Presented by the author at the 2003 New England Seminar in Forensic Sciences, 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
Additional Refs:
Daubert v. Merrel Dow Pharmaceuticals 509 U.S. 579
(1993), 509,
4.
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
5:1964–1969.
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
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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