Notes, hyperlinks, updates, and errata


A word about the notes

            These notes are intended both for the general reader who wants to learn more about a particular topic as well as for medical professionals and researchers who want to investigate an area in greater depth. Abstracts to articles in the medical literature can be accessed at no cost by anyone with internet access via This is the PubMed site of the National Library of Medicine, which provides access to over 12 million medical citations from some 4,600 journals going back to the mid-1960s. These generally include the abstract for a given paper; full text is increasingly available online as well, and is sometimes free. References are also listed below for subject-specific websites through which a reader can follow up on particular topics of interest. The frequency of citations to the work of our group merely reflects the book�s focus on that research; many other important citations from other centers could have been listed if space permitted. These notes are intended not to be exhaustive, but to present a limited number of representative articles and links. Additional material, updates, links to references, and corrections will be periodically added at the book�s website,


            Stroke prevention in atrial fibrillation: Evidence had accumulated by the early 1990s that drugs like warfarin could reduce the risk of stroke by two-thirds in such patients. See, for example, a review by the Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Arch Intern med 1994; 154: 1449-1457.

            PPA and stroke: Kernan WN et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000; 343:1826-1832.

Underuse of drugs in patients who can�t afford them: Steinman MA, Sands LP, Covinsky KE. Self-restriction of medications due to costs in seniors without prescription coverage. J Gen Intern Med 2001; 16: 793-799.

Drugs vs. angioplasty in heart attack: T Aversano et al., �Thrombolytic Therapy vs. Primary Percutaneous Coronary Intervention for Myocardial Infarction,� Journal of the American Medical Association 2002; 287: 1943-1951.

Comparison of commonly used medications for high blood pressure: ALLHAT Officers. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 2981-2997. Numerous followup papers appeared after the publication of ALLHAT, including new clinical trial data; several came to different conclusions. These can be found via the �Related articles� link in PubMed.

            Deaths from Posicor: a former FDA official commented on this in a letter to the British Medical Journal: Landow L. FDA approves drugs even when experts on its advisory panels raise safety questions. BMJ 1999; 318: 944. See also: Po LW, Zhang WY. What lessons can be learnt from withdrawal of mibefradil from the market? Lancet 1998: 351: 1829.

            Medications as a cause of reduced death from cardiovascular disease: see Wald MJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326:1419-1420.


            Misleading evidence that estrogens prevent heart disease: One of the last of several well-intentioned but ultimately incorrect papers on this topic from the Nurses� Health Study was: Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000; 133: 933-941.

            Problematic evidence that estrogens prevent heart disease: For example, see F. Grodstein et al., �A Prospective, Observational Study of Postmenopausal Hormone Therapy and Primary Prevention of Cardiovascular Disease,� Annals of Internal Medicine 2000; 133: 933-941.

Early pro-estrogen literature directed at patients: Wilson RA. Feminine Forever. New York: M Evans and Co. and J. B. Lippincott Co., 1966.      

Adverse effects of hormone replacement therapy: The first large randomized controlled trial to test long-term estrogen replacement therapy in women was the HERS study: Hulley S et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280: 605-613.  The main results of the Women�s Health Initiative study were published as Roussouw JE. Risks and benefits of estrogen plus progestin in healthy post-menopausal women. JAMA 2002; 288: 321-333.  On the doubling of risk of developing symptoms of Alzheimer�s-like senility with estrogen use: Shumaker SA et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in post-menopausal women. JAMA 2003; 289: 2651-2662.

The Tuskegee experiment: see Jones, James H. Bad Blood: The Tuskegee Syphilis Experiment. New York: The Free Press, 1993.


            The plague: Tuchman, Barbara. A Distant Mirror: The Calamitous Fourteenth Century. New York: Alfred A. Knopf, 1978.

            Holmes on drugs: Lecture at Harvard Medical School. Cited in: Bartlett, John. Bartlett�s Familiar Quotations, 10th ed. Boston: Little, Brown, 1919.

            Evolution of drug studies: see Marks, Harry. The Progress of Experiment: Science and Therapeutic Reform in the United States, 1900-1990. Cambridge: The Cambridge University Press, 1997.

History of the FDA and the evolution of drug regulatory policy:  see Hilts, Philip J. Protecting America�s Health: The FDA, Business, and One Hundred Years of Regulation.FDA. New York: Alfred A. Knopf, 2003.

            Placebo effect: Lasagna L et al. A study of the placebo response. Amer J Med 1954; 16: 770-779. See also: Fields HL, Price DD. Toward a neurobiology of placebo analgesia. In: The Placebo Effect: an Interdisciplinary Exploration. Ed. By A. Harrington. Cambridge: Harvard University Press, 1997.

            The first clinical trial: The Book of Daniel, Chapter 1.

            Scurvy: Lind, James. Treatise on the Scurvy. Edinburgh, A. Kincaid and A. Donaldson, 1753. Excerpts from the book and much related material on the evolution and logic of clinical trials can be found on a website created by the Royal College of Physicians of Edinburgh to commemorate the 250th anniversary of the publication of Lind�s work:

            Karl Popper: his most important work in this connection is: Popper, Karl. Logik der Forschung [The Logic of Scientific Discovery]. Vienna: Julius Springer Verlag, 1935. He wrote on the implications of his work for social policy in The Open Society and Its Enemies. London: Routledge, 1945. A website devoted to his work can be found at

            Statistical significance: An interactive way to experience the logic of the coin-toss experiment is at   A good discussion of the perils of simple-minded reliance on arbitrary definitions of statistical significance can be found in Rothman, Kenneth J. Epidemiology: an Introduction. New York: Oxford University Press, 2002, Chapter 6.

            Sodom and Gomorrah: The book of Genesis, Chapters 18-19.

            Existentialism and medical practice: Camus, Albert. The Plague (translated by Stuart Gilbert). New York: Vintage books, 1991. (Original edition: 1948)

Post-modernism: the most important but painfully obscure work applying post-modernist analysis to medicine is Foucault, Michel. The Birth of the Clinic: an Archaeology of Medical Perception. New York: Vintage books, 1994 [originally published in 1963].

Supplements: The Dietary Supplement Health and Education at of 1994 is Public Law No. 103-417. See also Fontanarossa PB, Rennie D, DeAngelis CD. The need for regulation of dietary supplements � lessons from ephedra. JAMA 2003; 289: 1568-1570.

Morris C, Avorn J. Internet marketing of herbal products. JAMA 2003; 290: 1505-1509.

            Postmodernism: An important but painfully obscure work applying a kind of postmodernist analysis to medicine is Michel Foucault, The Birth of the Clinic: An Archaeology of Medical Perception (New York: Vintage, 1994: orig. ed., 1963)


            Paracelsus: the National Library of Medicine established a Paracelsus Home Page to commemorate the 500th anniversary of his birth. It contains an excellent overview of his work and of the world of alchemy in which it occurred:

      Wyeth: This company is not likely to win an award from the National Organization for Women; its corporate umbrella also came to include the manufacturer of the Dalkon Shield, an intrauterine contraceptive device that produced sterility and serious infections, and Norplant, a sustained-release birth-control delivery system that led to frequent side effects, widespread litigation, and concerns over its effectiveness; it has now been taken off the U.S. market.

            The fen-phen story is told in detail in Mundy, Alicia. Dispensing With the Truth. New York: St. Martin�s Press, 2001. The pivotal French study was Abenhaim L et al. Appetite suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996; 335: 609-616.

            Brigham letter to the editor: Dillon K, Putnam K, Avorn J. Death from irreversible pulmonary hypertension associated with short-term use of fenfluramine and phentermine.  JAMA 1997; 278:1320. 

            The same case was described in Mark EJ et al. Fatal pulmonary hypertension associated with short-term use of fenfluramine and phentermine. N Engl J Med 1997; 337: 602-606.

            Heart valve damage: Connolly HM et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997; 337: 581-588.

            FDA�s required drug surveillance studies don�t get done: Food and Drug Administration. �Report on the performance of drugs and biologics firms in conducting postmarketing commitment studies. Federal Register, May 21, 2003, pp. 27822-27823. Described at:


            Los Angeles Times reporting on Rezulin: Much information on the story behind Rezulin�s approval was unearthed by David Willman of the Los Angeles Times and published in a series of articles beginning in late 2000.

            Conflict of interest at NIH: Willman D. Drug maker hired NIH researcher. Los Angeles Times, December 7, 1998. See also: Cimons M. NIH opens conflict-of-interest investigation. Nature Medicine 1999; 5:129-130.

The underuse of liver function monitoring in Rezulin patients: Graham DJ et al. Liver enzyme monitoring in patients treated with troglitazone. JAMA 2001; 286: 831-833.

            British view of Rezulin debacle: Gale EAM. Lessons from the glitazones: a story of drug development. Lancet 2001; 357: 1870-1875.


            Yale study: see paper by Kernan in notes to Chapter 1.


            John Snow: the most recent and comprehensive re-telling of his story is in Peter Vinten et al. Cholera, Chloroform and the Science of Medicine: a Life of John Snow. Oxford: Oxford University Press, 2003. A fine website describing Snow�s work is maintained by the UCLA Department of Epidemiology:

            Bob Dylan: �Subterranean Homesick Blues� is from his 1965 album Bringing It All Back Home, a particularly appropriate title in this context. The same cut also contained the lyric that gave rise to the name another group used (�You don�t need a weatherman to know which way the wind blows�) in a much darker attempt to translate insight into action.

            Russian trio: The programming for all of the epidemiological studies from our group was conducted by Igor Choodnovskiy, Helen Mogun, and Raisa Levin, to whom I am deeply indebted.

            Pharmacoepidemiology in general: A good introduction to this field is Strom, Brian. Pharmacoepidemiology. In addition to the Rothman book cited in the notes to Chapter 3, a more advanced text is his Modern Epidemiology.

            Calcium channel blockers and heart attacks: Psaty BM et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995; 274:620-625.

            Glaucoma medications and lung disease: Avorn J, Glynn RJ, Gurwitz JH, Bohn RL, Monane M, Everitt DE, Gilden D, Choodnovskiy I.  Adverse pulmonary effects of topical beta-blockers used in the treatment of glaucoma.  J Glaucoma 1993; 2:158-165.

            Prozac and suicidal tendencies: Teicher MH, Glod C, Cole JO. Emergence of intense suicidal preoccupation during fluoxitene treatment. Amer J Psychiat 1990; 147: 207-210.

            Bendectin: a comprehensive evaluation of the published research concluded that it was definitely not a teratogen (cause of birth defects), but that its notorious history of litigation made it �the most prevalent tortogen�: Brent RL. Bendectin: Review of the medical literature of a comprehensively studied human non-teratogen. Reprod Toxicol 1995; 9: 337-349.

            Use of cholesterol drugs and �immortality�: Glynn RJ et al. Paradoxical relations of drug treatment with mortality in older persons. Epidemiol 2001;12:682-689.

            Roueche, Berton. Eleven Blue Men and Other Narratives of Medical Detection. Boston: Little, Brown, 1953.


            Aging and medical care: see Avorn J.  Medicine, health, and the geriatric transformation.  Daedalus: J Am Acad Art Sci 1986; 115:211-225.  This paper was reprinted in: Pifer A and Bronte L, eds.  Our aging society:  Paradox and promise.  New York:  W. W. Norton, 1986. The book is a good overview of the effects of a growing elderly population on many aspects of life.

            For a fuller discussion of medication effects in the elderly, see: Avorn J, Gurwitz JH, Rochon P.  Principles of pharmacology.  In:  Geriatric Medicine, 4th edition.  Cassel C et al, eds.  New York:  Springer, 2003. This text is one of the best books on geriatrics overall. Also see: Avorn J, Wang PS. Prescribing psychotropic drugs for the elderly: Epidemiologic and policy considerations. In: Salzman, C, ed. Clinical Geriatric Psychopharmacology, 4th edition. New York: McGraw-Hill (2004).

            Under-representation of elderly in drug studies: Gurwitz JH, Col N, Avorn J.  Exclusion of elderly and women from clinical trials in acute myocardial infarction.  JAMA 1992; 268:1417-1422. An update of these findings, with distressingly similar results, appeared 9 years later in JAMA 2001; 286:708-713.

            Medication-induced symptoms mistaken for new Parkinson�s Disease: Avorn J et al. Neuroleptic drug exposure and treatment of parkinsonism in the elderly: a case-control study.  Am J Med 1995; 99:48-54. See also: Avorn J et al. Increased incidence of L-dopa therapy following metoclopramide use. JAMA 1995; 274:1780-1782; Avorn J et al.  Clinical assessment of extra- pyramidal signs in nursing home patients given antipsychotic medication.  Arch Int Med 1994; 154:1113-7; Kalish SC, Bohn RL, Mogun H, Glynn RJ, Gurwitz JH, Avorn J.  Antipsychotic prescribing patterns and the treatment of extrapyramidal symptoms in older people.  J Am Geriat Soc 1995; 43:967-973. Much of this work was funded by the National Institute on Aging of the NIH.


            Faustus: an appealing little website prepared by Professor D. L. Ashliman pulls together several Faust legends and links to a variety of literary and musical variations on this theme: 

            Making structured decisions in the face of uncertainty: The classic work here is Raiffa, Howard. Decsion Analysis. New York: McGraw-Hill 1997 [originally published in 1968].

            Clinical uses of decision analysis: the standard reference work is Gold, Marthe, Gold, Siegel, and Weinstein, Milton. Cost-Effectiveness in Health and Medicine. New York: Oxford University Press, 1996.

            Anticoagulation to prevent stroke: see the paper by the Atrial Fibrillation Investigators cited in the notes on Chapter 1.


            An earlier version of some of the arguments presented here first appeared in: Avorn J.  Benefit and cost analysis in geriatric care: turning age discrimination into health policy.  N Engl J Med 1984; 310: 1294-1301.

            Quantifying the quality-of-life contribution of Viagra: Smith KJ, Roberts MS. The cost-effectiveness of sildenafil. Ann Intern Med 2000; 132: 933-937.

            Framing and decisionmaking: a comprehensive collection of the seminal work by the two cognitive psychologists who founded this area of inquiry: Kahneman, Daniel and Tversky, Amos (eds.). Choices, Values, and Frames. Cambridge: Cambridge University Press, 2000. An early seminal paper was Tversky A, Kahneman D. The framing of decisions and the psychology of choice. Science 1981; 211:453-458.

            Bernoulli�s paradox: the original paper first published in 1738 was reprinted 216 years later as: Bernoulli D. Exposition of a new theory on the measurement of risk. Econometrica 1954; 22: 23-36.

            NICE is discussed further in Chapter 21.

            Improving patient decisionmaking: a brief recent overview is O�Connor AM et al. Standard consultations are not enough to ensure decision quality regarding preference-sensitive options. J Natl Cancer Inst 2003; 95:570-571.


            PDR: Physicians� Desk Reference, 57th edition. Montvale, N.J.: Thomson Publishing, 2003.

            Communicating about risk: Powell D, Leiss W. Mad Cows and Mother�s Milk: the Perils of Poor Risk Communication. Montreal: McGill-Queen�s University Press, 1997.

            Viagra risk: Kloner RA. Sex and the patient with cardiovascular risk factors. Am J Med 2000; 109 suppl A: 13S-21S.


            Treatment of septic shock with Activated Protein C: the pivotal study was first published as Bernard GR et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709. For followup studies and debate, see also N Engl J Med 2002; 347: 993-1000 and 1027-1030.

            FDA advisory committee reports: the FDA website ( has a search function which makes it possible to find all mentions of any drug throughout the agency�s site. Adding �Advisory Committee� to the search term will make it easier to get to the public transcripts of a panel�s deliberations.

            Thalidomide and risk management: Annas GJ, Elias S. Thalidomide and the Titanic: reconstructing the technology tragedies of the 20th century. Am J Public Health 1999; 89: 98-101.

            Accutane and pregnancy: Mitchell AA et al. A pregnancy-prevention program in women on childbearing age receiving isotretinoin. N Engl J Med 1995; 333:124-125.

         Drug-induced illness in long-term care facilities: Gurwitz JH et al.  Incidence and preventability of adverse drug events in nursing homes.  Am J Med 2000; 109:87-94.


            Reductions in essential drug use after New Hampshire �cap� policy: Soumerai SB, Avorn J, Gortmaker S et al.  Payment restrictions for prescription drugs in Medicaid: Effects on therapy, cost, and equity.  New Engl J Med 1987; 317:550-556.  Its effects on clinical outcomes: Soumerai SB, Ross-Degnan D, Avorn J, et al.  Effects of Medicaid drug-payment limits on admission to hospitals and nursing homes.  N Engl J Med 1991; 325:1072-1077.

            Current state policies to limit drug expenses under Medicaid, as well as many other developments related to prescription drug coverage, are tracked well on the website of the Henry J. Kaiser Family Foundation:


OTA 1993 report on R&D and pharma: Office of Technology Assessment, Pharmaceutical R&D: Costs, Risks, and Returns.  Washington, D.C.: Government Printing Office, 1993.

Public research funding and drug development: see Gluck M. Federal policies affecting the cost and availability of new pharmaceuticals. Washington, D.C.: Georgetown University Institute for Health Care Research, 2002. This work was commissioned by the Henry J. Kaiser Family Foundation and is available on their website:

Coxib discovery: U.S. Patent No. 6,048,850 (issued April 11, 2000): �Method of Inhibiting Prostaglandin Synthesis in a Human Host.� Judge Larimer�s decision: University of Rochester v. G.D. Searle, 249 F. Supp. 2d 216 (Western Dist. New York 2003).

Vioxx side effects: D. H. Solomon et al., �Relationship Between Selective Cyclooxygenase-2 Inhibitors and Acute Myocardial Infarction in Older Adults,� Circulation 2004; 109: 2068-2073.

Report on public funding and Taxol, requested by Sen. Ron Wyden: General Accounting Office. NIH-Private Sector Partnership in the Development of Taxol. Washington, D.C.: General Accounting Office, 2003. Available at

Innovation and large pharmaceutical companies: National Institute for Health Care Management. Changing Patterns of Pharmaceutical Innovation. Washington, D.C.: NICHM Foundation, 2002. Available at: A wide-ranging critique of the industry�s approach to research and to business can be found in Angell M and Relman A. America�s Other Drug Problem. The New Republic, December 16, 2002.

Economic analysis of the drug industry: Health Care Industry Market Update: Pharmaceuticals, the federal government�s calculations about the industry�s expenditures prepared by the Department of Health and Human Services, can be found at

 The Securities and Exchange Commission site containing required corporate filings is

These data are used in the report: Families USA. Profiting from Pain: Where Prescription Drug Dollars Go. Washington, D.C.: Families USA, 2002. Available at: A few caveats are in order. The subparts of the �sales, general, and administrative� category are generally not broken down in the reports that companies make to the S.E.C., so we cannot know how much of that lump sum is spent on marketing and advertising on the one hand, vs. general administration on the other. One company that did provide a breakdown of these costs reported that 36% of its total income went to marketing and distribution, and just 5% to general administration and overhead. Most estimates put the industry�s direct promotion to prescribers at about $20 billion annually, with another $2 billion spent each year on company-sponsored educational events designed to promote product sales. An additional $3 billion is devoted to direct-to-consumer advertising. Adding in a modest additional expenditure for the administration of these programs, the total for promotion-related activities comes to nearly $30 billion a year of the $200 billion the nation spends on prescription drugs, or about one out of every seven dollars.

The story of Gleevec�s discovery: Waalen J. Gleevec�s glory days. Howard Hughes Medical Institute Bulletin, December 2001 []; For the perspective from the Dana-Farber Cancer Institute, see Gleevec: the Dana-Farber connection. Paths of Progress, Fall/Winter 2001. []. The manufacturer�s website is

Medicare overpayments to oncologists for chemotherapy: Government Accounting Office. Medicare: Payments for covered out-patient drugs exceed providers� cost. Washington, D.C.: GAO, 2001. Report GAO-01-1118, available at

The growing influence of business in academia: Derek Bok, Universities in the Marketplace: The Commercialization of Higher Education (Princeton, N.J.: Princeton University Press, 2003).


Cost of prescription drugs: The Department of Health and Human Services estimated in 2003 that the nation would spend $204.7 billion on prescription drugs in 2004. This does not include medications used in hospitals and nursing homes. The figure represents 11.5% of  total national health expenditures of $1.78 trillion. See National Health Care Expenditures Projections at

            Underuse of drugs by elderly: Steinman MA, Sands LP, Covinsky KE. Self-restriction of medication use due to cost in seniors without prescription coverage. J Gen Intern Med 2001; 16: 793-799.

            Cross-national comparison of expenditures on drugs and other health care: Organisation for Economic Cooperation and Development: Health at a Glance. Paris: OECD, 2001. Available through

            Five-country survey: This is an ongoing study conducted by researchers at the Harvard School of Public Health, supported by the Commonwealth Fund. Two recent reports are: Blendon RJ et al. Common concerns amid diverse systems: Health care experience in five countries. Health Affairs 2003; 22:106-121, and Blendon RJ et al. Inequities in health care: A five-country survey. Health Affairs 2002; 21:182-191. More information on the studies is available at the Commonwealth Fund�s website:

            Statements by the Federal Trade Commission chairman: F.M. Muris, �Competition in the Pharmaceutical Industry,� testimony before the U.S. Senate Committee on Commerce, Science and Transportation, April 23, 2002, and testimony before the U.S. House of Representatives Subcommittee on Health, October 9, 2002. Available at

            Drug industry profitability: Fortune, April 14, 2003.


            The economic discussion here also draws on my essay in The New England Journal of Medicine cited in the notes to Chapter 10.

            More recent human-capital approaches: Murray CJL, Lopez AD, eds. The Global Burden of Disease. Cambridge: Harvard University Press, 1996. For a skeptical view, see: Anand S, Hanson K. Disability-adjusted life-years: a critical review. J Health Econ 1997; 16: 685-702.

            Willingness-to-pay: for two reviews of this and related approaches, see: Johnson FD, Fries EE, Banzhaf HS. Valuing morbidity: an integration of the willingness-to-pay and health-status index literatures. J Health Econ 1997; 16: 641-665, and Blumenschein K, Johannesson M. Incorporating quality of life changes into economic evaluations of health care: an overview. Health Policy 1996; 37: 199-204.

            Expected utility approach: von Neumann J and Morgenstern O:  Theory of Games and Economic Behavior. Princeton, N.J.: Princeton University Press, 1944.

            Futilon isn�t so unrealistic; lifelong use of many drugs to manage risk states like high blood pressure or cholesterol yield only about a month of added life, on average, in many subgroups of patients.

The GUSTO study: Some controversy continues about the accuracy of the GUSTO findings, but our discussion gets messy enough without considering this. For simplicity, we�ll ignore those arguments and treat the trial data as if they are the last word on the subject, even though some doubt whether that�s true. Our economic analysis was published as: Kalish S, Gurwitz JH, Krumholz H et al.  A cost-effectiveness model of thrombolytic therapy for acute myocardial infarction.  J Gen Intern Med 1995; 10:321-330. A similar study by investigators at Duke University independently came up with a strikingly similar number in their analysis of the cost-effectiveness of the two drugs.

            The cost of a quality-adjusted life-year: Winkelmayer WC et al. Health economic evaluations: the special case of end-stage renal disease treatment. Med Decis Making 2002; 22: 417-430.

The cost of a good erection: see the paper by Smith and Roberts cited in the notes to Chapter 10.                                                                                                                                                      Bentham J, An Introduction to the Principles of Morals and Legislations. Oxford, U.K.:  Blackwell, 1948 [originally published in 1789].

            Underuse of statins in Europe: Mantel-Teeuwisse AK et al. Undertreatment of hypercholesterlaemia: a populaton-based study. Br J Clin Pharmacol 2003;55:389-397.

Treating very costly hemophilia patients: Colowick AB, Bohn RL, Avorn J, et al.

Immune tolerance induction in hemophilia patients with inhibitors: Costly can be cheaper.  Blood 2000; 96:1698-702.

The policy aspects of these questions are taken up in Part Five.


            Signal transduction: for a good review, see Scott JD, Pawson T. Cell communication: the inside story. Sci Am 2000; 282:72-79.

            The ALLHAT study: see the 2002 JAMA paper cited in the notes to Chapter 1.

            High-dose chemotherapy with bone marrow transplantation for the treatment of cancers: Stadtmauer EA et al. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J. Med 2000; 342:1069-1076. For a good overview of the policy aspects of this treatment, see: Mello MM, Brennan TA. The controversy over high-dose chemotherapy with autologous bone marrow transplant for breast cancer. Health Affairs 2001; 20:101-117.

            The website for the federal CERTs program is

            Non-compliance: see Monane M et al. Compliance with antihypertensive therapy: the role of age, gender, and race. Am J Public Health 1996; 86:1805-1808; Avorn J et al.  Persistence of use of lipid-lowering medications: a cross-national study.  JAMA 1998;279:1458-1462; Benner JS et al. Long-term persistence in use of statin therapy in elderly patients. JAMA 2002; 288:455-461.

            FDA history: The story of the agency�s thwarted attempts to require that accurate and impartial patient information be included with prescriptions is well detailed in a presentation to the agency by consumer advocates: Sasich LD, Wolfe SM. Public Citizen�s Health Research Group�s comments on the status of useful written prescription drug information for patients. FDA Docket No. 00N-0352, March 1, 2000; available at The results of the analysis FDA commissioned to study the problem can be found in Svarstad BL, Mount JK. Evaluation of written prescription information provided in community pharmacies, 2001; available at

Direct-to-consumer drug advertising: this section is based in part on Avorn J. Advertising and prescription drugs: promotion, education, and the public�s health. Health Affairs 2003; available at


            Kudzu: weird pictures of cars and houses overtaken by kudzu overgrowth can be found at

            Effect of advertising vs. data on doctors� drug knowledge : Avorn J, Chen M, Hartley R. Scientific vs. commercial sources of influence on physician prescribing behavior.  Am J Med 1982; 73:4-8.

         Promotion-driven patterns of prescribing for high blood pressure: Monane M et al.

Trends in medication choices for hypertension in the elderly: the decline of the thiazides. 

Hypertension 1995; 125:1045-1051.  See also: Knight EL et al.  Failure of evidence-based medicine in the treatment of hypertension in older patients. J Gen Intern Med 2000;133:128-35.

            How-to manual for drug detailers: Currier D, Frost J. Be Brief, Be Bright, Be Gone: Career Essentials for Pharmaceutical Representatives. San Jose: Writers Club Press, 2001.

            Drug industry�s data: Industry Profile 2002. Washington, D.C.: Pharmaceutical Research and Manufacturers of America, 2002. Availble at

            Drug promotion: the major publication for this aspect of the industry is Medical Marketing and Media. Much candid and interesting content from its issues can be accessed through The broad menu of promotional services offered by the Grey Healthcare Group can be viewed at

            British Medical Journal issue on drug promotion: Its contents are available free on-line at  Of particular interest are the editorial, and the paper by Lexchin analyzing the relationship between pharmaceutical  company sponsorship of studies and the results they report.

            The �No Free Lunch� site ( contains a comprehensive list of readings on the relationship between the drug industry and the medical profession, as well as a ready-to-use slide-lecture presentation on this topic. It also offers a �pen amnesty� program in which a free No Free Lunch ball-point will be sent to any health care worker in exchange for pens and other baubles received from drug manufacturers.

            Some of the websites mentioned:;;; Information is also available at and

            Paradoxical counterproductivity: Illich I. Medical Nemesis. New York: Random House, 1976.

Chronic stunning in heart failure: Braunwald EB, Kloner RA. The stunned myocardium. Circulation 1982; 66:1146-1149.


            The government�s Agricultural Extension Service is still at it: its current activities are described at

            The cocaine paper was published as: Avorn J.  The role of cocaine in treating intractable pain in terminal disease.  In: Jeri R, ed.  Cocaine:  Proceedings of the Interamerican seminar of medical and sociological aspects of cocoa and cocaine.  Lima, Peru:  Pan-American Health Organization, 1979: 227-235.

            Academic detailing: The first paper published on this topic was: Avorn J, Soumerai SB.  Improving drug-therapy decisions through educational outreach:  A randomized controlled trial of academically based "detailing."  N Engl J Med 1983; 308:1457-1463. A followup paper defined the financial aspects of the process: Soumerai SB, Avorn J.  Economic and policy analysis of university-based drug "detailing."  Med Care 1986; 24:313-331.  The work done by the team at Vanderbilt University can be found in Schaffner W et al. Improving antibiotic prescribing in office practice. JAMA 1983; 250: 1728-1732. See also: Avorn J, Soumerai SB.  A new approach to reducing sub-optimal drug use (editorial).  JAMA 1983; 250:1752-1753.  By 1990, there was so much interest in the practical aspects of how to run these programs that we published an expanded version of the proposal I had written in 1979, laying out the rationale and methods of academic deatailing. This appeared as Soumerai SB, Avorn J.  Principles of educational outreach ("academic detailing") to improve clinical decisionmaking. JAMA 1990; 263:549-556. The literature on academic detailing has now become so large that the Cochrane Collaborative has established a systematic review of papers published in this area: Thomson O�Brien MA et al. Educational outreach visits: effects on professional practice and health care outcomes. In: the Cochrane Library, issue 3. Oxford: Update Software, 2003. Available at For a review of similar studies, see Cauffman JG et al. Randomized controlled trials of continuing medical education. J Contin Educ Health Prof 2002; 22:214-221.

            Problematic drug use in nursing homes: Beers M, Avorn J, Soumerai SB et al.  Psychoactive medication use in intermediate-care facility residents.  JAMA 1988; 260:3016-3020.

            Misuse of drugs in board-and-care facilities: Avorn J, Dreyer P, Connelly K et al.  Use of psychoactive medication and the quality of care in rest homes:  Findings and policy implications of a state-wide study.  N Engl J Med 1989; 320:227-32.

            Outcomes of the �academic detailing� geriatrics study: Avorn J et al.  A randomized trial of a program to reduce the use of psychoactive drugs in nursing homes.  N Engl J Med 1992; 327:168-173. See also Everitt DE, Fields D, Avorn J, et al.  Resident behavior and staff distress in the nursing home.  J Am Geriatrics Soc 1991; 39:792-798. This work was supported by the John A. Hartford Foundation.

            The Brigham division: Its website is; see also Some of the division�s work is described in: Avorn J. Balancing the cost and value of medicines: the dilemma facing clinicians. Pharmacoeconomics 2002; 20 suppl 3:67-72.

Reducing excessive antibiotics: see Solomon DH, et al. Academic detailing to improve use of broad-spectrum antibiotics at an academic medical center. Arch Intern Med 2001;161:1897-1902.

            Dutch study of academic detailing: Van Eijk ME, Avorn J, Porsius AJ et al.  Reducing prescribing of highly anticholinergic antidepressants for elderly people:  a randomised trial of group versus individual academic detailing.  BMJ 2001; 322: 654-657.

            Karl Popper: see the references to his work in the notes to Chapter 3.


            Ibsen, H. An Enemy of the People [1882].

            Semmelweis I. The Cause, Concept, and Prophylaxis of Childbed Fever [1861]. Madison: University of Wisconsin Press, 1893.  Carter KS, Abbot S, Siebach JL. Five documents relating to the final illness and death of Ignatz Semmelweis. Bull Hist Med 1955; 69: 255-270. The newest biography blames Semmelweis for his own downfall: Nuland SB. The Doctor�s Plague: Germs, Childbed Fever, and the Strange Story of Ignac Semmelweis. New York: W.W. Norton, 2003.

            The Boston contribution: Holmes OW. The Contagiousness of Puerperal Fever. The Harvard Classics, volume 38, part 5. New York:  P.F. Collier and Son, 1910.


            Australia�s cost-effectiveness requirements: difficulties in the early stages of this program are described in Hill SR et al. Problems with the interpretation of pharmacoeconomic analyses. JAMA 2000; 283: 2116-2121.

            The website for the Australian National Prescribing Service contains a good description of the program as well as a vast number of useful educational materials about drugs:

The British National Institute for Clinical Excellence is at The decision-support software developed by the National Health Service for that nation�s practitioners can be accessed by anyone at It also contains useful material for patients about specific drugs and diseases. Two very helpful sources of information about prescription and over-the-counter medications are also based in the U.K. but are available globally: the British National Formulary ( and the Electronic Medicines Compendium, distributed electronically through the Virtual Health Network: (

            Canadian evaluations of drugs and other medical interventions can be found at the site maintained by the Canadian Coordinating Office for Health Technology Assessment: The University of British Columbia has been particularly active in this area. Its Centre for Health Services and Policy Research tracks work done in these fields across the entire country (, and its Therapeutics Initiative produces excellent materials on optimal drug use, as well as providing links to related sites: The province of Saskatchewan has a comprehensive province-wide academic detailing program that regularly disseminates and updates comparative information on drugs. The impressive materials it uses in its physician education programs are available free at In Alberta, the Canadian Centre for Health Evidence publishes an internet-based User�s Guide to Evidence-Based Practice for patients, practitioners, and policymakers at .


            Wilson, EO. Consilience: the Unity of Knowledge. New York: Knopf, 1998.

The work of the Cochrane Collaborative can be found at and

            Other programs that perform health care technology assessment: Some of these handle medications only peripherally, but their methods and output of other technologies provide a model of what this approach can accomplish. See, for example,;;;;;

            The Oregon drug assessment initiative: go to

            Kuttner R. Everything for Sale: the Virtues and Limits of Markets. New York: Knopf, 1998.

            The work of Dr. Sidney Wolfe and colleagues at the Public Citizen Health Research Group can be found at 

            A better way to assess new drugs: Ray W, Griffin M, Avorn J.  Evaluating drugs after approval for clinical use.  N Engl J Med 1993; 329:2029-2032.

            Efficacy of Liptor: Cannon CP, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndrom. N Engl J Med 2004; 350:1495-1504.


            Savings from more appropriate treatment of blood pressure: Fischer MA, Avorn J. Economic implications of evidence-based prescribing for hypertension. JAMA 2004 ;291:1850-1856.

            Medical informatics as seen from the 1970s: Avorn J.  The future of doctoring:  Information technology and health care delivery.  The Atlantic Monthly 1974; 234:71-79.


            Standards for optimal medication use in older patients: Knight EL, Avorn J. Quality indicators for appropriate medication use in the care of the vulnerable elderly.  Ann Intern Med 2001;135:703-710. This was one of several papers from the ACOVE project that were published in the October 16, 2001 issue of the Annals. Further information is at The project was supported by Pfizer, which provided unrestricted funding for the work but exercised no control over its content.

British Columbia policy reduces drug costs without clinical harm: Schneeweiss S et al. Outcomes of reference pricing for ACE inhibitors. N Engl J Med 2002; 346: 822-829. That study was funded by the U.S. Agency for Healthcare Research and Quality; Dr. Schneeweiss� ongoing policy research in British Columbia is also funded by the National Institute on Aging of NIH.

            �Ideologically androgynous policy�: the term is from Miller, Matthew. The Two Percent Solution: Fixing America�s Problems in Ways Liberals and Conservatives Can Love. New York: Public Affairs, 2003.