Comparative analysis of cost-effectiveness between isosorbide-5-mononitrate and isosorbide: a retrospective real-world evaluation.

Aim: The cost-effectiveness of isosorbide-5-mononitrate (5-ISMN) and isosorbide dinitrate (ISDN) in real-world use in patients with coronary heart disease (CHD; either angina pectoris or myocardial infarction) was retrospectively compared. Method: In this retrospective real-world evaluation, patients with established CHD satisfying the following criteria were selected from information system of two tertiary hospitals in China: with pharmacy claiming for at least one injection of 5-ISMN or ISDN between July 2008 and May 2017; and, CHD patients. By using propensity score matching (PSM), we compared clinical aspects of efficacy, safety, length of hospital stay and cost during hospitalization between 5-ISMN and ISDN group. All data were processed by R statistical package v.2.13.1 (R Foundation for Statistical Computing, Vienna, Austria). Result: Of 5609 patients selected, 4047 received 5-ISMN and 1562 received ISDN. After PSM, we acquired 1555 pairs based on balancing of age, sex, insurance and comorbidities on admission. The frequency (4.2 ± 6.6-times vs 6.5 ± 9.5-times; p < 0.05) and total dosage (47.5 ± 153.4 vs 136.4 ± 261.0 mg; p < 0.05) of sublingual nitroglycerin use decreased and hypotension incidence lowered (8.0 vs 13.0%; p < 0.05) in 5-ISMN group compared with ISDN group. Hospital stay (16.0 ± 11.3 days vs 17.7 ± 13.2; p < 0.05) and hospitalization expenditure ([the ratio of cost in the study to the average hospitalization cost in the city] [odds ratio: 2.5 vs 2.6; p < 0.05]) were reduced in 5-ISMN group as with that of ISDN group. Moreover, the main component of hospitalization cost was medical consumables and medications in both the groups. Conclusion: In the present retrospective real-world evaluation, by using PSM analysis, we found that newer injection agent of 5-ISMN was associated with fewer use of sublingual nitroglycerin, less hypotension incidence, shorter length of hospital stay and less hospitalization expenditure related to its comparator ISDN in patients with established CHD. Further evaluation and clinical experience are need in different circumference for the usage of ISDN.

Clinical Effectiveness of Hydralazine-Isosorbide Dinitrate Therapy in Patients With Heart Failure and Reduced Ejection Fraction: Findings From the Get With The Guidelines-Heart Failure Registry.

BACKGROUND: In clinical trials, hydralazine-isosorbide dinitrate (H-ISDN) for heart failure with reduced ejection fraction reduced morbidity and mortality among black patients and patients with intolerance to angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. The effectiveness of H-ISDN in clinical practice is unknown. METHODS AND RESULTS: Using data from a clinical registry linked with Medicare claims, we examined the use and outcomes of H-ISDN between 2005 and 2011 among older patients hospitalized with heart failure and reduced ejection fraction. We adjusted for demographic and clinical characteristics using Cox proportional hazards models and inverse probability weighting. Among 4663 eligible patients, 22.7% of black patients and 18.2% of patients not on an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker were newly prescribed H-ISDN therapy at discharge. By 3 years, the cumulative incidence rates of mortality and readmission were similar between treated and untreated patients. After multivariable adjustment, 3-year outcomes remained similar for mortality [black patients: hazard ratio (HR), 0.92; 95% confidence interval (CI), 0.75-1.13; other patients: HR, 0.93; 95% CI, 0.79-1.09], all-cause readmission (black patients: HR, 0.98; 95% CI, 0.84-1.13; other patients: HR, 1.02; 95% CI, 0.90-1.17), and cardiovascular readmission (black patients: HR, 0.99; 95% CI, 0.82-1.19; other patients: HR, 0.94; 95% CI, 0.81-1.09). A post hoc analysis of Medicare Part D data revealed low postdischarge adherence to therapy. CONCLUSIONS: Guideline-recommended initiation of H-ISDN therapy at hospital discharge was uncommon, and adherence was low. For both black patients and patients of other races, there were no differences in outcomes between those treated and untreated at discharge.

Heart failure in African Americans: disparities can be overcome.

African Americans are disproportionately affected by heart failure, with a high prevalence at an early age. Hypertension, diabetes, obesity, and chronic kidney disease are all common in African Americans and all predispose to heart failure. Neurohormonal imbalances, endothelial dysfunction, genetic polymorphisms, and socioeconomic factors also contribute. In general, the same evidence-based treatment guidelines that apply to white patients with heart failure also apply to African Americans. However, the combination of hydralazine and isosorbide dinitrate is advised specifically for African Americans.

[Treatment of chronic anal fissures: diltiazem or isosorbide dinitrate as first choice?]. / Behandeling van chronische anale fissuren. Diltiazem of isosorbidedinitraat als middel van eerste keus?

Chronic anal fissures are a painful condition frequently seen in general practice, with an incidence of 2,5/1000 per year. According to the practice guidelines of the Dutch College of General Practitioners, isosorbide dinitrate 1% ointment (ISDN) is the treatment of first choice for chronic anal fissures. Systemic side-effects such as headache are reported in 27% of all cases. This side effect in combination with the frequent application of ISDN (4-6 times daily) leads to a low compliance for this therapy. A meta-analysis of the Cochrane Collaboration showed similar efficacy of diltiazem compared to ISDN. Diltiazem has several advantages: the application frequency is only twice daily, no systemic side-effects have been reported, the total costs of treatment are lower than the costs of ISDN and a standard preparation of diltiazem ointment is available. Therefore, diltiazem 2% ointment should be the first line treatment for chronic anal fissures.

Primary care physicians' attitudes regarding race-based therapies.

BACKGROUND: There is little to no information on whether race should be considered in the exam room by those who care for and treat patients. How primary care physicians understand the relationship between genes, race and drugs has the potential to influence both individual care and racial and ethnic health disparities. OBJECTIVE: To describe physicians' use of race-based therapies, with specific attention to the case of BiDil (isosorbide dinitrate/hydralazine), the first drug approved by the FDA for a race-specific indication, and angiotensin-converting enzyme (ace) inhibitors in their black and white patients. DESIGN: Qualitative study involving 10 focus groups with 90 general internists. PARTICIPANTS: Black and white general internists recruited from community and academic internal medicine practices participated in the focus groups.Of the participants 64% were less than 45 years of age, and 73% were male. APPROACH: The focus groups were transcribed verbatim, and the data were analyzed using template analysis. RESULTS: There was a range of opinions relating to the practice of race-based therapies. Physicians who were supportive of race-based therapies cited several potential benefits including motivating patients to comply with medical therapy and promoting changes in health behaviors by creating the perception that the medication and therapies were tailored specifically for them. Physicians acknowledged that in clinical practice some medications vary in their effectiveness across different racial groups, with some physicians citing the example of ace inhibitors. However, physicians voiced concern that black patients who could benefit from ace inhibitors may not be receiving them. They were also wary that the category of race reflected meaningful differences on a genetic level. In the case of BiDil, physicians were vocal in their concern that commercial interests were the primary impetus behind its creation. CONCLUSIONS: Primary care physicians' opinions regarding race-based therapy reveal a nuanced understanding of race-based therapies and a wariness of their use by physicians.

Dysfunctional corin i555(p568) allele is associated with impaired brain natriuretic peptide processing and adverse outcomes in blacks with systolic heart failure: results from the Genetic Risk Assessment in Heart Failure substudy.

BACKGROUND: Corin, a transmembrane serine protease expressed in cardiomyocytes, cleaves pro-atrial natriuretic peptide and pro-brain natriuretic peptide (BNP) into biologically active peptide hormones. The minor corin I555(P568) allele, defined by the T555I and Q568P mutations, is common in persons of African ancestry and associated with increased risk for hypertension and cardiac concentric hypertrophy. The corin gene product containing the T555I and Q568P mutations has significantly reduced natriuretic peptide processing capacity. We hypothesized that the corin I555(P568) allele would be associated with adverse outcomes and impaired BNP processing in blacks with systolic heart failure. METHODS AND RESULTS: This is a retrospective study of 354 subjects in the African American Heart Failure Trial Genetic Risk Assessment in Heart Failure substudy. In the corin variant group (n=50) compared with corin nonvariant group (n=300), BNP-32 (amino acids 77 to 108) was lower (190 pg/mL versus 340 pg/mL, P=0.007), but the ratio of unprocessed BNP(1 to 108)/processed BNP-32 was significantly higher (P=0.05). Stratified analyses were conducted because of evidence of significant interaction between the corin I555(P568) allele and treatment assignment. In the placebo arm, multivariable analysis demonstrated that the corin I555(P568) allele was associated with increased risk for death or heart failure hospitalization (relative risk 3.49; 95% CI, 1.45 to 8.39; P=0.005); however, in the treatment arm (fixed-dose combination isosorbide-dinitrate/hydralazine), the corin I555(P568) allele was not associated with adverse outcomes. CONCLUSIONS: We have identified a pharmacogenomic interaction in blacks with systolic heart failure. The corin I555(P568) allele is associated with an increased risk for death or heart failure hospitalization in patients receiving standard neurohormonal blockade, but the addition of fixed-dose combination isosorbide-dinitrate/hydralazine ameliorates this risk. A plausible mechanism for this pharmacogenomic interaction is the impaired processing of BNP in carriers of the corin I555(P568) allele as compared with noncarriers.

Isosorbide mononitrate versus alendronate for postmenopausal osteoporosis.

OBJECTIVE: To compare the effectiveness, safety, and affordability of isosorbide mononitrate with alendronate for postmenopausal osteoporosis. METHODS: A randomized controlled trial of 60 postmenopausal women with osteoporosis. Participants were randomly assigned to receive either 20 mg daily of isosorbide mononitrate or 70 mg weekly of alendronate for 12 months. Bone mineral density (BMD) was measured using dual X-ray absorptiometry (DXA) at baseline and after 12 months. RESULTS: Both groups showed significant improvement in BMD. Isosorbide mononitrate yielded a comparable effect to alendronate for BMD and T-score at the end of the follow-up period. For BMD and T score the mean differences between the 2 groups were -0.005 (95% CI, -0.02 to 0.03) and 0.31 (95% CI, -0.03 to 0.64), respectively. A 10.8% and 12.1% change in BMD after 12 months was seen for isosorbide mononitrate and alendronate, respectively. CONCLUSION: Isosorbide mononitrate is comparable to alendronate. Nitric oxide donors may be an effective and affordable therapy to improve bone mineral density.

Pharmacotherapy for heart failure with left ventricular dysfunction: beyond angiotensin-converting enzyme inhibitors and beta-blockers.

Angiotensin-converting enzyme (ACE) inhibitors and beta-blockers make up the cornerstone of therapy for patients with heart failure involving left ventricular dysfunction. These drug classes have been proven to decrease morbidity and mortality in patients with heart failure. Unfortunately, many patients remain symptomatic and experience disease progression despite taking both an ACE inhibitor and a beta-blocker. Others may be unable to tolerate one or both of these agents. In recent years, several other drug classes have been shown to provide additional morbidity and mortality benefits in patients with heart failure. These include angiotensin II receptor blockers (ARBs), aldosterone antagonists, and the combination of isosorbide dinitrate plus hydralazine. To select the most appropriate drug therapy for patients with heart failure, clinicians should consider results from clinical trials in specific patient populations, adverse-event profiles, tolerability, cost, and dosing regimens.

Pharmacogenetics, race and global injustice.

This paper discusses the link between pharmacogenetics and race, and the global justice issues that the introduction of pharmacogenetics in pharmaceutical research and clinical practice will raise. First, it briefly outlines the likely impact of pharmacogenetics on pharmaceutical research and clinical practice within the next five to ten years and then explores the link between pharmacogenetic traits and 'race'. It is shown that any link between apparent race and pharmacogenetics is problematic and that race cannot be used as a proxy for pharmacogenetic knowledge. The final section considers the implications of the development of pharmacogenetics for health care systems in low- and middle-income countries.

Cost comparison analysis: pentaerythrithyl tetranitrate (PETN) and isosorbide dinitrate (ISDN) prescribed to diabetic patients in primary care practices in Germany.

INTRODUCTION: Both pentaerythrithyltetranitrate (Pentalong, PETN) and isosorbide dinitrate (ISDN) are commonly used in the therapy of ischemic heart disease (IHD). However, little is known about the therapeutic patterns in diabetic patients and no comparative data are available regarding the prescription costs of these two substances. Thus, the aim of this investigation was to compare the costs for PETN and ISDN therapy in diabetic patients in primary care. MATERIAL AND METHODS: All continuously treated patients aged > or = 40 years with diabetes (anti-diabetic agents) and IHD or angina pectoris (ICD codes) and newly started on PETN or ISDN therapy (index date) in the period 2000-2005 were selected from a database containing data from 400 practices throughout Germany (Disease Analyzer, IMS Health). Prescriptions costs for PETN and ISDN, as well as costs for cardiovascular comedication, were determined for the period 183 days before and after the index date, and that changes in costs after the index date were calculated. Differences in costs between the two groups were evaluated using multivariate regression, adjusting for age, sex and comorbidity. Patients in Eastern (n = 137, age 71 +/- 10 years, 55% male) and Western Germany (n = 212, age 73 +/- 9 years, 50% male) were analyzed separately since there is a longer history of PETN use in Eastern Germany. RESULTS: Significantly more patients were treated with PETN in Eastern Germany (61 vs. 11%, p < 0.05). The patient groups treated with PETN and ISDN differed with respect to sex and comorbidity. PETN therapy was more expensive than ISDN therapy in both German regions (adjusted cost differences were 10 and 17 Euro). However, when comedication was taken into account, a smaller cost increase after the index date was observed in the PETN group than in the ISDN group (non-significant cost savings of 43 and 52 Euro after adjustment for Western and Eastern Germany, respectively). CONCLUSION: PETN therapy tends to produce a saving in costs compared to ISDN therapy in diabetic patients when costs for comedication are taken into account and after adjustment for age and comorbidity. The prescription patterns in Eastern and Western Germany and the patient characteristics of those receiving PETN and ISDN differed, indicating differences in patients selection and prescribing by physicians in the two regions.

BiDil (isosorbide dinitrate and hydralazine): a new fixed-dose combination of two older medications for the treatment of heart failure in black patients.

BiDil is a new fixed-dose combination of 2 older medications, isosorbide dinitrate (ISDN) and hydralazine. ISDN is an organic nitrate that is biotransformed into nitric oxide, a potent vasodilator. Hydralazine is believed to have both vasodilatory properties specific to the arteries and antioxidant properties, which address both the biochemical alterations in the failing cardiovascular system as well as the issue of nitrate tolerance. A drug regimen combining an NO stimulator (ISDN) with an antioxidant (hydralazine) favorably influences the nitroso-redox balance. Retrospective analyses of previous heart failure (HF) clinical trials comparing the combination of ISDN and hydralazine with placebo and enalapril, respectively, demonstrated a benefit in the black population, setting the precedent for a race-based therapeutic study, the African-American Heart Failure Trial (A-HeFT). A-HeFT examined the use of BiDil added to standard HF therapy in blacks with New York Heart Association functional class III and IV HF. BiDil demonstrated a 43% reduction in mortality when compared with placebo. As a result, current evidence-based treatment guidelines recommend that the addition of ISDN and hydralazine in black patients with moderate to severe HF optimized on standard therapy be considered. BiDil is currently indicated for the treatment of HF as an adjunct to standard therapy in black patients. The use of BiDil for black patients with mild disease or in nonblack patients with HF has not been studied. Future clinical trials involving an ethnically and clinically diverse population of patients would further define the role of combined ISDN and hydralazine in the treatment of HF.

BiDil: assessing a race-based pharmaceutical.

Isosorbide and hydralazine in a fixed-dose combination (BiDil) has provoked controversy as the first drug approved by the Food and Drug Administration marketed for a single racial-ethnic group, African Americans, in the treatment of congestive heart failure. Family physicians will be better prepared to counsel their patients about this new drug if they understand a number of background issues. The scientific research leading to BiDil's approval tested the drug only in African American populations, apparently for commercial reasons, so the drug's efficacy in other populations is unknown. Race as a biological-medical construct is increasingly controversial; BiDil offers a good example of how sociocultural factors in disease causation may be overlooked as a result of an overly simplistic assumption of a racial and hence presumed genetic difference. Past discrimination and present disparities in health care involving African American patients are serious concerns, and we must welcome a treatment that promises to benefit a previously underserved group; yet the negative aspects of BiDil and the process that led to its discovery and marketing set an unfortunate precedent. Primary care physicians should be aware of possible generic equivalents that will affect the availability of this drug for low-income or uninsured patients.

Race, pharmacogenomics, and marketing: putting BiDil in context.

This article endeavors to place into context recent developments surrounding the United States Food and Drug Administration recent approval of BiDil (isosorbide dinitrate/hydralazine hydrochloride) (NitroMed, Inc., Lexington, MA) as the first ever race-specific drug--in this case to treat heart failure in African Americans. It focuses in particular on both commercial incentives and statistical manipulation of medical data as framing the drive to bring BiDil to market as a race-specific drug. In current discourse about pharmacogenomics, targeting a racial audience is perceived as necessary because at this point the technology and resources do not exist to scan efficiently every individual's genetic profile. The article argues that medical researchers may say they are using race as a surrogate to target biology in drug development, but corporations are using biology as a surrogate to target race in drug marketing. Pharmacogenomics may hold great promise, but on our way to that Promised Land, it is imperative to review such short cuts with a critical eye.

Being specific about race-specific medicine.

Gary Puckrein's paper "BiDil: From Another Vantage Point" misrepresents rather than refutes our previously published analysis of BiDil. Puckrein claims that if our analysis were to prevail, patients would be denied life-saving therapy. Any reasonable reading of our paper suggests exactly the opposite. Indeed, based on the evidence, we urge doctors to prescribe the generics or BiDil itself as they see fit, but without regard to the race of their patient.

BiDil: from another vantage point.

In a recent Health Affairs Web Exclusive, Pamela Sankar and Jonathan Kahn argue against the Food and Drug Administration's approval of BiDil as a new drug for the treatment of heart failure in African Americans. Their paper questions the existence of disparities between African American and other heart-failure patients and the motivations of BiDil's developers and manufacturer. The disparities are confirmed and persistent, however, and BiDil's effectiveness is proven. If the authors' logic were to prevail, patients would be denied life-saving therapy. Continued investigation will likely narrow identification of patients who will benefit.