The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists. While the exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants. As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing, severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease. The diagnosis of resistant hypertension requires use of good blood pressure technique to confirm persistently elevated blood pressure levels. Pseudoresistance, including lack of blood pressure control secondary to poor medication adherence or white coat hypertension, must be excluded. Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens. As a subgroup, patients with resistant hypertension have not been widely studied. Observational assessments have allowed for identification of demographic and lifestyle characteristics associated with resistant hypertension, and the role of secondary causes of hypertension in promoting treatment resistance is well documented; however, identification of broader mechanisms of treatment resistance is lacking. In particular, attempts to elucidate potential genetic causes of resistant hypertension have been limited. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the lack of systematic assessments of 3 or 4 drug combinations. Studies of resistant hypertension are limited by the high cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; the presence of multiple disease processes (eg, sleep apnea, diabetes, chronic kidney disease, atherosclerotic disease) and their associated medical therapies, which confound interpretation of study results; and the difficulty in enrolling large numbers of study participants. Expanding our understanding of the causes of resistant hypertension and thereby potentially allowing for more effective prevention and/or treatment will be essential to improve the long-term clinical management of this disorder.

Resistant Hypertension: Diagnosis, Evaluation, and Treatment A Scientific Statement From the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research

Summary Guidance is provided in a European setting on the assessment and treatment of postmenopausal women with or at risk from osteoporosis. Introduction The European Foundation for Osteoporosis and Bone disease (subsequently the International Osteopo- rosis Foundation) published guidelines for the diagnosis and management of osteoporosis in 1997. This manuscript updates these in a European setting. Methods The following areas are reviewed: the role of bone mineral density measurement for the diagnosis of osteoporo- sis and assessment of fracture risk; general and pharmaco- logical management of osteoporosis; monitoring of treatment; assessment of fracture risk; case finding strategies; investigation of patients; health economics of treatment. Results and conclusions A platform is provided on which specific guidelines can be developed for national use.

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European guidance for the diagnosis and management of osteoporosis in postmenopausal women

Summary
This report describes the epidemiology, burden, and treatment of osteoporosis in the 27 countries of the European Union (EU27).

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Osteoporosis in the European Union: medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA).

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1524-4733.2007.00213.x

Medication Compliance and Persistence: Terminology and Definitions

Background: Clinical trials have demonstrated that drug therapy can reduce osteoporosis-related fracture risk in women over 50 years of age. Noncompliance could considerably limit the effectiveness observed in actual practice, however. The objective of this study was therefore to estimate fracture risk in relation to compliance with osteoporosis medication in actual practice. Methods: Demographic, prescription drug use, physician services, and hospitalization information for women with osteoporosis who were dispensed an osteoporosis medication between 1996 and 2001 was obtained from the Saskatchewan health data files. Compliance to treatment was defined as drug available to cover 80% of the time. Subsequent fractures were identified via hospitalizations or physician contacts with a relevant diagnostic or procedure code. The risk of fractures in relation to compliance was examined using a Cox proportional hazards model with time-dependent covariates. The impact of other patient characteristics, including age, having suffered a prior fracture, and prior use of osteoporosis medication and steroids, was also examined. Results: 11,249 women suffering from osteoporosis were identified with a mean age at the time of the index prescription of 68.4 years and average follow-up of 2 years. The overall fracture rate was 4.5% per year. Patients who complied experienced a 16% lower fracture rate. This association was maintained within subgroups and after controlling for other patient characteristics that independently predict the fracture rate. Conclusion: These results indicate that improving compliance in actual practice may significantly decrease osteoporosis-related fracture risk.

The impact of compliance with osteoporosis therapy on fracture rates in actual practice

BACKGROUND: Despite the existence of efficacious medications, many patients in actual practice remain with uncontrolled hypertension. Randomized clinical trials, cannot address this issue well given their highly restricted environment. This paper examines persistence with antihypertensive therapy among patients in actual practice. METHODS: Cohort study of patients who received a diagnosis of hypertension and were treated between 1989 and 1994 identified through the Saskatchewan Health databases. Patients with concurrent diagnoses likely to affect initial treatment choice were excluded. The resulting population of 79,591 subjects was grouped into those with established hypertension (52,227 [66%]) and those with newly diagnosed hypertension (27,364 [34%]). The initial antihypertensive prescription, subsequent changes in treatment and persistence with antihypertensive therapy were analysed. RESULTS: Persistence with antihypertensive therapy decreased in the first 6 months after treatment was started and continued to decline over the next 4 years. Of the patients with newly diagnosed hypertension, only 78% persisted with therapy at the end of 1 year, as compared with 97% of the patients with established hypertension (p

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Persistence with treatment for hypertension in actual practice

BACKGROUND: Rational medical decisions should be based on the best possible evidence. Clinical trial results, however, may not reflect conditions in actual practice. In hypertension, for example, trials indicate equivalent antihypertensive efficacy and safety for many medications, yet blood pressure frequently remains uncontrolled, perhaps owing to poor compliance. This paper examines the effect of initial choice of treatment on persistence with therapy in actual practice. METHODS: The authors examined all outpatient prescriptions for antihypertensive medications filled in Saskatchewan between 1989 and 1994 by over 22,000 patients with newly diagnosed hypertension whose initial treatment was with a diuretic, beta-blocker, calcium-channel blocker or angiotensin-converting-enzyme (ACE) inhibitor. Rates of persistence over the first year of treatment were compared. RESULTS: After 6 months, persistence with therapy was poor and differed according to the class of initial therapeutic agent: 80% for diuretics, 85% for beta-blockers, 86% for calcium-channel blockers and 89% for ACE inhibitors (p

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Effect of initial drug choice on persistence with antihypertensive therapy: the importance of actual practice data

OBJECTIVE To estimate direct medical costs of managing the complications of type 2 diabetes. RESEARCH DESIGN AND METHODS Costs were estimated for 15 diabetic complications by applying unit costs to typical resource-use profiles. Resource use and unit costs were estimated from many sources, including acute care discharge databases, clinical guidelines, government reports, fee schedules, and peer-reviewed literature. For each complication, the event costs are those associated with resource use that is specific to the acute episode and any subsequent care occurring in the 1st year. State costs are the annual costs of continued management. All costs are expressed in 1996 U.S. dollars. RESULTS As expected, the more severe or debilitating events, such as acute myocardial infarction ($27,630 event cost; $2,185 state cost), generate a greater financial burden than do early-stage complications, such as microalbuminuria ($62 event cost; $14 state cost). Yet, complications that are initially relatively low in cost (e.g., microalbuminuria) can progress to more costly advanced stages (e.g., end-stage renal disease, $53,659 state cost); therefore, minor complications should also be considered in any economic analysis of diabetes. CONCLUSIONS The recent literature has lacked cost estimates that may be readily translated into patient-level cost inputs for an economic model. Emerging therapies that may reduce the incidence of some diabetic complications will need to be scrutinized economically in today9s cost-conscious environment. The cost estimates from this study provide one piece of the economic analysis needed to evaluate these new interventional therapies.

Direct medical costs of complications resulting from type 2 diabetes in the U.S.

Objective: To develop a framework for estimating the long-term health and economic consequences of AD based on patient characteristics at a given point in time. Methods: A pharmacoeconomic model (Assessment of Health Economics in Alzheimer’s Disease, AHEAD) was developed based on equations that relate the probability of needing full-time care (FTC) over time to patient characteristics summarized in index scores. These equations were developed from published data on interquartile times until FTC is needed and until death, using nonlinear regressions of the resulting index-specific hazards. These equations were then incorporated into a hidden Markov framework that allows for calculation of expected time to FTC and to death, as well as of the economic consequences of disease progression. There are three major states in the model: not requiring FTC (“pre-FTC”), requiring FTC, and death. Results: Outcomes for five sample patients are derived to illustrate application of the AHEAD model. The impact of altering disease markers in these patients is also considered. Conclusion: The need for a generally applicable tool to forecast long-term outcomes based on relatively short-term data is becoming increasingly acute with the advent of new therapies for AD. The AHEAD model provides a relatively simple framework for the prediction of time to FTC requirement based on short-term observed data such as those from clinical trials. Although subject to the uncertainties inherent in modeling, the model nevertheless provides a standard estimation technique that may facilitate comparisons between existing and emerging therapies.

Gabriel Raggio

Papers

The impact of compliance with osteoporosis therapy on fracture rates in actual practice

Persistence with treatment for hypertension in actual practice

Effect of initial drug choice on persistence with antihypertensive therapy: the importance of actual practice data

Direct medical costs of complications resulting from type 2 diabetes in the U.S.

Assessment of health economics in Alzheimer’s disease (AHEAD) based on need for full-time care