Gender differences in presentation, management, and cardiac event-free survival in patients with syncope.

In a MEDLINE search of published English studies (1966 to 1996), no prior study was identified that examined gender-based differences in the management and prognosis of patients admitted with syncope. We studied 109 consecutive patients (48 women) admitted with syncope at the Massachusetts General Hospital (1989 to 1990). All patients underwent Holter monitoring, signal-averaged electrocardiography, and echocardiography according to study protocol. Follow-up was 100% complete (10 +/- 4 months). Women were older (74 +/- 2 vs 66 +/- 2 years, p <0.01) and less likely to have premonitory symptoms when compared with men (46% vs 66%, p <0.05). A greater proportion of men had left ventricular ejection fractions of <0.40 (18% vs 0%, p <0.01), abnormal signal-averaged electrocardiograms (28% vs 8%, p <0.01), and a cardiac cause for syncope (49% vs 25%, p <0.01). Although referral for diagnostic electrophysiologic testing was >3 times as frequent for men compared with women (20% of men vs 6% of women, p <0.05), this difference was not significant after adjustment for age, ventricular arrhythmia, and referral for coronary angiography. During follow-up, 21% of men versus 6% of women (p <0.05) had cardiac events (recurrent syncope, myocardial infarction, or sudden death). Cardiac event-free survival rates were worse for men (p = 0.045). Thus, we have identified gender-based differences in the clinical presentation of syncope for hospital admission. Left ventricular dysfunction and an abnormal signal-averaged electrocardiogram occur more frequently in men. Men are more likely to have cardiac syncope and worse cardiac event-free survival when compared with women.

Concordance of preoperative clinical risk with angiographic severity of coronary artery disease in patients undergoing vascular surgery.

BACKGROUND: Preoperative clinical indexes to stratify cardiac risk have not been validated angiographically. Our aims were to determine the concordance of clinical risk with severity of coronary stenosis and to develop and validate a preoperative clinical index to exclude the presence of significant coronary stenosis. METHODS AND RESULTS: We carried out a prospective study of 878 consecutive patients (including the derivation and validation sets). "Severe" stenosis was defined as three-vessel (> or = 50% stenosis in each), two-vessel (> or = 50% stenosis in one when the other is > or = 70% stenosis of the left anterior descending), or left main disease (> or = 50%); "critical" stenosis was three-vessel (> or = 70% stenosis in each) and/or left main stenosis > or = 70%. A preoperative clinical index (diabetes mellitus, prior myocardial infarction, angina, age > 70 years, congestive heart failure) was used to stratify patients. A gradient of risk for severe stenosis was seen with increasing numbers of clinical markers. The following prediction rules were developed: The absence of severe coronary stenoses can be predicted with a positive predictive value of 96% for patients who have no (1) history of diabetes, (2) prior angina, (3) previous myocardial infarction, or (4) history of congestive heart failure. The absence of critical coronary stenoses can be predicted with a positive predictive value of 94% for those who have no (1) prior angina, (2) previous myocardial infarction, or (3) history of congestive heart failure. CONCLUSIONS: By reliably identifying a large proportion of patients with a low likelihood of significant stenoses, these prediction rules can help to substantially reduce healthcare costs associated with preoperative cardiac risk assessment for noncardiac surgery.

Geriatric patients with acute myocardial infarction: Cardiac risk factor profiles, presentation, thrombolysis, coronary interventions, and prognosis.

Elderly patients have a higher mortality after acute myocardial infarction (MI) yet are treated less aggressively than younger patients. To determine (l) the risk-factor profiles, (2) presentation, (3) management, and (4) hospital outcomes for the elderly (> or = 75 years) compared with middle aged (66 to 74 years) and younger (< or = 65 years) patients in the 1990s, we studied 561 consecutive patients with acute MI. Compared with younger patients, the elderly more frequently had congestive heart failure (40 percent vs 14 percent; p < 0.00001) and non-Q wave infarctions (76 percent vs 56 percent; p < 0.005), received thrombolysis (9 percent vs 34 percent; p < 0.0001), and underwent catheterization (35 percent vs 73 percent; p < 0.00001), percutaneous transluminal coronary angioplasty (9 percent vs 31 percent; p < 0.0002), and coronary artery bypass grafting (5 percent vs 15 percent; p < 0.03) less frequently. Those who did not receive thrombolysis all had contraindications. Mortality was higher in the elderly (19 percent vs 5 percent; p < 0.004), especially among those who did not receive thrombolysis (20 percent vs 7 percent; p < 0.03). Multivariate predictors of mortality included age, and congestive heart failure. In addition, when clinical course and management variables were considered, use of the intraaortic balloon pump was a predictor of mortality, whereas undergoing coronary angiography was a negative predictor (relative risk, 0.3; 95 percent confidence intervals, 0.1 to 0.6).

Development and validation of a Bayesian model for perioperative cardiac risk assessment in a cohort of 1,081 vascular surgical candidates.

OBJECTIVES: This study sought to develop and validate a Bayesian risk prediction model for vascular surgery candidates. BACKGROUND: Patients who require surgical treatment of peripheral vascular disease are at increased risk of perioperative cardiac morbidity and mortality. Existing prediction models tend to underestimate risk in vascular surgery candidates. METHODS: The cohort comprised 1,081 consecutive vascular surgery candidates at five medical centers. Of these, 567 patients from two centers ("training" set) were used to develop the model, and 514 patients from three centers were used to validate it ("validation" set). Risk scores were developed using logistic regression for clinical variables: advanced age (>70 years), angina, history of myocardial infarction, diabetes mellitus, history of congestive heart failure and prior coronary revascularization. A second model was developed from dipyridamole-thallium predictors of myocardial infarction (i.e., fixed and reversible myocardial defects and ST changes). Model performance was assessed by comparing observed event rates with risk estimates and by performing receiver-operating characteristic curve (ROC) analysis. RESULTS: The postoperative cardiac event rate was 8% for both sets. Prognostic accuracy (i.e., ROC area) was 74 +/- 3% (mean +/- SD) for the clinical and 81 +/- 3% for the clinical and dipyridamole-thallium models. Among the validation sets, areas were 74 +/- 9%, 72 +/- 7% and 76 +/- 5% for each center. Observed and estimated rates were comparable for both sets. By the clinical model, the observed rates were 3%, 8% and 18% for patients classified as low, moderate and high risk by clinical factors (p<0.0001). The addition of dipyridamole-thallium data reclassified >80% of the moderate risk patients into low (3%) and high (19%) risk categories (p<0.0001) but provided no stratification for patients classified as low or high risk according to the clinical model. CONCLUSIONS: Simple clinical markers, weighted according to prognostic impact, will reliably stratify risk in vascular surgery candidates referred for dipyridamole-thallium testing, thus obviating the need for the more expensive testing. Our prediction model retains its prognostic accuracy when applied to the validation sets and can reliably estimate risk in this group.

Care of acute myocardial infarction by noninvasive and invasive cardiologists: procedure use, cost and outcome.

OBJECTIVES: This study sought to determine how noninvasive and invasive cardiologists may differ in the hospital care of patients with acute myocardial infarction. BACKGROUND: Scant information exists regarding the effect of noninvasive and invasive cardiology subspecialization on invasive cardiac procedural use, cost and outcome in the care of patients with acute myocardial infarction. METHODS: This study analyzed a prospective cohort of 292 patients admitted to an urban tertiary care hospital from the emergency room under the care of noninvasive or invasive cardiologists. Clinical characteristics; hospital course, including management, utilization of diagnostic coronary angiography and percutaneous transluminal coronary angioplasty; direct hospital costs; length of hospital stay; and post-hospital discharge follow-up data were collected by a prospective data base instrument. RESULTS: Despite similar clinical characteristics, extent and severity of coronary artery disease and utilization of diagnostic coronary angiography in the two groups of patients, those under the care of an invasive cardiologist were significantly more likely to undergo coronary angioplasty than those under the care of a noninvasive cardiologist. The direct hospital costs and length of stay of the noninvasive and invasive group patients who underwent coronary angioplasty were similar, although overall the direct hospital costs and length of stay were higher for the invasive than for the noninvasive group patients. CONCLUSIONS: Noninvasive and invasive cardiologists differ in their rate of utilization of coronary angioplasty in similar patients with acute myocardial infarction.

Do gender-based differences in presentation and management influence predictors of hospitalization costs and length of stay after an acute myocardial infarction?

Previous studies have reported conflicting results on gender differences in the management of acute myocardial infarction (AMI) and have not evaluated hospital length of stay or costs. To determine gender-based differences in presentation, management, length of stay, costs, and prognosis after AMI, we studied 561 patients with AMI. Women were older, had systemic hypertension, diabetes mellitus, and a non-Q-wave AMI more frequently, whereas more men smoked cigarettes. Predictors of coronary angiography were: male gender (RR 1.9; 95% CI 1.2 to 3.1), chest pain at presentation (RR 1.8; 95% CI 1.0 to 3.3), recurrent angina (RR 4.1; 95% CI 2.5 to 6.8), admission via the emergency room (RR 0.2; 95% CI 0.1 to 0.3), and younger age. Gender did not predict mortality. Among presenting features, the predictors of length of stay were diabetes, prior coronary bypass and prior coronary angioplasty in men, and age alone in women. Pulmonary edema and need for coronary bypass during the hospital course were predictors of length of stay in men only. Among presenting features, predictors of cost were diabetes in men and congestive heart failure in women. Predictors of cost during hospitalization for men were pulmonary edema, coronary angiography, intraaortic balloon pump use, and coronary bypass; for women, they were peak levels of creatine kinase and coronary bypass. Thus, predictors of length of stay and hospitalization costs differ based on gender. Efforts at cost containment may need to be gender-specific.

A stepwise strategy for coronary risk assessment for noncardiac surgery.

Physicians should adapt a systematic approach to cardiac risk stratification for patients being considered for noncardiac surgery, involving clinical evaluation, functional assessment, and surgical risk assessment for all patients and then deciding which patient needs to undergo noninvasive testing, coronary angiography and revascularization, perioperative monitoring, and aggressive postoperative care.

Comparative early and late cardiac morbidity among patients requiring different vascular surgery procedures.

PURPOSE: The evaluation of coronary artery disease (CAD) in patients undergoing vascular surgery can provide information with respect to perioperative and long-term risk for CAD-related events. However, the extent to which the required surgical procedure itself imparts additional risk beyond that dictated by the presence of CAD determinants remains in question. The purpose of this study was to quantify the relative contributions of specific vascular procedures and CAD markers on perioperative and long-term cardiac risk. METHODS: The study cohort comprised 547 patients undergoing vascular surgery from two medical centers who underwent clinical evaluation, dipyridamole thallium testing, and either aortic (n = 321), infrainguinal (n = 177), or carotid (n = 49) vascular surgery between 1984 and 1991. Perioperative and late cardiac risk of fatal or nonfatal myocardial infarction (MI) was compared for the three procedures before and after adjustment for the influence of comorbid factors. These adjusted estimates may be regarded as the component of risk because of type of surgery. RESULTS: Perioperative MI occurred in 6% of patients undergoing aortic and carotid artery surgery, and in 13% of patients undergoing infrainguinal procedures (p = 0.019). Significant (p < 0.05) predictors of MI were history of angina, fixed and reversible dipyridamole thallium defects, and ischemic ST depression during testing. Although patients undergoing infrainguinal procedures exhibited more than twice the risk for perioperative MI compared with patients undergoing aortic surgery (relative risk: 2.4[1.2 to 4.5, p = 0.008]), this value was reduced to insignificant levels (1.6[0.8 to 3.2, p = 0.189]) after adjustment for comorbid factors. There was little change in comparative risk between carotid artery and aortic procedures before (1.0[0.3 to 3.6, p = 0.95]) or after (0.6[0.2 to 2.3, p = 0.4]) covariate adjustment. The 4-year cumulative event-free survival rate was 90% +/- 2% for aortic, 74% +/- 5% for infrainguinal, and 78% +/- 7% for carotid artery procedures (p = 0.0001). Predictors of late MI included history of angina, congestive heart failure, diabetes, fixed dipyridamole thallium defects, and perioperative MI. Patients undergoing infrainguinal procedures exhibited a threefold greater risk for late events compared with patients undergoing aortic procedures (relative risk: 3.0[1.8 to 5.1, p = 0.005]), but this value was reduced to 1.3(0.8 to 2.3, p = 0.32) after adjustment. Long-term risk among patients undergoing carotid artery surgery was less dramatically altered by risk factor adjustment. CONCLUSION: In current practice, among patients referred for dipyridamole testing before operation, observed differences in cardiac risk of vascular surgery procedures may be primarily attributable to readily identifiable CAD risk factors rather than to the specific type of vascular surgery. Thus the cardiac and diabetic status of patients should be given careful consideration whenever possible, regardless of surgical procedure to be performed.

Sex differences in perioperative and long-term cardiac event-free survival in vascular surgery patients. An analysis of clinical and scintigraphic variables.

BACKGROUND: Little information is available regarding the occurrence of perioperative and late cardiac events in women with vascular disease. The current study was performed to examine whether sex-specific differences exist in these outcomes in a large population of vascular surgery patients and to determine the value of clinical and dipyridamole thallium variables in predicting myocardial infarction and cardiac death. METHODS AND RESULTS: Preoperative dipyridamole thallium imaging was performed in 567 vascular surgery patients, including 380 men and 187 women. The incidence of nonfatal myocardial infarction and cardiac death was noted during the perioperative period and during a follow-up period of 50 +/- 5 months. Fixed and reversible thallium perfusion abnormalities were more common in men than in women (P < .001 and P = .004, respectively). Perioperative cardiac event rates were similar in men and women, 8.4% and 7.5%, respectively (P = .07). A transient thallium defect was associated with an increased risk of cardiac events by 3.9-fold in men (CI, 1.5 to 10.2) and 5.5-fold in women (CI, 1.4 to 22). Various clinical factors also were predictive of events but demonstrated substantial sex differences. For example, dipyridamole-induced ST-segment depression was strongly associated with perioperative events in men but not in women. There were 22 nonfatal myocardial infarctions and 29 cardiac deaths in men during the follow-up period, with comparable event rates noted for women. Cardiac event-free survival rates also were similar for men and women (P = .40). Multivariate analysis demonstrated that a history of heart failure was an important prognostic variable for both sexes, as was a fixed thallium defect. Significant sex differences in the predictive value of other clinical factors for late cardiac events was apparent. CONCLUSIONS: The present study demonstrates that (1) thallium perfusion defects are more common in men; (2) transient thallium defects are associated with perioperative myocardial infarction and cardiac death in both sexes; (3) long-term survival rates after vascular surgery are similar between men and women; (4) a fixed perfusion defect is predictive of late cardiac events in women, with a trend noted in men; and (5) sex-specific differences were noted with regard to the prognostic value of various clinical risk factors. Therefore, dipyridamole thallium plays a significant role in the assessment of perioperative and long-term prognosis for both male and female vascular surgery patients. On the basis of these observations, modifications in risk stratification based on sex may be appropriate for men and women with vascular disease.

A clinical rule to predict preserved left ventricular ejection fraction in patients after myocardial infarction.

OBJECTIVE: To derive and validate a clinical prediction rule that identifies patients after myocardial infarction who have preserved left ventricular systolic function. DESIGN: Retrospective analysis of a prospective cohort study, with a derivation set to generate a clinical prediction rule and a validation set to test the prediction rule. SETTING: Urban tertiary care hospital. PATIENTS: 314 consecutive patients admitted with myocardial infarction who had one or more of the following tests to determine left ventricular ejection fraction: transthoracic echocardiography, contrast left ventriculography, or radionuclide ventriculography. MEASUREMENTS: Left ventricular ejection fractions were determined by transthoracic echocardiography, contrast left ventriculography, and gated blood pool scan. RESULTS: Multivariate analysis of patients in the derivation set yielded the following rule: The left ventricular ejection fraction is predicted to be 40% or more in patients who have 1) an interpretable electrocardiogram, 2) no previous Q-wave myocardial infarction, 3) no history of congestive heart failure, and 4) an index myocardial infarction that is not a Q-wave anterior infarction. In the derivation and the validation sets, the positive predictive value of the prediction rule was more than 0.98. CONCLUSIONS: A simple clinical prediction rule using easily obtained historical and electrocardiographic data reliably identifies a substantial percentage of patients after myocardial infarction (40% in our hospital) who are likely to have preserved left ventricular systolic function. If validated in other patient populations, application of this prediction rule in clinical practice could result in a substantial decrease in the cost of treating uncomplicated myocardial infarction.

Use of exercise test parameters to predict presence and duration of ambulatory ischemia in patients with coronary artery disease.

Myocardial ischemia is an indicator of adverse prognosis. In patients with stable angina and positive exercise tests, prolonged cumulative ischemia on ambulatory electrocardiographic monitoring identifies a high-risk group with severe coronary artery disease and poor survival. To determine whether features of the exercise test can accurately (1) predict the occurrence of ambulatory ischemia, and (2) classify patients into subgroups at varying levels of risk for ambulatory ischemia, we studied 48 patients with a history of angina and documented coronary disease who underwent the standard Bruce protocol and ambulatory monitoring. All patients had a positive exercise treadmill test, and 26 had ischemia on Holter monitoring (total of 2,922 minutes, 173 episodes, 94% with silent ischemia). The remaining 22 patients did not have ischemia. The exercise test parameters showing significant differences between the 2 groups were (1) time to > or = 1 mm ST-segment depression (p < 0.0003), (2) maximal ST-segment depression (p < 0.004), and (3) exercise capacity (p < 0.037). These data were used to develop a model for predicting the presence and the severity of ambulatory ischemia. Time to onset of > or = 1 mm ST-segment depression and maximal ST-segment depression on exercise treadmill testing can be used to determine the likelihood of mild (1 to 5 episodes or lasting < or = 60 minutes) or severe prolonged (> 5 episodes or lasting > 60 minutes) ambulatory ischemia. Patients with a very high or very low probability of ischemia on Holter monitoring can be identified by certain exercise test parameters and may not need to undergo monitoring.(ABSTRACT TRUNCATED AT 250 WORDS)

Single-stage reconstruction of key pinch and extension of the elbow in tetraplegic patients.

The results in ten arms of nine patients who had post-traumatic tetraplegia at the fifth or sixth cervical level were reviewed after combined transfer of the brachioradialis to the flexor pollicis longus and of the posterior part of the deltoid to the triceps tendon to restore key pinch and extension of the elbow. The average age of the patients was twenty-nine years, the average time from the injury to the operation was five years, and the average duration of follow-up was thirty-one months. Key pinch improved from essentially none preoperatively to an average of 2.0 pounds (0.9 kilogram) postoperatively: an average of 3.0 pounds (1.4 kilograms) for the patients who had tetraplegia at the sixth cervical level and an average of 0.9 pound (0.4 kilogram) for those who had tetraplegia at the fifth cervical level. Key pinch was favorably influenced by extension of the wrist, while the position of the elbow had no effect. Maximum active extension of the elbow against gravity was within 20 degrees of full extension in eight of the ten arms. There was an improvement in the performance of activities of daily living, including wheelchair use, and most of the patients discontinued use of special equipment for the upper extremity. The results of this study, when compared with those of each procedure performed separately, suggest that a combination of the operations improves function of the upper extremity and shortens the duration of dependence postoperatively.

Costs and effectiveness of angiotensin converting enzyme inhibition in patients with congestive heart failure.

BACKGROUND: Chronic heart failure is associated with a poor prognosis and reduced survival rates. The addition of vasodilator drug therapy to conventional therapy for congestive heart failure has resulted in improved survival. METHODS: Adopting a societal viewpoint, we designed a decision analytic model to analyze the costs and effectiveness of three therapies available for the treatment of congestive heart failure: standard therapy (digoxin and diuretic therapy) plus (1) no vasodilator agents, (2) hydralazine hydrochloride-isosorbide dinitrate combination, and (3) enalapril. In addition, we performed sensitivity analyses to determine which model variables were influential in determining incremental cost-effectiveness ratios (cost of drug, cost of hospitalization, efficacy of agents, etc). We used data from three major randomized controlled trials to estimate treatment efficacy, mortality rates, and hospitalization rates. RESULTS: An additional year of life gained by a patient receiving hydralazine-isosorbide combination therapy compared with standard therapy required an additional expense (incremental cost-effectiveness ratio) of $5600. Compared with the hydralazine-isosorbide combination therapy, the incremental cost-effectiveness ratio for enalapril therapy was $9700 per year of life saved. These results were insensitive to wide variations in our baseline assumptions. CONCLUSIONS: The cost per year of life saved by vasodilator therapy is much lower than that of other accepted medical therapies. Although the cost per year of life saved for hydralazine-isosorbide combination therapy is lower than that for enalapril therapy, enalapril therapy saves more lives, and the incremental cost of enalapril therapy is justified by the added benefits.

Phase I-II study of epirubicin in multiple myeloma.

Forty patients with relapsed (26) or refractory (14) myeloma were treated with epirubicin of doses of 75, 90, 105, and 120 mg/m2 in groups of 6 or more patients to test for response, maximum tolerated dose, and toxicity. Thirteen patients had received prior doxorubicin and were included in the dose findings part of the study only. Staging was I (1), II (5), and III (34). Partial responses were seen in 5 patients (18.5%) (duration 1.5, 2, 2.5, 10, and 18 months) not previously treated with doxorubicin. No responses were seen in patients treated with prior anthracycline. Responses were not dependent upon dose level of epirubicin. Median nadir white blood cell count at the four-dose levels were 2,300, 1,000, 1,600, and 1,700/mm3 with median nadir granulocyte counts of 897, 720, 688, and 192/mm3. Fever/neutropenia was infrequently observed at the three lower dose levels but occurred in 6 of 10 patients at 120 mg/m2. Platelet nadirs were 110,000, 83,000, 169,000, and 42,000/mm3. Nonhematological toxicity was not dose dependent and included alopecia (100%), nausea/vomiting (40%), and stomatitis (25%). Six patients had greater than or equal to 0.10 changes in the resting ejection fraction with one patient developing congestive heart failure that responded to medical management. This patient had received prior doxorubicin and had a history of myocardial infarction. Epirubicin can produce remissions in patients with previously treated myeloma who have not received prior doxorubicin. Since the response rate was not enhanced at 120/m2 and since fever/neutropenia was seen regularly at this dose level, the recommended dose for further study is 105 mg/m2.

Phase II study of aclarubicin in acute myeloblastic leukemia.

Aclarubicin is a new anthracycline antibiotic that produces substantially less cardiotoxicity in animals that does doxorubicin. Based upon prior Phase I and II trials in leukemia, a Phase II study in acute myeloblastic leukemia was developed to assess the response rate and toxicity in previously treated patients. Forty patients received aclarubicin 100 mg/m2 per day X 3 with repeated course on days 14-16 if marrow hypoplasia was not produced. Complete responses were achieved in 27.5% (11/40) with durations of 1.5, 2, 2, 2, 3, 3+, 4, 5+, 32+, 33+, and 34+ months. Toxic effects of this therapy included severe neutropenia and thrombocytopenia, nausea/vomiting, mucositis, and diarrhea. No patient developed significant changes in the left ventricular ejection fraction, as measured by radionuclide angiography, or any clinical cardiac symptoms. Alopecia was minimal. Aclarubicin can produce a significant response rate in previously treated patients with acute myeloblastic leukemia and should be considered for study in initial therapy.

Etoposide in combination with cytarabine, doxorubicin, and 6-thioguanine for treatment of acute nonlymphoblastic leukemia in a protocol adjusted for age.

Etoposide combined with cytarabine, doxorubicin, and 6-thioguanine was used to treat 34 patients with acute nonlymphoblastic leukemia (ANLL) in an age-adjusted protocol, with patients greater than 50 years old receiving fewer days of therapy. Complete remissions (CR) occurred in 85% of all patients (29 of 34 patients). Patients less than or equal to 50 years of age achieved a 94% CR rate (17 of 18 patients) compared to a 75% CR rate (12 of 16 patients) in older patients. Duration of remission was less for those greater than 50 years of age. The remission rate for primary ANLL was 86% (19 of 22 patients) and for secondary or relapsed ANLL was 83% (ten of 12 patients). Thus, this is effective therapy for primary and secondary or relapsed ANLL. When the days of therapy are reduced for older patients' age, the remissions are fewer and less durable.

Phase II study of rDNA alpha-2 interferon (INTRON A) in patients with multiple myeloma utilizing an escalating induction phase.

Twenty previously treated patients with multiple myeloma were treated with rDNA human alpha-2 interferon (INTRON A) in a phase II trial. Patients received an induction phase of therapy consisting of 3-100 X 10(6) IU/m2 iv given every other day pending myelosuppression. Patients then received 10 X 10(6) IU/m2 three times a week sc. In patients not responding to the iv and sc protocol, prednisone (20 mg orally) was given with each dose of INTRON A to determine whether additional responses could be produced and whether toxicity could be reduced. During the sc phases of therapy, INTRON A was escalated pending hematologic and nonhematologic toxicity. Three partial remissions were achieved in patients receiving the initial iv/sc therapy, and one additional patient responded when prednisone was added (durations of remission, 5, 6, 8, and 9 months). Myelosuppression was the dose-limiting toxic effect in both the iv and sc phases of therapy. Constitutional symptoms (flu-like) were seen in the majority of patients, but were tolerable. With the utilization of prednisone, flu-like symptoms were reduced in frequency and degree. Escalation of the dose of INTRON A was possible in the majority of patients when prednisone was added; however, only one patient (of seven) responded to combination therapy. INTRON A can produce remissions in 20% of patients with previously treated multiple myeloma. No improvement in the response rate was achieved utilizing a high-dose induction program. Although the dose of INTRON A could be escalated when prednisone was added, the response rate was not enhanced.

Combination chemotherapy for multiple myeloma with BCNU, cyclophosphamide, vincristine, melphalan, and prednisone (M-2 protocol).

54 consecutively referred, previously untreated patients with stage II and III multiple myeloma have been treated with the M-2 protocol. 50% of patients had a performance status of less than 50%. 13% were stage II and 87% stage III. In 50 of 54 patients (90%), and objective response according to the Myeloma Task Force was achieved; 10% of the responses have been complete (9+, 15+, 17+, 18+ and 66+ months). Remissions now range from 1 to 86+ months. The actuarial median survival determined from the initiation of therapy will exceed 4 years. Toxicity was acceptable with mild myelosuppression. These results confirm the efficacy of the M-2 protocol in multiple myeloma with regards to response rate and survival.