Presented by the author at the 2003 New England Forensic Sciences Conference at Colby
College: Polypharmacy: What Cost in Morbidity and Mortality?©

----------------

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&#8211;72.

Horrobin, D.F. 1990. The philosophical basis of peer review and the
suppression of innovation. J. Am. Med. Assoc. 263:1438&#8211;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&#8211;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&#8211;1969.

Horrobin, D.F. 2000. Innovation in the pharmaceutical industry. J.
R. Soc. Med. 93:341&#8211;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).