Jennifer H. Martin

Reducing Inappropriate Polypharmacy: The Process of Deprescribing

Inappropriate polypharmacy, especially in older people, imposes a substantial burden of adverse drug events, ill health, disability, hospitalization, and even death. The single most important predictor of inappropriate prescribing and risk of adverse drug events in older patients is the number of prescribed drugs. Deprescribing is the process of tapering or stopping drugs, aimed at minimizing polypharmacy and improving patient outcomes. Evidence of efficacy for deprescribing is emerging from randomized trials and observational studies. A deprescribing protocol is proposed comprising 5 steps: (1) ascertain all drugs the patient is currently taking and the reasons for each one; (2) consider overall risk of drug-induced harm in individual patients in determining the required intensity of deprescribing intervention; (3) assess each drug in regard to its current or future benefit potential compared with current or future harm or burden potential; (4) prioritize drugs for discontinuation that have the lowest benefit-harm ratio and lowest likelihood of adverse withdrawal reactions or disease rebound syndromes; and (5) implement a discontinuation regimen and monitor patients closely for improvement in outcomes or onset of adverse effects. Whereas patient and prescriber barriers to deprescribing exist, resources and strategies are available that facilitate deliberate yet judicious deprescribing and deserve wider application.

Assessment of nonischemic myocardial fibrosis

Myocardial fibrosis is recognized as the pathologic entity of extracellular matrix remodeling. Diffuse, reactive fibrosis is being increasingly recognized in a variety of conditions despite the absence of ischemia. Regardless of the etiology, fibrosis leads to increased myocardial stiffness thereby promoting cardiac dysfunction. This may present clinically with symptoms of cardiac failure although often this is a subclinical disease. Various imaging modalities and collagen biomarkers have been used as surrogate markers to assess the presence, extent, and turnover of myocardial fibrosis. Techniques using echocardiography, cardiac magnetic resonance, and nuclear imaging have been developed to detect early features of systolic and diastolic left ventricular dysfunction and impaired contractile reserve. Further identification of diffuse reactive fibrosis may be possible with evolving cardiac magnetic resonance and molecular techniques. The goal of these approaches is to enable targeted therapy to be instituted earlier, leading to prevention of disease progression and fibrosis accumulation long term.

Therapeutic drug monitoring of antimicrobials

Optimizing the prescription of antimicrobials is required to improve clinical outcome from infections and to reduce the development of antimicrobial resistance. One such method to improve antimicrobial dosing in individual patients is through application of therapeutic drug monitoring (TDM). The aim of this manuscript is to review the place of TDM in the dosing of antimicrobial agents, specifically the importance of pharmacokinetics (PK) and pharmacodynamics (PD) to define the antimicrobial exposures necessary for maximizing killing or inhibition of bacterial growth. In this context, there are robust data for some antimicrobials, including the ratio of a PK parameter (e.g. peak concentration) to the minimal inhibitory concentration of the bacteria associated with maximal antimicrobial effect. Blood sampling of an individual patient can then further define the relevant PK parameter value in that patient and, if necessary, antimicrobial dosing can be adjusted to enable achievement of the target PK/PD ratio. To date, the clinical outcome benefits of a systematic TDM programme for antimicrobials have only been demonstrated for aminoglycosides, although the decreasing susceptibility of bacteria to available antimicrobials and the increasing costs of pharmaceuticals, as well as emerging data on pharmacokinetic variability, suggest that benefits are likely.

Resveratrol Does Not Benefit Patients With Nonalcoholic Fatty Liver Disease

BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD), characterized by accumulation of hepatic triglycerides (steatosis), is associated with abdominal obesity, insulin resistance, and inflammation. Although weight loss via calorie restriction reduces features of NAFLD, there is no pharmacologic therapy. Resveratrol is a polyphenol that prevents high-energy diet-induced steatosis and insulin resistance in animals by up-regulating pathways that regulate energy metabolism. We performed a placebo-controlled trial to assess the effects of resveratrol in patients with NAFLD. METHODS Overweight or obese men diagnosed with NAFLD were recruited from hepatology outpatient clinics in Brisbane, Australia from 2011 through 2012. They were randomly assigned to groups given 3000 mg resveratrol (n = 10) or placebo (n = 10) daily for 8 weeks. Outcomes included insulin resistance (assessed by the euglycemic-hyperinsulinemic clamp), hepatic steatosis, and abdominal fat distribution (assessed by magnetic resonance spectroscopy and imaging). Plasma markers of inflammation, as well as metabolic, hepatic, and antioxidant function, were measured; transcription of target genes was measured in peripheral blood mononuclear cells. Resveratrol pharmacokinetics and safety were assessed. RESULTS Eight-week administration of resveratrol did not reduce insulin resistance, steatosis, or abdominal fat distribution when compared with baseline. No change was observed in plasma lipids or antioxidant activity. Levels of alanine and aspartate aminotransferases increased significantly among patients in the resveratrol group until week 6 when compared with the placebo group. Resveratrol did not significantly alter transcription of NQO1, PTP1B, IL6, or HO1 in peripheral blood mononuclear cells. Resveratrol was well-tolerated. CONCLUSIONS Eight weeks administration of resveratrol did not significantly improve any features of NAFLD, compared with placebo, but it increased hepatic stress, based on observed increases in levels of liver enzymes. Further studies are needed to determine whether agents that are purported to mimic calorie restriction, such as resveratrol, are safe and effective for complications of obesity. Clinical trials registration no: ACTRN12612001135808.

Association of imaging markers of myocardial fibrosis with metabolic and functional disturbances in early diabetic cardiomyopathy

Background— Metabolic and vascular disturbances contribute to diabetic cardiomyopathy, but the role of interstitial fibrosis in early disease is unproven. We sought to assess the relationship between imaging markers of diffuse fibrosis and myocardial dysfunction and to link this to possible causes of early diabetic cardiomyopathy. Methods and Results— Hemodynamic and metabolic data were measured in 67 subjects with type 2 diabetes mellitus (age 60±10 years) with no cardiac symptoms. Myocardial function was evaluated with standard echocardiography and myocardial deformation; ischemia was excluded by exercise echocardiography. Calibrated integrated backscatter was calculated from parasternal long-axis views. T1 mapping was performed after contrast with a modified Look-Locker technique using saturation recovery images. Amino-terminal propeptides of procollagens type I and III, as well as the carboxy-terminal propeptide of procollagen type I, were assayed to determine collagen turnover. Subjects with abnormal early diastolic tissue velocity (Em) had shorter postcontrast T1 values (P=0.042) and higher calibrated integrated backscatter (P=0.007). They were heavier (P=0.003) and had worse exercise capacity (P<0.001), lower insulin sensitivity (P=0.003), and blunted systolic tissue velocity (P=0.05). Postcontrast T1 was associated with diastolic dysfunction (Em r=0.28, P=0.020; E/Em r=−0.24, P=0.049), impaired exercise capacity (r=0.30, P=0.016), central adiposity (r=−0.26, P=0.046), blood pressure (systolic r=−0.30, P=0.012; diastolic r=−0.49, P<0.001), and insulin sensitivity (r=0.30, P=0.037). The association of T1 with E/Em (&bgr;=−0.31, P=0.017) was independent of blood pressure and metabolic disturbance. Amino-terminal propeptide of procollagens type III was linked to diastolic dysfunction (Em r=−0.32, P=0.008) and calibrated integrated backscatter (r=0.30, P=0.015) but not T1 values. Conclusions— The association between myocardial diastolic dysfunction, postcontrast T1 values, and metabolic disturbance supports that diffuse myocardial fibrosis is an underlying contributor to early diabetic cardiomyopathy.

Resveratrol - pills to replace a healthy diet?

Nutrapharmacology, or the use of bioactive food compounds at pharmacological doses is emerging as a therapeutic approach to target the complex metabolic dysregulations in ageing and obesity-related chronic disease. Resveratrol, a polyphenol found in the skin of grapes, and other edible plants and related food products, has received extensive attention through the link with the French paradox, and later with its chemopreventive activity demonstrated in vitro and in animal cancer models. A plethora of laboratory investigations has provided evidence for the multi-faceted properties of resveratrol and suggests that resveratrol may target ageing and obesity-related chronic disease by regulating inflammation and oxidative stress. A number of obstacles stand in the path to clinical usage however, not least the lack of clinical evidence to date, and the myriad of doses and formulations available. Further, data on the effects of resveratrol consumption in a capsule vs. food form is conflicting, and there are uncertain effects of long term dosing. The review will summarize the human pharmacokinetic and pharmacodynamic published data, and the topics for research if resveratrol is to become a multi-target therapeutic agent addressing chronic disease.

Minimizing Inappropriate Medications in Older Populations: A 10-step Conceptual Framework

The increasing burden of harm resulting from the use of multiple drugs in older patient populations represents a major health problem in developed countries. Approximately 1 in 4 older patients admitted to hospitals are prescribed at least 1 inappropriate medication, and up to 20% of all inpatient deaths are attributable to potentially preventable adverse drug reactions. To minimize this drug-related iatrogenesis, we propose a quality use of medicine framework that comprises 10 sequential steps: 1) ascertain all current medications; 2) identify patients at high risk of or experiencing adverse drug reactions; 3) estimate life expectancy in high-risk patients; 4) define overall care goals in the context of life expectancy; 5) define and confirm current indications for ongoing treatment; 6) determine the time until benefit for disease-modifying medications; 7) estimate the magnitude of benefit versus harm in relation to each medication; 8) review the relative utility of different drugs; 9) identify drugs that may be discontinued; and 10) implement and monitor a drug minimization plan with ongoing reappraisal of drug utility and patient adherence by a single nominated clinician. The framework aims to reduce drug use in older patients to the minimum number of essential drugs, and its utility is demonstrated in reference to a hypothetic case study. Further studies are warranted in validating this framework as a means for assisting clinicians to make more appropriate prescribing decisions in at-risk older patients.

Deciding when to stop: towards evidence-based deprescribing of drugs in older populations.

Minimising the harm from inappropriate prescribing in older populations is a major urgent concern for modern healthcare systems. In everyday encounters between prescribers and patients, opportunities should be taken to identify patients at high risk of harm from polypharmacy and reappraise their need for specific drugs. Attempts to reconcile life expectancy, comorbidity burden, care goals and patient preferences with the benefits and harms of medications should be made in every patient at significant risk. Drugs identified by this process of reconciliation as conferring little or no benefit and/or excessive risk of harm should be candidates for discontinuation. Evidence supporting a structured approach to drug discontinuation (or deprescribing) is emerging, and while many barriers to deprescribing exist in routine practice, various enabling strategies can help overcome them.

In vitro inhibitory effects of atorvastatin on cardiac fibroblasts: implications for ventricular remodelling.

1. Hydroxy‐3‐methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) reduce mortality after myocardial infarction (MI). Although this may be predominantly due to their known anti‐ischaemic actions, these drugs are known to have other beneficial effects.

Cytochrome P450 drug interactions within the HMG-CoA reductase inhibitor class: are they clinically relevant?

The present review outlines the clinical relevance of pharmacokinetic drug interactions within the HMG-CoA reductase inhibitor class. These interactions can result in markedly increased or decreased plasma concentrations of some drugs within this class. However, the relationship between altered plasma concentrations and adverse effects or toxicity may not be linear. It is likely that other variables affect this concentration-effect relationship including: rapid changes in the concentration, concomitant lipid-lowering therapy or host genetic factors that code for different forms or amounts of metabolising enzymes and drug receptors.It is not currently possible to predict which patients will manifest clinically important drug-drug interactions, nor what concentration of an HMG-CoA reductase inhibitor will cause rhabdomyolysis. Thus, until prescribers have better scientific information from which to develop a ‘therapeutic range’ for each agent, caution should be exercised. In particular, patients taking a CYP3A4-metabolised agent, e.g. atorvastatin, simvastatin and lovastatin, should not be started on a CYP3A4 inhibitor or inducer without close monitoring.