Polypharmacy Challenged - Cost in Lives is Unknown
Doctors frequently prescribe more than one drug to patients to take contemporaneously, although interactions between drugs have hardly been tested. This practice - polypharmacy - is often deadly, studies indicate. Charles Sullivan, D.O. has challenged polypharmaceutical prescription at the New England Forensic Sciences Conference held in August 2003 at Colby College. Exact numbers of adverse events and loss of patient life are not known, but drug adverse events are one of the leading causes of death in western countries.
In the light of the adverse effects of drugs, recent comments about the supposed "threat to cancer care" of natural remedies such as garlic, cod liver oil and St. John's wort sound less than serious. Might the medical world be trying to divert attention from its own record of deaths and illness caused by their drugs?
After citing generic warnings "from pharmacists" against the natural remedies, Prof. Robert Souhami, of Cancer Research UK, states that "more work needs to be done to get a clearer picture about how complementary medicines react with conventional drugs". Hardly a basis for indicting safe and non-toxic traditional remedies, while cancer drugs of known high toxicity are routinely administered.
Here follows Charles Sullivan's paper on the morbidity and mortality associated with Polypharmacy:
Polypharmacy: What Cost in Morbidity and Mortality?©
Presented by the author at the 2003 New England Forensic Sciences Conference at Colby College
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 "less than 30% of medical practice was backed by controlled studies". 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.
179 Main St Suite 403
Waterville, ME
(207)877-0950
(207)877-2441 FAX
(775)458-1135 FAX to email
path@doctorchuck.com"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
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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, PhDArch 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, PhDJAMA. 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 smaller than .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, PhDArch 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,MScArch 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.
Presented by the author at the 2003 New England Forensic Sciences Conference at Colby College:
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, MDArch 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, MScJAMA. 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, PhDJAMA. 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, MDJAMA. 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).
See also:Why Death Rates Decrease When Doctors Go On Strike
posted by Sepp Hasslberger on Wednesday January 21 2004
updated on Tuesday December 21 2010URL of this article:
http://www.newmediaexplorer.org/sepp/2004/01/21/polypharmacy_challenged_cost_in_lives_is_unknown.htm
