Adverse Drug Events Cause Many Hospitalizations in Elders

A few medications cause most of the problems that lead to emergency hospitalization in older patients.

Adverse drug events (ADEs) leading to emergency department (ED) visits or emergency hospitalizations are particularly common in older patients. The recent national focus on preventable rehospitalizations brings identifying and addressing high-risk medications to the healthcare forefront.

Investigators used 2007–2009 data from a nationally representative sample of 58 hospitals to estimate that nearly 100,000 emergency hospitalizations (1.5% of all emergency hospitalizations among elders) occurred annually due to medication injury in older patients (age, 65); they excluded cases of intentional self-harm, drug abuse, therapeutic failures, or drug withdrawal. Almost half (48%) of ADE-related hospitalizations among elders were in patients older than 80. Four medications accounted for more than two thirds of these ADE-related emergency hospitalizations: warfarin (33%), insulins (14%), oral antiplatelet agents (13%), and oral hypoglycemic agents (11%). Warfarin-related hemorrhages accounted for an estimated 21,000 emergency hospitalizations annually. Interestingly, medications designated as high risk by national quality measures (i.e., Healthcare Effectiveness Data and Information Set [HEDIS] high-risk medications or Beers-criteria potentially inappropriate medications) rarely caused emergency hospitalizations (1.2% and 6.6%, respectively) among older patients.

Comment: The nearly 100,000 annual emergency hospitalizations caused by ADEs in older patients represent an opportunity to prevent patient harm and lower healthcare use. Augmenting efforts to reconcile medications accurately at care transitions, as well as more aggressive drug monitoring for medications that commonly cause hospitalizations (including drug management programs), would help improve patient safety and prevent ADE-related hospitalizations. Policies to promote patient safety should target these identified medication classes for which evidence of patient harm exists.

— Daniel D. Dressler, MD, MSc, SFHM

Published in Journal Watch Hospital Medicine November 23, 2011

November 23, 2011 — Results from the long-term follow-up of the Heart Protection Study (HPS) may offer reassurance that statins are safe and effective in patients at high risk for vascular disease, according to new research published online November 23 in The Lancet.

The average decline in low-density lipoprotein cholesterol with statins in the initial 5-year period that patients received them was 1.0 mmol/L, with a 23% proportional drop in major vascular events (95% confidence interval [CI], 19 - 28; P < .0001). The benefit persisted largely unchanged during the 11-year follow-up period, with no further improvements in either major vascular events (risk ratio [RR], 0.95; 95% CI, 0.89 - 1.02) or vascular mortality (RR, 0.98; 95% CI, 0.90 - 1.07). There was also no evidence of added harm during the combined in-trial and follow-up period for cancer at all sites (RR, 0.98; 95% CI, 0.92 - 1.05), or any particular site, or in mortality attributed to cancer (RR, 1.01; 95% CI, 0.92 - 1.11), or for nonvascular causes (RR, 0.96; 95% CI, 0.89 - 1.03).

The authors, from the HPS Collaborative Group, Clinical Trial Service Unit, Oxford, United Kingdom, write: "These findings provide further support for the prompt initiation and long-term continuation of statin treatment in people at increased risk of vascular events."

The study is based on extended follow-up data from the randomized HPS, conducted in the United Kingdom. Between July 1994 and May 1997, investigators randomly assigned 20,536 high-risk men and women between the ages of 40 and 80 years to receive 40 mg simvastatin daily or placebo for approximately 5 years. At final follow-up in 2001, investigators instructed the patients to continue taking the statins unless there were any contraindications. The absolute benefits of treatment continued during the 5-year in-trial period and rose year after year, but they plateaued in the years after the trial.

Patients were followed for an average of 5.3 years (standard deviation, 1.2), with posttrial follow-up lasting an average of 11 years (standard deviation, 0.6). Other important findings include that a first diagnosis of any cancer (other than nonmelanoma skin cancers) was the same throughout the in-trial and extended follow-up periods, at 1749 (17.0%) in the simvastatin group vs 1744 (17.0%) in the placebo group (RR, 0.98; 95% CI, 0.92 - 1.05; P = .60). For patients aged 70 years or more at baseline, there was also no increase in genitourinary, gastrointestinal, respiratory, hematological, or any other malignant disease.

The study was blinded for the most part, unless physicians felt it important to know whether their patients were receiving the drug or not. As a result, 18% of the simvastatin-treated patients and 13% of the patients receiving the placebo were unblinded. Some observational studies found that statins were linked to excess cancers, particularly in the elderly, making posttrial follow-up a priority.

In an accompanying commentary, Payal Kohli, MD, and Christopher P. Cannon, MD, from the TIMI Study Group, and Cardiovascular Division of Brigham and Women's Hospital, Boston, Massachusetts, point to several randomized studies that have demonstrated the safety of statins on extended follow-up. They write: "The original concerns about statin safety...were probably heavily confounded. We now have strong evidence from HPS and several other randomized controlled trials that prolonged treatment with statins is indeed efficacious, safe, and has long-lasting beneficial effects, even after discontinuation of therapy."

The study was funded by the UK Medical Research Council, the British Heart Foundation, Merck & Co, and Roche Vitamins. The authors of the HPS Collaborative Group and Dr. Kohli have disclosed no relevant financial relationships. Dr. Cannon states that he has received research funding from Accumetrix, AstraZeneca, Glaxo SmithKline, Merck, and Takeda. He also has received honoraria from Pfizer and AstraZeneca, has participated in advisory boards for Bristol-Myers Squibb/sanofi-aventis, Novartis, and Alnylam, and has equity in Automedics Medical Systems.

Lancet. Published online November 23, 2011. Abstract

By Andrew M. Seaman

NEW YORK (Reuters Health) Nov 15 - Doctors and nutritionists have long recommended avoiding all animal fats to trim cholesterol, but Danish researchers report that cheese may not be so bad, and probably shouldn't be lumped in the same category as butter.

Their study, published online October 26 in the American Journal of Clinical Nutrition, found that people who ate daily servings of cheese for six-week intervals had lower LDL cholesterol than when they ate a comparable amount of butter. The cheese-eaters also did not have higher LDL during the experiment than when the same subjects ate a normal diet.

Dr. Elizabeth Jackson, assistant professor of medicine at the University of Michigan Health Systems, told Reuters Health that the study was well done, but does not really change what cardiologists currently recommend.

"We want people to have a diet focused on whole grains and vegetables and moderate fats," said Dr. Jackson, who was not involved in the work.

The researchers, from the University of Copenhagen in Denmark, set out to learn what effects cheese and butter had on heart disease risk factors, such as HDL, LDL and total cholesterol levels.

They followed about 50 people who answered ads in local newspapers. Each person was put on a controlled diet and added a measured amount of cheese or butter daily.

Throughout, each participant was compared against his or herself, to follow the changes in the body caused by the foods.

Researchers gave each person cheese or butter, both made from cows milk, equal to 13% of their daily energy consumption from fat.

During six-week intervals, each person ate the set amount of cheese or butter, separated by a 14-day cleansing period in which they returned to their normal diet. Then they switched, and for six weeks those who had eaten the cheese before, ate butter, while the butter eaters in the first phase changed over to cheese.

Despite eating more fat than had been in their normal diet, the cheese eaters showed no increase in LDL or total cholesterol. While eating butter, however, the same subjects had LDL levels about 7% higher on average.

While eating cheese, subjects' HDL cholesterol dropped slightly compared to when they ate butter, but not compared to their normal eating period.

The authors speculate there could be several reasons why cheese behaved differently than butter, but nothing conclusive.

For one, cheese has a lot of calcium, which has been shown to increase the amount of fat excreted by the digestive tract. (See Reuters Health story of October 21, 2011).

The researchers did detect a little more fecal fat during the time the group ate cheese, but the amounts were not statistically significant.

Other possible explanations involve the large amount of protein in cheeses and its fermentation process, both of which could affect the way it's digested compared with butter.

The study was supported by the Danish Dairy Board and the National Dairy Research Institute.

SOURCE: http://bit.ly/vDIMx7

Am J Clin Nutr 2011.

NEW YORK (Reuters Health) Nov 15 -

Clinicians can face a difficult choice in deciding what class of antihypertensive medication to prescribe for their patients. However, all medications used to treat hypertension are not equal in their effects on important cardiovascular outcomes. A review by De Caterina and Leone, which appeared in the May 15, 2010, issue of The American Journal of Cardiology, concluded that beta-blockers are associated with worse results in the prevention of stroke compared with the use of other antihypertensive medications. Moreover, beta-blockers may not prevent coronary artery disease when used to treat patients with hypertension. They fail to lower central blood pressure to the degree of other antihypertensive drugs, and they have negative metabolic effects, which might contribute to higher rates of cardiovascular disease.

Beta-blockers have also been associated with worsened cognitive outcomes compared with angiotensin II receptor blockers (ARBs). It is possible that both angiotensin-converting enzyme (ACE) inhibitors and ARBs can reduce the risk for incident dementia. The current study by Kehoe and colleagues examines this possibility in a large cohort of patients.

Study Synopsis and Perspective

Controlling blood pressure with an ARB rather than other antihypertensive agents may significantly reduce the risk for Alzheimer's disease (AD) and vascular dementia (VaD), suggest results of a large observational study from the United Kingdom.

In the study, the risk for AD was 53% lower in older adults prescribed an ARB compared with those prescribed other antihypertensive agents. The risk was 24% lower in those prescribed an ACE inhibitor.

Patrick G. Kehoe, PhD, coleader of the Dementia Research Group at Frenchay Hospital, Bristol, and colleagues report their study in the October issue of the Journal of Alzheimer's Disease.

Dr. Kehoe and colleagues say their findings support those of a recent study in a predominantly male population from the United States. In that study, reported previously by Medscape Medical News, men prescribed ARBs had a lower incidence and rate of progression of AD than those prescribed ACE inhibitors or other cardiovascular drugs.

The accumulating observational and biological evidence in favor of ARBs protecting against dementia "strengthens the need for them to be studied more rigorously in the future," Dr. Kehoe and colleagues conclude.

Although "interesting, these are not conclusive findings," coauthor Richard M. Martin, PhD, from the University of Bristol, notes in a statement. "We now need to do the clinical trials to properly test our observations."

Accumulating Evidence

The study was a nested case-control study within the UK general practice research database. It was designed to see whether ARBs and ACE inhibitors are more strongly associated with AD, VaD, and other dementias relative to other antihypertensive drugs such as calcium channel blockers, beta-blockers, or thiazide diuretics.

Although both ARBs and ACE inhibitors reduce angiotensin II signaling, "now believed to be involved in the pathobiology of AD, ARBs are unlikely to interrupt ACE-mediated [amyloid-beta] degradation," unlike ACE inhibitors, the researchers note in their article. "These mechanisms of action suggest that ARBs may have benefits over [ACE inhibitors] in the etiology of AD," they write.

Included in the analysis were 9197 patients, aged 60 years and older, who were diagnosed between 1997 and 2008 with probable or possible AD (n = 5797), VaD (n = 2186), or unspecified/other dementia (n = 1214). Each case patient was matched by age, general practice, and sex to up to 4 control patients (n = 39,166).

The researchers observed that patients ever prescribed either ARBs or ACE inhibitors were less likely to develop AD, VaD, or other dementia than patients ever prescribed other antihypertensive medications. The associations were stronger for ARBs than for ACE inhibitors.

Table. Dementia Outcomes With ARBs and ACE Inhibitors vs Other Agents

Outcome	ARBs, OR (95% CI)	ACE inhibitors, OR (95% CI)
Probable AD	0.47 (0.37 - 0.58)	0.76 (0.69 - 0.84)
Probable VaD	0.70 (0.57 - 0.85)	0.82 (0.75 - 0.91)
Unspecified/other dementia	0.62 (0.47 - 0.81)	0.85 (0.75 - 0.96)

OR, odds ratio; CI, confidence interval

These associations did not differ by age, comorbidities, or blood pressure, suggesting little confounding by observed comorbidities, the researchers say. There was also evidence of a dose–response relationship between ARBs and AD (P = .009).

In analyses restricted to patients exposed either to ARBs or ACE inhibitors as their only therapy, there was an inverse association of ARB sole therapy (OR, 0.63; 95% CI, 0.45 - 0.88), but not ACE inhibitor sole therapy (OR, 1.01; 95% CI, 0.91 - 1.12).

"Preaching to the People"

Reached for comment, Gustavo C. Román, MD, medical director of the Nantz National Alzheimer Center at the Methodist Neurological Institute in Houston, Texas, who was not involved in the study, said it "reaffirms the need to control blood pressure, and the sooner, the better."

Dr. Román said he has been "preaching to the people that you need to keep your blood pressure under good control because it really seems that vascular disease, and especially hypertension, opens the gate to the amyloid-beta changes, although the mechanism is not very clear.

"Whatever the mechanism, it has been demonstrated over and over that vascular disease, in particular hypertension, is a risk factor for the development of [AD]," he added.

The study was supported by the North Bristol National Health Service Trust. The authors and Dr. Román have disclosed no relevant financial relationships.

J Alzheimers Dis. 2011;26:699-708. Abstract

Howell MD, Novack V, Grgurich P, et al
Arch Intern Med. 2010;170:784-790

Study Summaries

The incidence and severity of Clostridium difficile infections (CDI) are increasing at an alarming rate. Because the gastric acid barrier is one of the defense mechanisms for protecting the integrity of the normal gut microflora environment, acid-suppression therapy has beensuggested as treatment for a number of intestinal pathogenic infections -- including C difficile -- but this remains controversial.

These 2 reports suggest that the increased risk for CDI with proton pump inhibitors (PPIs) is not at all modest, and that gastric acid is potentially important in protecting against infection from this pathogen.

The study by Linsky and colleagues is a pharmacoepidemiologic cohort trial in which a secondary analysis was performed with data collected prospectively on 101,796 patients discharged from a tertiary care medical center during a 5-year period. As use of acid-suppression therapy increased, the reported risk for nosocomial CDI also increased, from 0.3% (95% confidence interval [CI], 0.21%-0.31%) in patients who did not receive acid-suppression therapy, to 0.6% (95% CI, 0.49%-0.79%) in those who did receive histamine2-receptor antagonist (H₂RA) therapy, to 0.9% (95% CI, 0.80%-0.98%) in patients who received daily PPI treatment, and to 1.4% (1.15%-1.71%) in those who received more frequent PPI therapy.

Lancet 2011 Aug 13; 378:584.
Diet, Genes, and Stroke Risk: Another Look at Homocysteine and Folate
A genetic analysis and a meta-analysis suggest that lowering homocysteine levels reduces stroke risk more in low-folate regions than in areas with folate fortification, and that folate status modifies the effect of MTHFR alleles on stroke risk.
The MTHFR 677CT polymorphism is associated with elevated homocysteine levels and with increased stroke risk. Vitamin therapy with folic acid, vitamin B6, and vitamin B12 lowers homocysteine levels; however, randomized controlled trials (RCTs) of vitamin therapy for elevated homocysteine levels have not shown reductions in stroke risk (Arch Intern Med 2010; 170:1622). Folate consumption affects serum homocysteine levels and varies by geographic region. The RCTs evaluating the effect of homocysteine lowering on stroke risk were predominantly performed in areas with folic acid supplementation, which could explain the lack of benefit.
To investigate the potential modifying effect of folate status on the association between the MTHFR 677CT variant and stroke risk, researchers reassessed genetic studies that included data for homocysteine concentration and stroke. The investigators compared their genetic-analysis findings with a meta-analysis of 13 RCTs of homocysteine-lowering treatments to reduce stroke risk and found the following:

• The effect of the MTHFR 677CT polymorphism on homocysteine concentration was modified substantially by folate consumption: The effect was larger in low-folate areas (e.g., Asia) than in areas with folate fortification (e.g., the U.S.).
• The effect of the MTHFR 677CT polymorphism on stroke risk was also larger in low-folate regions than in areas with folate fortification.
• In an analysis limited to only large studies, the authors predicted that lowering homocysteine levels would reduce stroke risk more in low-folate regions than in areas with folate fortification.

Comment: These findings suggest that homocysteine-lowering therapy would have the greatest effect in geographic areas with low dietary folate consumption. Because RCTs have failed to show benefit of folate therapy (Arch Intern Med 2010; 170:1622) and have suggested that there may even be harm (N Engl J Med 2006; 354:1578), I would not currently recommend folate supplementation. However, folate supplementation may have a role in those with the MTHFR 677CT variant, particularly in low-folate regions. To date, no trial has been conducted exclusively in a low-folate region to evaluate the effect of homocysteine reduction on stroke risk. The ongoing China Stroke Primary Prevention Trial — which is comparing stroke risk with enalapril alone to enalapril plus folic acid in hypertensive individuals without established cardiovascular disease — may show whether homocysteine lowering can reduce stroke risk in low-folate regions.
— Amytis Towfighi, MD Dr. Towfighi is Assistant Professor, Department of Neurology, University of Southern California, Los Angeles; and Chair, Department of Neurology, Rancho Los Amigos National Rehabilitation Center, Downey, CA.
Published in Journal Watch Neurology October 25, 2011
Citation(s): Holmes MV et al. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: A meta-analysis of genetic studies and randomised trials. Lancet 2011 Aug 13; 378:584.
http://www.ncbi.nlm.nih.gov/pubmed/21803414?dopt=Abstract

ScienceDaily (Oct. 3, 2011) — Magnetic Resonance Imaging (MRI), an important diagnostic test, has traditionally been off limits to more than 2 million people in the United States who have an implanted pacemaker to regulate heart rhythms or an implanted defibrillator to prevent sudden cardiac death. Now, in a study published in the October 4 issue of Annals of Internal Medicine, cardiologists at Johns Hopkins report that a protocol they developed has proved effective in enabling patients with implanted cardiac devices to safely undergo an MRI scan.

"We believe this is the largest prospective study of MRI in patients with implanted devices," says lead author Saman Nazarian, a Johns Hopkins cardiac electrophysiologist and an assistant professor of medicine at the Johns Hopkins University School of Medicine.

"The guidelines we have published can be used to make MRI more available to people who could benefit from early detection of cancer and other diseases and for guiding surgeons during procedures. MRI is considered superior to CT scans in many clinical scenarios, especially for brain and spinal cord imaging," adds Nazarian. To date, more than 700 patients with implanted cardiac devices have safely undergone MRI exams at Johns Hopkins.

Guidelines suggest serum B₁₂ measurement in patients with suspected dementia in order to screen for severe B₁₂ deficiency as a potentially treatable cause of cognitive decline. There remains a concern that some individuals with more modestly low levels of B₁₂ may also experience cognitive decline that may be made clinically worse by high levels of serum folate, a more common occurrence in the United States since the introduction of mandatory folic acid grain supplementation. A recent study (Tangney et al., 2011) aimed to examine the relationship between cognitive decline, MRI changes, and levels of B₁₂ and other biochemical markers of B₁₂ deficiency, namely serum homocysteine and methylmalonic acid (MMA).

Participants in the study were part of the Chicago Health and Aging Project, a longitudinal cohort study of 6158 persons. At baseline, all patients received in-home interviews that included cognitive testing repeated in 3-year cycles. Stratified random sampling of patients at each cycle triggered both a clinical neurologic evaluation and phlebotomy. The present study includes 121 of these randomly selected patients who underwent cognitive testing followed by brain MRI on average 4.6 years later. The average age of the patients included was 79 years, and 51% were women. Of the group, 17.5% demonstrated elevated serum homocysteine values (>14 µmol/L) and 15.2% had elevated MMA (>271 nmol/L).

The authors found that both homocysteine and MMA were significantly associated with poorer cognitive testing across multiple domains; B₁₂ levels demonstrated no such association. For each 1-µmol/L increase in homocysteine, for example, the global cognitive score decreased by 0.03 standardized units (p = .04). Examination of MRI measures demonstrated that serum homocysteine concentration was significantly associated with an increased volume of white matter hyperintensities even after adjustment for age, sex, race, education, dementia, and APOE4 status. Higher levels of homocysteine and MMA were each significantly associated with decreased total brain volume (a measure of atrophy) even after adjustment. Interestingly, the association of homocysteine with cognitive function was no longer significant after adjustment for white matter volume or cerebral infarcts, and the association of MMA with cognitive function was no longer significant after adjustment for total brain volume.

This study is not the first to examine these relationships, but it does paint a tantalizing picture that modest amounts of B₁₂ deficiency, as noted by elevation of MMA and homocysteine, may either lead to or speed the rate of cognitive decline in elderly patient populations. The model that emerges is that elevated MMA (a more specific marker for B₁₂ deficiency) may affect cognition through reduction in total brain volume, and homocysteine (which can also be elevated in folate deficiency and other conditions) may mediate effects on cognition through increased white matter hyperintensities and cerebral infarcts. For the clinician, it is reasonable to encourage adequate B₁₂ intake among the elderly, but future studies are needed to determine whether B₁₂ levels should be measured routinely (perhaps via serum MMA or homocysteine levels) in patients without cognitive decline and then supplementation initiated in hopes of preventing decline.