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| Presented by the author at the 2003 New England Forensic Sciences
Conference at Colby College:
Polypharmacy: What Cost in Morbidity and Mortality?©
It is common practice in Medicine to put patients on combinations of
drugs. The vast majority of these combinations of drugs (especially
where 3 or more drugs are involved) have never been studied at all, let
alone in double-blind trials ( with the exception of Oncology/AIDS
treatment, where the toxicity of the drugs demands study); yet it is
frequent practice to prescribe these multiple-drug combinations.
It is well accepted in Pharmacology that it is scientifically impossible
to accurately predict the side effects or clinical effects of a
combination of drugs without studying that particular combination of
drugs in test subjects. Knowledge of the pharmacologic profiles of the
individual drugs in question does not in any way
assure accurate prediction of the side effects of combinations of those
drugs, especially when they have different mechanisms of action, which
is very common because polypharmacy is most often prescribed to patients
with "multiple illnesses". More than 100,000 patients in this country
die from identified adverse drug reactions (perhaps the 4th to 6th
leading cause of death in the U.S.)3 The number who die as a
consequence of polypharmacy is, to my knowledge, unknown.
The argument that the prescribing of drugs is the "Art" of Medicine is
not valid in defending polypharmacy, because drugs are developed
(indications, dose and administration, etc.) and approved through a
"scientific" process (double-blind, placebo-controlled studies). The
fact that the medicines are often prescribed for "different conditions"
is irrelevant (especially to the patient's physiology). The idea that
" we are doing the best we can ", a frequent defense of Polypharmacy,
does not in any way uphold a scientific argument in favor of it. (We
are, indeed, trying the best we can, with tools which do not improve at
the rate we would wish!) The fact that "there is a limit to how much
research can be done" in no way makes the research unnecessary in order
to predict the side effects of specific combinations of drugs.
It has been said in the past that <30% of medical practice was backed by
controlled studies ¹ · ². Has this changed? How do we know? Are we
looking closely enough at our way of practicing Medicine? Can the use
of unstudied polypharmacy really be considered evidence-based,
"scientific" Medicine? Can the Pathology community help initiate
meaningful debate regarding this subject at a level that will produce
more widespread awareness?
Charles Sullivan, D.O.
Waterville, ME
"Science progresses, funeral by funeral." - Max Planck
1.) Office of Technology Assessment: Assessing the efficacy and safety
of
medical technologies. U.S. Government Printing Office, Washington, 1978
2.) Smith R: Where is the wisdom . . . ? the poverty of medical
evidence.
BMJ 1991;303:798
3.) Incidence of Adverse Drug Reactions in Hospitalized Patients. JAMA.
1998;279:1200-1205
4. "...only about 15% of medical interventions are supported by solid
scientific evidence; in other words, eighty-five percent are not."
Smith, R (editor of British Medical Journal), The ethics of ignorance,
Journal of Medical Ethics, 1992;18:117
==============================
Additional Refs:
Daubert v. Merrel Dow Pharmaceuticals 509 U.S. 579 (1993), 509,
579.
Goodstein, D. 2000. How Science Works. In U.S. Federal Judiciary
Reference Manual on Evidence, pp. 66–72.
Horrobin, D.F. 1990. The philosophical basis of peer review and the
suppression of innovation. J. Am. Med. Assoc. 263:1438–1441.
Horrobin, D.F. 1996. Peer review of grant applications: A harbinger
for mediocrity in clinical research? Lancet 348:1293-1295.
Horrobin, D.F. 1981-1982. Peer review: Is the good the enemy of the
best? J. Res. Commun. Stud. 3:327–334.
Rothwell, P.M. and Martyn, C.N. 2000. Reproducibility of peer
review in clinical neuroscience: Is agreement between reviewers any
greater than would be expected by chance alone? Brain
123:1964–1969.
Horrobin, D.F. 2000. Innovation in the pharmaceutical industry. J.
R. Soc. Med. 93:341–345.
Abstracts
David A. Flockhart, and Jose E. Tanus-Santos Implications of Cytochrome
P450 Interactions When Prescribing Medication for Hypertension
Archives of Internal Medicine 162: 405-412.
Kathryn A. Phillips, David L. Veenstra, Eyal Oren, Jane K. Lee, and
Wolfgang Sadee Potential Role of Pharmacogenomics in Reducing Adverse
Drug Reactions: A Systematic Review
JAMA 286: 2270-2279.
Just Ebbesen, Ingebjørg Buajordet, Jan Erikssen, Odd Brørs, Thor
Hilberg, Helge Svaar, and Leiv Sandvik Drug-Related Deaths in a
Department of Internal Medicine
Archives of Internal Medicine 161: 2317-2323.
Jeffrey M. Rothschild, Frank A. Federico, Tejal K. Gandhi, Rainu
Kaushal, Deborah H. Williams, and David W. Bates Analysis of
Medication-Related Malpractice Claims: Causes, Preventability, and Costs
Archives of Internal Medicine 162: 2414-2420.
Mark T. Holdsworth, Richard E. Fichtl, Maryam Behta, Dennis W. Raisch,
Elena Mendez-Rico, Alexa Adams, Melanie Greifer, Susan Bostwick, and
Bruce M. Greenwald Incidence and Impact of Adverse Drug Events in
Pediatric Inpatients
Arch Pediatr Adolesc Med 157: 60-65.
David N. Juurlink, Muhammad Mamdani, Alexander Kopp, Andreas Laupacis,
and Donald A. Redelmeier Drug-Drug Interactions Among Elderly Patients
Hospitalized for Drug Toxicity
JAMA 289: 1652-1658.
Jason Lazarou, Bruce H. Pomeranz, and Paul N. Corey Incidence of Adverse
Drug Reactions in Hospitalized Patients: A Meta-analysis of Prospective
Studies
JAMA 279: 1200-1205.
Karen E. Lasser, Paul D. Allen, Steffie J. Woolhandler, David U.
Himmelstein, Sidney M. Wolfe, and David H. Bor Timing of New Black Box
Warnings and Withdrawals for Prescription Medications
JAMA 287: 2215-2220.
Abstract 1 of 8
Implications of Cytochrome P450 Interactions When Prescribing Medication
for Hypertension
David A. Flockhart, MD, PhD and Jose E. Tanus-Santos, MD, PhD
Arch Intern Med. 2002;162:405-412.
Many of the estimated 50 million Americans with high blood pressure
receive medications for hypertension and for other conditions, placing
them at risk for adverse drug interactions. The risk for hypertension
and for adverse drug reactions is highest in the elderly, who have the
greatest need for pharmacologic therapy. The most important class of
drug interactions involves the cytochrome P450 microsomal enzyme system,
which handles a variety of xenobiotic substances. A potential for
interactions with these enzymes exists with calcium channel blockers,
{beta}-adrenergic blocking agents, angiotensin-converting enzyme
inhibitors, and angiotensin receptor blockers but not with diuretic
antihypertensives, which are renally eliminated and more vulnerable to
drug interactions that occur in the kidney. This article reviews the
cytochrome P450 enzyme system, identifies drugs and foods that have been
implicated in metabolic interactions with antihypertensive agents, and
suggests measures for reducing the risk of adverse events when drugs are
coadministered.
From the Division of Clinical Pharmacology, Indiana university School of
Medicine, Indianapolis. Dr Flockhart is now with the Department of
Medicine, Indiana university School of Medicine, Wishard Hospital,
Indianapolis.
Abstract 2 of 8
Potential Role of Pharmacogenomics in Reducing Adverse Drug Reactions
A Systematic Review
Kathryn A. Phillips, PhD, David L. Veenstra, PhD, PharmD, Eyal Oren, BA,
Jane K. Lee, BA and Wolfgang Sadee, PhD
JAMA. 2001;286:2270-2279.
Context Adverse drug reactions are a significant cause of morbidity and
mortality. Although many adverse drug reactions are considered
nonpreventable, recent developments suggest these reactions may be
avoided through individualization of drug therapies based on genetic
information, an application known as pharmacogenomics.
Objective To evaluate the potential role of pharmacogenomics in
reducing the incidence of adverse drug reactions.
Data Sources MEDLINE English-language only searches for adverse drug
reaction studies published between January 1995 and June 2000 and review
articles of variant alleles of drug-metabolizing enzymes published
between January 1997 and August 2000. We also used online resources,
texts, and expert opinion.
Study Selection Detailed inclusion criteria were used to select
studies. We included 18 of 333 adverse drug reaction studies and 22 of
61 variant allele review articles.
Data Extraction All the investigators reviewed and coded articles using
standardized abstracting forms.
Data Synthesis We identified 27 drugs frequently cited in adverse drug
reaction studies. Among these drugs, 59% are metabolized by at least 1
enzyme with a variant allele known to cause poor metabolism. Conversely,
only 7% to 22% of randomly selected drugs are known to be metabolized by
enzymes with this genetic variability (range, P = 006-P<.001).
Conclusions Our results suggest that drug therapy based on individuals'
genetic makeups may result in a clinically important reduction in
adverse outcomes. Our findings serve as a foundation for further
research on how pharmacogenomics can reduce the incidence of adverse
reactions and on the resulting clinical, societal, and economic
implications.
Author Affiliations: Department of Clinical Pharmacy (Drs Phillips, Mr
Oren, and Ms Lee) and Biopharmaceutics (Dr Sadee) university of
California-San Francisco; Department of Pharmacy, university of
Washington, Seattle (Dr Veenstra).
Abstract 3 of 8
Drug-Related Deaths in a Department of Internal Medicine
Just Ebbesen, MD, Ingebjørg Buajordet, MSc, Jan Erikssen, MD, PhD, Odd
Brørs, MD, PhD, Thor Hilberg, MD, PhD, Helge Svaar, MD and Leiv Sandvik,
MSc, PhD
Arch Intern Med. 2001;161:2317-2323.
Background Drug therapy is associated with adverse effects, and fatal
adverse drug events (ADEs) have become major hospital problems. Our
study assesses the incidence of fatal ADEs in a major medical department
and identifies possible patient characteristics signifying fatal ADE
risk.
Methods During a 2-year period, a multidisciplinary study group
examined all 732 patients who died 5.2% of the 13 992 patients admitted
to the Department of Internal Medicine, Central Hospital of Akershus,
Nordbyhagen, Norway. Decisions about the presence or absence of fatal
ADEs were based on aggregated clinical records, autopsy results, and
findings from premortem and postmortem drug analyses.
Results In 18.2% of the patients (133/732) (95% confidence interval,
15.4%-21.0%), deaths were classified as being directly (64 [48.1%] of
133) or indirectly (69 [51.9%] of 133) associated with 1 or more drugs
(this equals 9.5 deaths per 1000 hospitalized patients). Those with
fatal ADEs (cases) were older, had more diseases, and used more drugs
than those without fatal ADEs (noncases). In 75 of the 133 patients with
fatal ADEs, autopsy findings and/or drug analysis data were decisive for
recognizing the ADEs; in 62 of the remaining 595 patients, similar data
proved necessary to exclude the suspicion of a fatal ADE. Major culprit
drugs were cardiovascular, antithrombotic, and sympathomimetic agents.
Conclusions Fatal ADEs represent a major hospital problem, especially
in elderly patients with multiple diseases. A higher number of drugs
administered was associated with a higher frequency of fatal ADEs, but
whether a high number of drugs is an independent risk factor for fatal
ADEs is unsettled. Autopsy results and the findings of premortem and
postmortem drug analyses were important for recognizing and excluding
suspected fatal ADEs.
From the Foundation for Health Services Research (Drs Ebbesen and
Sandvik) and the Departments of Internal Medicine (Dr Erikssen) and
Pathology (Dr Svaar), Central Hospital of Akershus, Nordbyhagen, Norway;
and the Norwegian Medicines Control Authority (Ms Buajordet), the
Division of Clinical Pharmacology and Toxicology, Clinical Chemistry
Department, Ullevaal university Hospital (Dr Brørs), and the National
Institute of Forensic Toxicology (Dr Hilberg), Oslo, Norway.
Abstract 4 of 8
Analysis of Medication-Related Malpractice Claims
Causes, Preventability, and Costs
Jeffrey M. Rothschild, MD,MPH, Frank A. Federico, RPh, Tejal K. Gandhi,
MD,MPH, Rainu Kaushal, MD,MPH, Deborah H. Williams, MHA and David W.
Bates, MD,MSc
Arch Intern Med. 2002;162:2414-2420.
Background Adverse drug events (ADEs) may lead to serious injury and
may result in malpractice claims. While ADEs resulting in claims are not
representative of all ADEs, such data provide a useful resource for
studying ADEs. Therefore, we conducted a review of medication-related
malpractice claims to study their frequency, nature, and costs and to
assess the human factor failures associated with preventable ADEs. We
also assessed the potential benefits of proved effective ADE prevention
strategies on ADE claims prevention.
Methods We conducted a retrospective analysis of a New England
malpractice insurance company claims records from January 1, 1990, to
December 31, 1999. Cases were electronically screened for possible ADEs
and followed up by independent review of abstracts by 2 physician
reviewers (T.K.G. and R.K.). Additional in-depth claims file reviews
identified potential human factor failures associated with ADEs.
Results Adverse drug events represented 6.3% (129/2040) of claims.
Adverse drug events were judged preventable in 73% (n = 94) of the cases
and were nearly evenly divided between outpatient and inpatient
settings. The most frequently involved medication classes were
antibiotics, antidepressants or antipsychotics, cardiovascular drugs,
and anticoagulants. Among these ADEs, 46% were life threatening or
fatal. System deficiencies and performance errors were the most frequent
cause of preventable ADEs. The mean costs of defending malpractice
claims due to ADEs were comparable for nonpreventable inpatient and
outpatient ADEs and preventable outpatient ADEs (mean, $64 700-74 200),
but costs were considerably greater for preventable inpatient ADEs
(mean, $376 500).
Conclusions Adverse drug events associated with malpractice claims were
often severe, costly, and preventable, and about half occurred in
outpatients. Many interventions could potentially have prevented ADEs,
with error proofing and process standardization covering the greatest
proportion of events.
From the Division of General Medicine, the Department of Medicine,
Brigham and Women's Hospital (Drs Rothschild, Gandhi, Kaushal, and Bates
and Ms Williams), and the Risk Management Foundation of the Harvard
Medical Institutions (Mr Federico), Boston, Mass.
Abstract 5 of 8
Incidence and Impact of Adverse Drug Events in Pediatric Inpatients
Mark T. Holdsworth, PharmD, Richard E. Fichtl, PharmD, Maryam Behta,
PharmD, Dennis W. Raisch, PhD, Elena Mendez-Rico, PharmD, Alexa Adams,
MD, Melanie Greifer, MD, Susan Bostwick, MD and Bruce M. Greenwald, MD
Arch Pediatr Adolesc Med. 2003;157:60-65.
Objectives To determine the incidence and causes of adverse drug events
(ADEs) and potential ADEs in hospitalized children, and to examine the
consequences of these events.
Design Prospective review of medical records and staff interviews were
performed. The ADEs were defined as injuries from medications or lack of
an intended medication, and potential ADEs, as errors with the potential
to result in injury.
Setting A general pediatric unit and a pediatric intensive care unit in
a metropolitan medical center.
Patients A total of 1197 consecutive patient admissions were studied
from September 15, 2000, to May 10, 2001. The admissions represented a
total of 922 patients and 10 164 patient-days.
Results The ADEs (6/100 admissions, 7.5/1000 patient-days) and
potential ADEs (8/100 admissions, 9.3/1000 patient-days) were common in
hospitalized children. Demographic variables associated with the
occurrence of these events were the length of hospital stay, case-mix
index, and amount of medication exposure. After adjusting for length of
stay, medication exposure continued to have a significant influence on
ADEs and potential ADEs. For ADEs, 18 (24%) were judged to be serious or
life threatening. Most ADEs were not associated with major or permanent
disability. Patients with both ADEs and potential ADEs were less likely
to be routinely discharged and more likely to be discharged with home
health care or to another institution, suggesting that patient
disposition was not related to the adverse event.
Conclusions Both ADEs and potential ADEs are common among hospitalized
children with greater disease burden and medication exposure. These
findings suggest that these events were a consequence, rather than a
cause, of more severe illness.
From the college of Pharmacy, university of New Mexico, Albuquerque (Dr
Holdsworth); Departments of Pharmacy (Drs Fichtl, Behta, and
Mendez-Rico) and Pediatrics (Drs Adams and Greifer), New
York-Presbyterian Hospital, New York, NY; Veterans Affairs Cooperative
Studies Program Research Pharmacy Coordinating Center, Albuquerque (Dr
Raisch); and Department of Pediatrics, Joan and Sanford I. Weill Medical
College of Cornell University, New York (Drs Bostwick and Greenwald).
Abstract 6 of 8
Drug-Drug Interactions Among Elderly Patients Hospitalized for Drug
Toxicity
David N. Juurlink, MD, FRCPC, Muhammad Mamdani, PharmD, MPH, Alexander
Kopp, Andreas Laupacis, MD, MSc and Donald A. Redelmeier, MD, MSc
JAMA. 2003;289:1652-1658.
Context Drug-drug interactions are a preventable cause of morbidity and
mortality, yet their consequences in the community are not well
characterized.
Objective To determine whether elderly patients admitted to hospital
with specific drug toxicities were likely to have been prescribed an
interacting drug in the week prior to admission.
Design Three population-based, nested case-control studies.
Setting Ontario, Canada, from January 1, 1994, to December 31, 2000.
Patients All Ontario residents aged 66 years or older treated with
glyburide, digoxin, or an angiotensin-converting enzyme (ACE) inhibitor.
Case patients were those admitted to hospital for drug-related toxicity.
Prescription records of cases were compared with those of controls
(matched on age, sex, use of the same medication, and presence or
absence of renal disease) for receipt of interacting medications
(co-trimoxazole with glyburide, clarithromycin with digoxin, and
potassium-sparing diuretics with ACE inhibitors).
Main Outcome Measure Odds ratio for association between hospital
admission for drug toxicity (hypoglycemia, digoxin toxicity, or
hyperkalemia, respectively) and use of an interacting medication in the
preceding week, adjusted for diagnoses, receipt of other medications,
the number of prescription drugs, and the number of hospital admissions
in the year preceding the index date.
Results During the 7-year study period, 909 elderly patients receiving
glyburide were admitted with a diagnosis of hypoglycemia. In the primary
analysis, those patients admitted for hypoglycemia were more than 6
times as likely to have been treated with co-trimoxazole in the previous
week (adjusted odds ratio, 6.6; 95% confidence interval, 4.5-9.7).
Patients admitted with digoxin toxicity (n = 1051) were about 12 times
more likely to have been treated with clarithromycin (adjusted odds
ratio, 11.7; 95% confidence interval, 7.5-18.2) in the previous week,
and patients treated with ACE inhibitors admitted with a diagnosis of
hyperkalemia (n = 523) were about 20 times more likely to have been
treated with a potassium-sparing diuretic (adjusted odds ratio, 20.3;
95% confidence interval, 13.4-30.7) in the previous week. No increased
risk of drug toxicity was found for drugs with similar indications but
no known interactions (amoxicillin, cefuroxime, and indapamide,
respectively).
Conclusions Many hospital admissions of elderly patients for drug
toxicity occur after administration of a drug known to cause drug-drug
interactions. Many of these interactions could have been avoided.
Author Affiliations: Sunnybrook and Women's college Health Sciences
Centre; the Clinical Epidemiology and Healthcare Research Program, and
Departments of Medicine (Drs Juurlink, Laupacis, and Redelmeier), and
Pharmacy (Dr Mamdani), university of Toronto; and the Institute for
Clinical Evaluative Sciences (Drs Juurlink, Mamdani, Laupacis, and
Redelmeier, and Mr Kopp), Toronto, Ontario.
Abstract 7 of 8
Incidence of Adverse Drug Reactions in Hospitalized Patients
A Meta-analysis of Prospective Studies
Jason Lazarou, MSc, Bruce H. Pomeranz, MD, PhD and Paul N. Corey, PhD
JAMA. 1998;279:1200-1205.
Objective. To estimate the incidence of serious and fatal adverse drug
reactions (ADR) in hospital patients.
Data Sources. Four electronic databases were searched from 1966 to 1996.
Study Selection. Of 153, we selected 39 prospective studies from US
hospitals.
Data Extraction. Data extracted independently by 2 investigators were
analyzed by a random-effects model. To obtain the overall incidence of
ADRs in hospitalized patients, we combined the incidence of ADRs
occurring while in the hospital plus the incidence of ADRs causing
admission to hospital. We excluded errors in drug administration,
noncompliance, overdose, drug abuse, therapeutic failures, and possible
ADRs. Serious ADRs were defined as those that required hospitalization,
were permanently disabling, or resulted in death.
Data Synthesis. The overall incidence of serious ADRs was 6.7% (95%
confidence interval [CI], 5.2%-8.2%) and of fatal ADRs was 0.32% (95%
CI, 0.23%-0.41%) of hospitalized patients. We estimated that in 1994
overall 2216000 (1721000-2711000) hospitalized patients had serious ADRs
and 106000 (76000-137000) had fatal ADRs, making these reactions between
the fourth and sixth leading cause of death.
Conclusions. The incidence of serious and fatal ADRs in US hospitals was
found to be extremely high. While our results must be viewed with
circumspection because of heterogeneity among studies and small biases
in the samples, these data nevertheless suggest that ADRs represent an
important clinical issue.
From the Departments of Zoology (Mr Lazarou and Dr Pomeranz), Physiology
(Dr Pomeranz), and Public Health Sciences (Dr Corey), university of
Toronto, Toronto, Ontario.
Abstract 8 of 8
Timing of New Black Box Warnings and Withdrawals for Prescription
Medications
Karen E. Lasser, MD,MPH, Paul D. Allen, MD,MPH, Steffie J. Woolhandler,
MD,MPH, David U. Himmelstein, MD, Sidney M. Wolfe, MD and David H. Bor,
MD
JAMA. 2002;287:2215-2220.
Context Recently approved drugs may be more likely to have unrecognized
adverse drug reactions (ADRs) than established drugs, but no recent
studies have examined how frequently postmarketing surveillance
identifies important ADRs.
Objective To determine the frequency and timing of discovery of new
ADRs described in black box warnings or necessitating withdrawal of the
drug from the market.
Design and Setting Examination of the Physicians' Desk Reference for
all new chemical entities approved by the US Food and Drug
Administration between 1975 and 1999, and all drugs withdrawn from the
market between 1975 and 2000 (with or without a prior black box
warning).
Main Outcome Measures Frequency of and time to a new black box warning
or drug withdrawal.
Results A total of 548 new chemical entities were approved in
1975-1999; 56 (10.2%) acquired a new black box warning or were
withdrawn. Forty-five drugs (8.2%) acquired 1 or more black box warnings
and 16 (2.9%) were withdrawn from the market. In Kaplan-Meier analyses,
the estimated probability of acquiring a new black box warning or being
withdrawn from the market over 25 years was 20%. Eighty-one major
changes to drug labeling in the Physicians' Desk Reference occurred
including the addition of 1 or more black box warnings per drug, or drug
withdrawal. In Kaplan-Meier analyses, half of these changes occurred
within 7 years of drug introduction; half of the withdrawals occurred
within 2 years.
Conclusions Serious ADRs commonly emerge after Food and Drug
Administration approval. The safety of new agents cannot be known with
certainty until a drug has been on the market for many years.
Author Affiliations: Department of Medicine, Cambridge Hospital and
Harvard Medical School, Cambridge, Mass (Drs Lasser, Allen, Woolhandler,
Himmelstein, and Bor); and Public Citizen Health Research Group,
Washington, DC (Dr Wolfe).
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