D and renal impairment is clearly recognized by national and international guidelines and largely acknowledged by the medical community according to the efficacy of the drug in the prevention of cardiovascular risk in addition to and beyond kidney prevention.

Management of hypertension with fixed dose combinations of candesartan cilexetil and hydrochlorothiazide: patient perspectives and clinical utility.

Hypertension treatment and control is largely unsatisfactory when guideline-defined blood pressure goal achievement and maintenance are considered. Patient- and physician-related factors leading to non-adherence interfere in this respect with the efficacy, tolerability, and convenient use of pharmacological treatment options. Blockers of the renin-angiotensin system (RAS) are an important component of antihypertensive combination therapy. Thiazide-type diuretics are usually added to increase the blood pressure lowering efficacy. Fixed drug-drug combinations of both principles like candesartan/hydrochlorothiazide (HCTZ) are highly effective in lowering blood pressure while providing improved compliance, a good tolerability, and largely neutral metabolic profile. Comparative studies with losartan/HCTZ have consistently shown a higher clinical efficacy with the candesartan/HCTZ combination. Data on the reduction of cardiovascular endpoints with fixed dose combinations of antihypertensive drugs are however scarce, as are the data for candesartan/HCTZ. But many trials have tested candesartan versus a non-RAS blocking comparator based on a standard therapy including thiazide diuretics. The indications tested were heart failure and stroke and particular emphasis was put on elderly patients or those with diabetes. In patients with heart failure, for example, the fixed dose combination might be applied in patients in whom individual titration resulted in a dose of 32 mg candesartan and 25 mg HCTZ which can then be combined into one tablet to increase compliance with treatment. Also in patients with stroke the fixed dose combination might be used in patients in whom maintenance therapy with both components is considered. Taken together candesartan/HCTZ assist both physicians and patients in achieving long-term blood pressure goal achievement and maintenance.

Candesartan cilexetil: a pharmacoeconomic review of its use in chronic heart failure and hypertension.

The addition of candesartan cilexetil (Atacand, Amias, Blopress, Kenzen, Ratacand) to standard therapy for chronic heart failure (CHF) provided important clinical benefits at little or no additional cost in France, Germany and the UK, according to a detailed economic analysis focusing on major cardiovascular events and prospectively collected resource-use data from the CHARM-Added and CHARM-Alternative trials in patients with CHF and left ventricular (LV) systolic dysfunction. Results of a corresponding cost-effectiveness analysis showed that candesartan cilexetil was either dominant over placebo or was associated with small incremental costs per life-year gained, depending on the country and whether individual trial or pooled data were used. Preliminary data from a US cost-effectiveness analysis based on CHARM data also showed favourable results for candesartan cilexetil. Two cost-effectiveness analyses of candesartan cilexetil in hypertension have been published, both conducted in Sweden. Data from the SCOPE trial in elderly patients with hypertension, which showed a significant reduction in nonfatal stroke with candesartan cilexetil-based therapy versus non-candesartan cilexetil-based treatment, were incorporated into a Markov model and an incremental cost-effectiveness ratio of euro12 824 per QALY gained was calculated (2001 value). Another modelled cost-effectiveness analysis of candesartan cilexetil was based on the ALPINE trial, in which the incidence of new-onset diabetes was significantly lower in patients with newly diagnosed hypertension who were randomised to candesartan cilexetil (with or without felodipine) than among those who received hydrochlorothiazide (with or without atenolol). Although candesartan cilexetil was dominant over hydrochlorothiazide, the ALPINE cost-effectiveness analysis relied on a small number of clinical events and did not evaluate the incremental cost of candesartan cilexetil per life-year or QALY gained. In conclusion, despite some inherent limitations, economic analyses incorporating CHARM data and conducted primarily in Europe have shown that candesartan cilexetil appears to be cost effective when added to standard CHF treatment in patients with CHF and compromised LV systolic function. The use of candesartan cilexetil as part of antihypertensive therapy in elderly patients with elevated blood pressure was also deemed to be cost effective in a Swedish analysis, primarily resulting from a reduced risk of nonfatal stroke (as shown in the SCOPE study); however, the generalisability of results to other contexts has not been established. Cost-effectiveness analyses comparing candesartan cilexetil with ACE inhibitors or other angiotensin receptor blockers in CHF or hypertension are lacking, and results reported for candesartan cilexetil in a Swedish economic analysis of ALPINE data focusing on outcomes for diabetes require confirmation and extension.

The KARTAN study: a postmarketing assessment of Irbesartan in patients with hypertension.

BACKGROUND: An important purpose of postmarketing surveillance of drugs is to better characterize the safety profile of drug therapy in the clinical setting. Another goal is to confirm the effectiveness of these drugs in patients who are candidates for antihypertensive therapy and who may have been excluded from Phase III studies. Irbesartan is a long-acting angiotensin II-receptor blocker specific for the angiotensin 1-receptor subtype that, in clinical trials in patients with hypertension, reduces blood pressure. OBJECTIVES: The KARTAN (this word was derived from the first and last syllables of Karvea [trademark of Bristol-Myers Squibb Group, Madrid, Spain] and irbesartan) study was designed to confirm and extend the findings from previous clinical trials using data from a large number of patients with hypertension treated with irbesartan in routine clinical practice. The primary goal was to assess the types and incidences of adverse drug reactions (ADRs) occurring at a low frequency (<0.05%) with irbesartan. The secondary objectives were to study the effect of irbesartan as an antihypertensive agent, to assess the types and incidences of the most frequent ADRs (>/=0.05%) occurring in routine clinical practice, and to detect possible interactions between irbesartan and other drugs frequently used in the primary care setting. METHODS: This 6-month, observational, open-label, uncontrolled, national, longitudinal, prospective study was conducted by 852 primary care physicians across Spain. Men and women aged >/=18 years with mild to moderate hypertension who, in their physicians' opinion, should have been treated with irbesartan were included. Each patient was followed up for 6 months, attending visits at baseline (ie, the start of treatment) and 1, 3, and 6 months after the start of treatment. A sample size of 3219 patients was calculated for the detection of >/=1 low-incidence (<0.05%) ADR. After the baseline visit, therapy typically was begun with irbesartan 150 mg/d. The initial dose was titrated up, at 300-mg increments based on the patient's response, at each visit as needed to achieve the treatment goals (systolic blood pressure, <140 mm Hg; diastolic blood pressure, <90 mm Hg). Information regarding ADRs was collected on case-report forms designed for each visit and analyzed by the scientific committee of the study. All recruited patients were included in the tolerability analysis. RESULTS: A total of 4887 patients were enrolled (2165 men, 2 772 women; mean [SD] age, 61.1 [11.0] years [range, 19-94 years]; 23.3% of patients were aged >70 years); 4612 were assessable for efficacy. One hundred eight patients (2.2%) experienced ADRs over the 6-month treatment period; 3 of these patients (0.1%) experienced >1 ADR. Of the total number of clinical manifestations of ADRs, 24 occurred at an incidence <0.05%. Irbesartan produced reductions in blood pressure that were statistically significant from the first visit (all p < 0.001), and 39.9% of the patients achieved the treatment goal at the end of the follow-up period. CONCLUSION: In this postmarketing surveillance study of patients with hypertension treated in routine clinical practice, irbesartan showed a satisfactory tolerability profile that was consistent with that seen in randomized, controlled trials.

Results of a postal survey of the reasons for non-response by doctors in a Prescription Event Monitoring study of drug safety.

PURPOSE: A Prescription Event Monitoring (PEM) study was carried out by the Drug Safety Research Unit (DSRU) to monitor the safety of irbesartan, an angiotensin II antagonist, immediately after launch in the United Kingdom in September 1997. The DSRU 'green form' questionnaire response rate was lower than expected. The manufacturer was conducting a concurrent postmarketing surveillance study. The aim of this cross-sectional study, was to identify reasons for non-response by general practitioners in England. METHODS: In PEM, questionnaires are posted to the prescribing general practitioner approximately 6 months after the date of the first prescription for each patient, requesting details of clinical events recorded in the patients' notes since starting treatment. Those that failed to respond were sent a second questionnaire, including tick box questions to elucidate reasons for non-response. RESULTS: A total of 21.3% (3088/14502) second send forms were returned. There were 1747 tick box responses. The most common reason specified for non-response was 'I was too busy' (31.2%) followed by 'no payment included' (13.4%). Participation in another study accounted for only 3.4%. CONCLUSIONS: The concurrent postmarketing surveillance study was not a significant factor. The general practitioner's workload appeared to have a far larger impact. While research remains a non-core activity and receives no payment, participation is likely to fall. Researchers need to find means of benefiting the general practitioner if participation is to continue.

A risk-benefit assessment of losartan potassium in the treatment of hypertension.

Losartan potassium is the first of a new class of orally active antihypertensive drugs which antagonise the action of angiotensin (AT) II at the AT1 receptor subtype. Losartan potassium is converted by the liver to the active metabolite E-3174, which is a more potent antagonist at the AT1 receptor. E-3174 is responsible for most of the pharmacological effects of losartan potassium, and its long half-life contributes to the extended duration of action of the drug. Losartan potassium is effective as a once-daily antihypertensive agent. In mild to moderate hypertension, losartan potassium has similar efficacy to enalapril, atenolol and felodipine extended release. When losartan potassium is combined with hydrochlorothiazide there is a further reduction in blood pressure. Losartan potassium is well tolerated in mild, moderate and severe essential hypertension, with dizziness being reported as the only drug-related adverse effect. The overall rate of patient withdrawal from therapy due to adverse experiences with losartan potassium is lower (2.3%) than that of placebo (3.7%). First-dose hypotension is uncommon, perhaps due to the slower onset of action of the drug, and cough does not appear to be a significant problem. A number of areas concerning the safety and efficacy of losartan potassium remain to be clarified. In particular, long term tolerability studies are needed; cough only became apparent as an adverse effect of ACE inhibitors after 3 to 4 years of use. Postmarketing surveillance has shown that angioedema, a rare but life-threatening adverse effect of ACE inhibitors, also occurs with losartan potassium. Further data are needed on the use of losartan potassium in patients with renal impairment before accepting the recommendation that dosage adjustment is not necessary. The pharmacokinetics and pharmacodynamics of losartan potassium in patients with hepatic disease also require further investigation. Losartan potassium increases uric acid secretion and lowers plasma uric acid levels, which may be of benefit when losartan potassium is combined with a thiazide diuretic, but which may otherwise lead to uric acid stone formation and possibly to nephropathy. Simple control of blood pressure is no longer an adequate goal in the management of hypertension. Any new antihypertensive agent should also reduce cardiovascular events, prevent or cause regression of end-organ damage such as left ventricular hypertrophy, atherosclerosis and renal failure, and should not impair quality of life. Such data on losartan potassium are not currently available. Losartan potassium is likely to be used in patients who are intolerant of ACE inhibitors, but its future in the management of hypertension will depend on long term tolerability studies and data on its effects beyond simple blood pressure control.

Medical and cost-economy aspects of modern antihypertensive therapy--with special reference to 2 years of clinical experience with losartan.

Health economy is often addressed in terms of acquisition cost, i.e. the cost of the pill. For various reasons, mainly the stricter demands from drug regulatory agencies (increased development costs), novel agents must be expected to be more expensive than older drugs. However, if the costs of changing therapy and the costs induced by side effects and extra clinic visits are considered, the economic aspects become less of a consideration. If compliance is enhanced and better blood pressure control is achieved with the newer agents, then the therapeutic gains must be weighed against the economic aspects. Losartan, the first agent of the new class of angiotensin II receptor antagonists of the AT1 type, has been available for clinical use for more than 2 years. Losartan has proven antihypertensive effects and its safety profile in the initial controlled trials (approximately 2900 patients) and in general practice (more than 14,000 patients in Sweden) has been very good. Its effect on long-term morbidity and mortality has not yet been established but a large mortality endpoint trial is underway in hypertensive patients with cardiac hypertrophy (the LIFE trial). In heart failure, losartan has been shown to reduce 3-month mortality (the ELITE trial). Although it is too early to assess the full therapeutic benefit of losartan in relation to the total patient costs, its efficacy and low incidence of side effects has made it a useful new therapy for the treatment of hypertension.