Spotlight on the Pharmacoeconomics of Candesartan Cilexetil in Chronic Heart Failure and Hypertension

The addition of candesartan cilexetil (Atacand®, Amias®, Biopress®, 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 favorable 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 €12 824 per quality-adjusted life-year (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 randomized 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 compromized 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 generalizability 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.     

Management of Genital Herpes

Genital herpes simplex virus (HSV) infection has substantial economic and quality-of-life consequences; not least is the risk of transmission to the fetus/infant during parturition with the subsequent effects on the family, society as a whole and healthcare providers. While general screening programs for HSV infection are not cost effective, screening of susceptible subgroups may be acceptable in some circumstances (e.g. immunocompromised patients, presumed discordant heterosexual couples, pregnant women) despite the high costs involved. First-line options for treatment and suppression of genital herpes in Europe and the US include valaciclovir, aciclovir and famciclovir. The established efficacy of valaciclovir, along with its potential for once-daily administration in many patients (versus administration up to five times daily for aciclovir), its positive effect on quality of life, its suppressive efficacy in late pregnancy and its proven reduction of viral transmission between heterosexual discordant partners support the drug’s position as a first-line therapy and suppression option in patients with genital herpes. However, the high acquisition costs compared with aciclovir will affect formulary decisions in some patients, and the favored niche for this drug, at least until evidence of prevention of transmission is demonstrated for other antivirale, would seem to be in the prevention of transmission in susceptible subgroups such as couples discordant for HSV infection (especially male-positive/female-negative couples who are planning a pregnancy), and the treatment and suppression of genital herpes in patients particularly receptive to once-daily administration.Potential disease management programs for genital herpes would thus need to balance the high costs of HSV screening and the relatively high acquisition costs of valaciclovir against the convenience of once-daily administration, the improved quality of life and the proven potential for reduced viral transmission to susceptible partners (with potential for downstream reductions in the overall socioeconomic burden of the disease) associated with oral valaciclovir.     

Clinical Usefulness of AJCC Response Criteria for Neoadjuvant Chemotherapy in Breast Cancer

Purpose

Recently, the American Joint Committee on Cancer (AJCC) 7th edition proposed new response criteria for neoadjuvant chemotherapy (NAC) in breast cancer. The purpose of this study was to evaluate the clinical usefulness of AJCC response criteria.

Methods

A total of 398 consecutive stage II or III breast cancer patients who received NAC were enrolled in this study. AJCC response criteria were as follows: (1) complete response (CR)—absence of invasive carcinoma in the breast and node; (2) partial response (PR)—decrease in either or both T or N stage; (3) no response (NR)—no change or increase in either or both T or N stage.

Results

Complete response, PR, and NR by AJCC criteria were 9.8, 59.3, and 30.7 %, respectively. Among the 398 patients, 337 patients were available for both paired pre- and post- breast MRI and chest CT. AJCC response criteria were significantly associated with RECIST criteria (P < 0.001). AJCC response was significantly associated with relapse-free survival (RFS) and overall survival (OS). The 5-year RFS rates were 89.6 % in CR, 74.1 % in PR, and 62.6 % in NR (P = 0.002). The 5-year OS rates were 97.4 % in CR, 88.6 % in PR, and 78.3 % in NR (P = 0.012). When adjusting potential prognostic factors, AJCC response was independently associated with RFS and OS.

Conclusions

AJCC response criteria for NAC in breast cancer have clinical usefulness in evaluating response of NAC, as well as predicting survival. AJCC response criteria can discriminate among patient subgroups with respect to survival.     

Immunopathology and immunotherapeutic strategies in severe acute respiratory syndrome coronavirus 2 infection

The outbreak of coronavirus disease 2019 (COVID‐19) and pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has become a major concern globally. As of 14 April 2020, more than 1.9 million COVID‐19 cases have been reported in 185 countries. Some patients with COVID‐19 develop severe clinical manifestations, while others show mild symptoms, suggesting that dysregulation of the host immune response contributes to disease progression and severity. In this review, we have summarized and discussed recent immunological studies focusing on the response of the host immune system and the immunopathology of SARS‐CoV‐2 infection as well as immunotherapeutic strategies for COVID‐19. Immune evasion by SARS‐CoV‐2, functional exhaustion of lymphocytes, and cytokine storm have been discussed as part of immunopathology mechanisms in SARS‐CoV‐2 infection. Some potential immunotherapeutic strategies to control the progression of COVID‐19, such as passive antibody therapy and use of interferon αβ and IL‐6 receptor (IL‐6R) inhibitor, have also been discussed. This may help us to understand the immune status of patients with COVID‐19, particularly those with severe clinical presentation, and form a basis for further immunotherapeutic investigations.     

Brivudin (bromovinyl deoxyuridine)

Brivudin is an oral thymidine analogue indicated for the early treatment of acute herpes zoster in immunocompetent adults. It has high, selective activity against varicella zoster virus (VZV), inhibiting VZV replication, possibly through competitive inhibition of viral DNA polymerase, or by acting as an alternative substrate to deoxythymidine triphosphate, causing viral DNA strand breakage. In a large, 7-day, phase III trial in immunocompetent patients with herpes zoster, once-daily brivudin 125mg was significantly more effective than oral acyclovir 800mg five times daily in reducing the mean time from start of treatment to last vesicular eruption, and was as effective as acyclovir at healing lesions and alleviating acute zoster-related pain. The likelihood of developing post-herpetic neuralgia (PHN) in immunocompetent patients aged > or =50 years was significantly lower with brivudin than with acyclovir. Brivudin was as effective as oral famciclovir 250mg three times daily in terms of the prevalence of PHN, the time to last vesicular eruption and lesion healing in another large, 7-day, phase III study in immunocompetent patients with herpes zoster. Oral brivudin is generally well tolerated, with a similar tolerability profile to those of oral acyclovir or famciclovir. Nausea was the most commonly reported adverse event.     

Nebivolol

▲ Nebivolol is a β-adrenergic receptor antagonist with a dual mechanism of action. It shows high selectivity for β₁-adrenergic receptors and appears to have nitric oxide-mediated vasodilatory activity. ▲ Once-daily nebivolol effectively lowered BP in patients with mild to moderate hypertension in four randomized, double-blind, placebo-controlled, 12-week trials. Trough sitting DBP and SBP were reduced to a significantly greater extent in nebivolol than in placebo recipients in trials in demographically heterogenous hypertensive patient groups, as well as in trials involving only Black patients and in patients continuing previous stable antihypertensive drug therapies. ▲ Treatment response (defined as a mean sitting DBP <90 mmHg or a ≥10 mmHg reduction from baseline) rates were significantly higher in nebivolol versus placebo recipients in trials enrolling patient groups considered representative of the US hypertensive population (46–65% vs 25%), in Black patients (57–64% vs 27%), and in patients concurrently treated with other antihypertensive drugs (53–65% vs 41%). ▲ Nebivolol was generally well tolerated in the treatment of hypertension, with the majority of adverse events described as being mild or moderate in severity. The incidences of fatigue, bradycardia, dyspnea, depression, and erectile dysfunction (events commonly associated with β-adrenergic receptor antagonist use) did not significantly differ between nebivolol and placebo recipients in the 12-week trials.     

Daptomycin: a review of its use in the management of complicated skin and soft-tissue infections and Staphylococcus aureus bacteraemia

Daptomycin (Cubicin) is the first of a new class of antibacterials, the cyclic lipopeptides, and is approved for use in the treatment of complicated skin and soft-tissue or skin-structure infections (hereafter referred to as cSSTI) caused by Gram-positive bacteria and Staphylococcus aureus bacteraemia including right-sided infective endocarditis.Daptomycin has activity in vitro against a wide variety of Gram-positive bacteria, including meticillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci.When administered as a once-daily intravenous infusion, daptomycin was not inferior to standard parenteral therapy (vancomycin or semi-synthetic penicillins) in terms of clinical and microbiological efficacy in patients with cSSTI or S. aureus bacteraemia with or without infective endocarditis (including MRSA infection) and was well tolerated.With the advantage of once-daily administration and a low potential for drug interactions, daptomycin is a useful addition to the range of parenteral antibacterial agents available for the treatment of patients with cSSTI or S. aureus bacteraemia with or without right-sided infective endocarditis. Efficacy against both meticillin-susceptible S. aureus (MSSA) and MRSA infections makes daptomycin suitable for empirical therapy in patients with serious Gram-positive infections.