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264 LETTERS dated by necropsy examination. For example, necropsy disclosure of clinically inapparent pulmonary disease (that might have com- plicated clinical assessment of the patient’s cardiac status) would have resulted in ex- clusion of that patient from the study. Third, Bristow’s statement that our crite- ria for the diagnosis of clinical cardiac toxicity were “. . . entirely nonquantitative . . .” is simply untrue: Echocardiographic and he- modynamic findings, listed in detail in Table I of our manuscript, supported the clinical diagnosis of cardiac toxicity in 16 (80%) of 20 such patients. Fourth, Bristow’s observation regarding “inconsistencies” among data used to estab- lish the diagnosis of clinical toxicity in 3 pa- tients, for example, with an elevated wedge pressure and a normal chest x-ray, or in 2 patients with pulmonary rales but no x-ray evidence of pulmonary venous hypertension, are not novel observations; similar “incon- sistencies” were demonstrated by Swan et al* > 10 years ago, and form the basis for the use of invasive monitoring. Fifth, there is a precedent for the “clinical diagnosis” of congestive heart failure: ac- cording to Bristow et al, “A clinical diagnosis of congestive heart failure, corroborated by chest roentgenographic findings and physical examination. was. accepted as evidence of cardiac dysfunction . .” in 1 of their studies designed to assess the accuracy of the biopsy technique.” Sixth, there is a precedent for the use of a retrospective chart review in evaluating the development of Adriamycin-induced heart failure: the often-quoted, classic study of Von Hoff et al,’ which confirmed the dose-toxicity relation of Adriamycin, used this method to review the courses of 3,941 patients. Seventh, Bristow states that our findings “ . . . are at striking variance with published reports from other institutions. . .” Of the 6 “published reports” referred to by Bristow, 5 were generated from a single institution- that of Bristow. In the only reference to work done by another institution, biopsy results in that report included only a single patient with cardiac toxicity. Eighth, Bristow suggests that discrepan- cies between the biopsy and necropsy expe- rience may be explained by the fact that the pathologic findings have been interpreted correctly in the biopsy experience, and in- correctly in the necropsy experience. There are several points to be made here: 1. Of 20 uatients we studied with docu- mented clinical toxicity, 7 (35%) had no his- tologic abnormalities at necropsy. If, as Bristow et al suggest, the histologic abnor- malities we identified as evidence of drug toxicity were due to postmortem artifact, this would fail to provide an explanation for the absence of any histologic abnormalities, in- cluding postmortem artifact, among these 7 patients. Such patients are not unique to the necropsy experience: Bristow et al, for ex- ample, described 4 of 50 patients with biopsy scores of 51 in whom catheterization data disclosed evidence of moderate or severe he- modynamic abnormaIlties.4 In another report by Bristow et al, biopsies from 2 of 7 patients with congestive heart failure after anthra- cycline therapy failed to show extensive his- tologic changes.” This figure, 2 of ‘7(28.6%), is similar to our finding of 7 of 20 (35%) with clinical toxicity unassociated with histologic toxicity. 2. Of our 44 patients without clinical signs of toxicity, 23 (52%) had histologic signs of toxicity. This observation is not at variance with the published experience of Bristow et al. Bristow et al reported biopsy scores of I + to 2+ (maximal possible score = 3+) in 23 of 28 patients with no evidence (including catheterization data) of clinical toxicity. Subsequently, Bristow et al described 11 patients with biopsy scores of 2/3 and 1 pa- tient with a biopsy score of 3/3 in whom no or only mild hemodynamic abnormalities were noted at characterization4 These observa- tions are, in fact, implicit in the use of the biopsy technique: Minimal histologic toxicity in the asymptomatic patient allows continued drug therapy, whereas extensive histologic toxicity in the asymptomatic patient does not allow continued drug therapy.s 3. We fully acknowledged in our manu- script that the decision not to examine the necropsy material by electron microscopy (because of problems involving postmortem artifact) constituted an important method- ologic difference between the biopsy and necropsy analyses. We also pointed out, however, that experience at Bristow’s insti- tution had indicated that pathologic abnor- malities such as “. myofibrillar lysis can be recognized by light microscopy.” Variance between the results of biopsy and necropsy analyses does not necessarily indi- cate a need to abandon, at this time, biopsy assessment of anthracycline cardiac toxicity; rather, such variance simply indicates that the biopsy test, like the complete blood counts, chest x-ray and electrocardiography has certain limitations. Recognition of such limitations may in fact improve the manner in which a particular test is used until which time a more accurate test is developed. In the meantime, if the clinical and pathologic diagnoses of Adriamycin cardiac toxicity can be performed accurately only by clinicians and pathologists at a particular institution, then evaluation and treatment of adriamycin toxicity may be, as Bristow suggests, “hope- lessly difficult.” On the other hand, it is likely that the experience of other institutions who also see substantial numbers of such patients may play a role in helping to refine the diag- nosis, treatment, and prevention of Adri- amycin cardiac toxicity. Jeffrey Y. her, MD Boston, Massachusetts 1. Von Hoff DD, Layard MW, Bass P, Davis HC, Jr, Von Hoff AL, Rosenswelg M, Wuggla FM. Risk factors for doxorubiciwinducad congestive heart failure. Ann Intern Med 1979:91:710-717. 2. Swan HJC, Ganz W, Forrester J, Marcus H, Diamond G, Chonette D. Catheterization of the heart in man with use of a flowdirected balloon-tipped catheter. N Engl J Med 1970;283:447-451. 3. Mason JW. B&tow MR. Billlnoham ME. Danlets JR. Invasive and non-invasive metcods of a&essing adri- amycin cardiotoxic effects in man: superiority of histo- pathologic assessment using endomyocardial biopsy. Cancer Treat Rep 19X$62:657-864. 4. Erlstow MR. Mason JW, BIllingham ME, Danlals JR. Dose-effect and structure-function relationships in doxorubicin cardiomyopathy. Am Heart J 1961;102: 709-716. 5. B&tow MA, Mason JW, Billingham ME, Daniets JR. Doxorubicin cardiomyopathy, endomyocardial biopsy, and cardiac catheterization. Ann Intern Med 1978:68: 166-175. 6. Brlstow MR, BIllIngham ME. Mason JW, Danlalh JR. Clinical spectrum of anthracycline antibiotic cardio- toxicity. Cancer Treat Rep 1978:62:673-880 PLEXECTOMY FOR CORONARY SPASM: WHERE ARE THE CONTROLS? The report by Weber et al on plexectomy (AJC, April 1983) records a well-executed. but regrettably unsuccessful, technical tour de force. I am sure that the writers are phy- sicians and surgeons of the highest intellect and skill, yet I was disturbed at how this kind of report could pass the normally eagle-eyed reviewers. As a by-product of their work the authors may well have contributed to un- derstanding coronary physiology, but as a treatment the procedure is experimental, and nowhere is there reference to informed con- sent. Next, the absence of control patients is most disturbing. The authors frankly admit failure in their patients, but without a control series their results cannot be interpreted ei- ther for or against this procedure. In a series of only 3 patients, chance alone might have resulted in the 2 patients with postoperative ‘infarcts and the patient with late recurrent spasm. Thus, if 3 matched control patients had been allocated to an alternate therapy (or no therapy), if 1 of them had also had a postoperative mishap the relation of the procedure to such an event would be in doubt. Thus, on scientific grounds this presentation can only be called a technical report of un- certain value. There is also an ethical issue. A control series, no matter how small (even if scientifically inconclusive) would have of- fered each patient an equal chance not to get the experimental therapy. Such a design is far more ethical, because investigators cannot know the dangers when the first patients are persuaded to undergo a new trial therapy. Certainly, risk-benefit balances have not been appropriately established for plexec- tomy-i.e., by controlled clinical trials-even in previous patients with spasm related to fixed coronary lesions. Because of these re- sults how do we know that even those with organic stenoses “successfully” plexecto- mized (authors’ reference 10) were not ulti- mately made worse by the addition of plex- ectomy to successful bypasses? This anecdotal report of 3 cases would not be acceptable for patients receiving medical therapies. Why is it acceptable for surgical treatment? This experience may become another instance of the pernicious influence of pilot trials.’ It will now discourage further attempts to use the procedure, perhaps un- justifiably-more evidence for randomizing the first patient.2 The scientific and ethical inadequacies are already noted. By random- izing, beginning with the first patient, the authors would have dealt with the behavioral aspect-a format that would impose both scientific and ethical behavior. David H. Spodlck, M, DSc Boston, Massachusetts 1. Chalmers TC. Ethical aspects of clinical trials. Am J Oohthalmol 1975:79:753-758. 2. Spodlck DH. Randomize the fwst patient: scientific, ethical and behavioral bases. Am J Cardiol 1963;51; 916-917. REPLY: We are in full agreement with Spodick that a prospective randomized study is the best methodologic approach to assess the usefulness of a new therapy, whether medical or surgical.
