Michael L. Terrin

Effect of hydroxyurea on the frequency of painful crises in Sickle cell anemia

BACKGROUND In a previous open-label study of hydroxyurea therapy, the synthesis of fetal hemoglobin increased in most patients with sickle cell anemia, with only mild myelotoxicity. By inhibiting sickling, increased levels of fetal hemoglobin might decrease the frequency of painful crises. METHODS In a double-blind, randomized clinical trial, we tested the efficacy of hydroxyurea in reducing the frequency of painful crises in adults with a history of three or more such crises per year. The trial was stopped after a mean follow-up of 21 months. RESULTS Among 148 men and 151 women studied at 21 clinics, the 152 patients assigned to hydroxyurea treatment had lower annual rates of crises than the 147 patients given placebo (median, 2.5 vs. 4.5 crises per year, P < 0.001). The median times to the first crisis (3.0 vs. 1.5 months, P = 0.01) and the second crisis (8.8 vs. 4.6 months, P < 0.001) were longer with hydroxyurea treatment. Fewer patients assigned to hydroxyurea had chest syndrome (25 vs. 51, P < 0.001), and fewer underwent transfusions (48 vs. 73, P = 0.001). At the end of the study, the doses of hydroxyurea ranged from 0 to 35 mg per kilogram of body weight per day. Treatment with hydroxyurea did not cause any important adverse effects. CONCLUSIONS Hydroxyurea therapy can ameliorate the clinical course of sickle cell anemia in some adults with three or more painful crises per year. Maximal tolerated doses of hydroxyurea may not be necessary to achieve a therapeutic effect. The beneficial effects of hydroxyurea do not become manifest for several months, and its use must be carefully monitored. The long-term safety of hydroxyurea in patients with sickle cell anemia is uncertain.

Liberal or Restrictive Transfusion in High-Risk Patients after Hip Surgery

BACKGROUND The hemoglobin threshold at which postoperative red-cell transfusion is warranted is controversial. We conducted a randomized trial to determine whether a higher threshold for blood transfusion would improve recovery in patients who had undergone surgery for hip fracture. METHODS We enrolled 2016 patients who were 50 years of age or older, who had either a history of or risk factors for cardiovascular disease, and whose hemoglobin level was below 10 g per deciliter after hip-fracture surgery. We randomly assigned patients to a liberal transfusion strategy (a hemoglobin threshold of 10 g per deciliter) or a restrictive transfusion strategy (symptoms of anemia or at physician discretion for a hemoglobin level of <8 g per deciliter). The primary outcome was death or an inability to walk across a room without human assistance on 60-day follow-up. RESULTS A median of 2 units of red cells were transfused in the liberal-strategy group and none in the restrictive-strategy group. The rates of the primary outcome were 35.2% in the liberal-strategy group and 34.7% in the restrictive-strategy group (odds ratio in the liberal-strategy group, 1.01; 95% confidence interval [CI], 0.84 to 1.22), for an absolute risk difference of 0.5 percentage points (95% CI, -3.7 to 4.7). The rates of in-hospital acute coronary syndrome or death were 4.3% and 5.2%, respectively (absolute risk difference, -0.9%; 99% CI, -3.3 to 1.6), and rates of death on 60-day follow-up were 7.6% and 6.6%, respectively (absolute risk difference, 1.0%; 99% CI, -1.9 to 4.0). The rates of other complications were similar in the two groups. CONCLUSIONS A liberal transfusion strategy, as compared with a restrictive strategy, did not reduce rates of death or inability to walk independently on 60-day follow-up or reduce in-hospital morbidity in elderly patients at high cardiovascular risk. (Funded by the National Heart, Lung, and Blood Institute; FOCUS ClinicalTrials.gov number, NCT00071032.).

Complications and validity of pulmonary angiography in acute pulmonary embolism.

BackgroundThe Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) addressed the value of ventilation/perfusion scans in acute pulmonary embolism (PE). The present study evaluates the risks and diagnostic validity of pulmonary angiography in 1,111 patients who underwent angiography in PIOPED. Methods and ResultsComplications were death in five (0.5%), major nonfatal complications in nine (1%), and less significant or minor in 60 (5%). More fatal or major nonfatal complications occurred in patients from the medical intensive care unit than elsewhere: five of 122 (4%) versus nine of 989 (1%) (p<0.02). Pulmonary artery pressure, volume of contrast material, and presence of PE did not significantly affect the frequency of complications. Renal dysfunction, either major (requiring dialysis) or less severe, occurred in 13 of 1,111 (1%). Patients who developed renal dysfunction after angiography were older than those who did not have renal dysfunction: 74±13 years versus 57±17 years (p<0.001). Angiograms were nondiagnostic in 35 of 1,111 (3%), and studies were incomplete in 12 of 1,111 (1%), usually because of a complication. Surveillance after negative angiograms showed PE in four of 675 (0.6%). Angiograms, interpreted on the basis of consensus readings, resulted in an unchallenged diagnosis in 96%. ConclusionsThe risks of pulmonary angiography were sufficiently low to justify it as a diagnostic tool in the appropriate clinical setting. Clinical judgment is probably the most important consideration in the assessment of risk.

A randomized trial of the efficacy of multidisciplinary care in heart failure outpatients at high risk of hospital readmission

OBJECTIVES We sought to determine whether a multidisciplinary outpatient management program decreases chronic heart failure (CHF) hospital readmissions and mortality over a six-month period. BACKGROUND Hospital admission for CHF is an important problem amenable to improved outpatient management. METHODS Two hundred patients hospitalized with CHF at increased risk of hospital readmission were randomized to a multidisciplinary program or usual care. A study cardiologist and a CHF nurse evaluated each patient and made recommendations to the patients primary physician before randomization. The intervention team consisted of a cardiologist, a CHF nurse, a telephone nurse coordinator and the patients primary physician. Contact with the patient was on a prespecified schedule. The CHF nurse followed an algorithm to adjust medications. Patients in the nonintervention group were followed as usual. The primary outcome was the composite of the number of CHF hospital admissions and deaths over six months, compared by using a log transformation t test by intention-to-treat analysis. RESULTS The median age of the study patients was 63.5 years, and 39.5% were women. There were 43 CHF hospital admissions and 7 deaths in the intervention group, as compared with 59 CHF hospital admissions and 13 deaths in the nonintervention group (p = 0.09). The quality-of-life score, percentage of patients on target vasodilator therapy and percentage of patients compliant with diet recommendations were significantly better in the intervention group. Cost per patient, in 1998 U.S. dollars, was similar in both groups. CONCLUSIONS This study demonstrates that a six-month, multidisciplinary approach to CHF management can improve important clinical outcomes at a similar cost in recently hospitalized high-risk patients with CHF.

Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction : results of the thrombolysis in myocardial infarction -TIMI), phase II trial

OBJECTIVES To assess the effects of invasive procedures, hemostatic and clinical variables, the timing of beta-blocker therapy, and the doses of recombinant plasminogen activator (rt-PA) on hemorrhagic events. DESIGN A multicenter, randomized, controlled trial. SETTING Hospitals participating in the Thrombolysis in Myocardial Infarction, Phase II trial (TIMI II). INTERVENTIONS Patients received rt-PA, heparin, and aspirin. The total dose of rt-PA was 150 mg for the first 520 patients and 100 mg for the remaining 2819 patients. Patients were randomly assigned to an invasive strategy (coronary arteriography with percutaneous angioplasty [if feasible] done routinely 18 to 48 hours after the start of thrombolytic therapy) or to a conservative strategy (coronary arteriography done for recurrent spontaneous or exercise-induced ischemia). Eligible patients were also randomly assigned to either immediate intravenous or deferred beta-blocker therapy. MEASUREMENTS Patients were monitored for hemorrhagic events during hospitalization. MAIN RESULTS In patients on the 100-mg rt-PA regimen, major and minor hemorrhagic events were more common among those assigned to the invasive than among those assigned to the conservative strategy (18.5% versus 12.8%, P less than 0.001). Major or minor hemorrhagic events were associated with the extent of fibrinogen breakdown, peak rt-PA levels, thrombocytopenia, prolongation of the activated partial thromboplastin time (APTT) to more than 90 seconds, weight of 70 kg or less, female gender, and physical signs of cardiac decompensation. Immediate intravenous beta-blocker therapy had no important effect on hemorrhagic events when compared with delayed beta-blocker therapy. Intracranial hemorrhages were more frequent among patients treated with the 150-mg rt-PA dose than with the 100-mg rt-PA dose (2.1% versus 0.5%, P less than 0.001). The extent of the plasmin-mediated hemostatic defect was also greater in patients receiving the 150-mg dose. CONCLUSIONS Increased morbidity due to hemorrhagic complications is associated with an invasive management strategy in patients with acute myocardial infarction. Our findings show the complex interaction of several factors in the occurrence of hemorrhagic events during thrombolytic therapy.

Cluster-Randomized Trial of a Mobile Phone Personalized Behavioral Intervention for Blood Glucose Control

OBJECTIVE To test whether adding mobile application coaching and patient/provider web portals to community primary care compared with standard diabetes management would reduce glycated hemoglobin levels in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A cluster-randomized clinical trial, the Mobile Diabetes Intervention Study, randomly assigned 26 primary care practices to one of three stepped treatment groups or a control group (usual care). A total of 163 patients were enrolled and included in analysis. The primary outcome was change in glycated hemoglobin levels over a 1-year treatment period. Secondary outcomes were changes in patient-reported diabetes symptoms, diabetes distress, depression, and other clinical (blood pressure) and laboratory (lipid) values. Maximal treatment was a mobile- and web-based self-management patient coaching system and provider decision support. Patients received automated, real-time educational and behavioral messaging in response to individually analyzed blood glucose values, diabetes medications, and lifestyle behaviors communicated by mobile phone. Providers received quarterly reports summarizing patient’s glycemic control, diabetes medication management, lifestyle behaviors, and evidence-based treatment options. RESULTS The mean declines in glycated hemoglobin were 1.9% in the maximal treatment group and 0.7% in the usual care group, a difference of 1.2% (P = 0.001) over 12 months. Appreciable differences were not observed between groups for patient-reported diabetes distress, depression, diabetes symptoms, or blood pressure and lipid levels (all P > 0.05). CONCLUSIONS The combination of behavioral mobile coaching with blood glucose data, lifestyle behaviors, and patient self-management data individually analyzed and presented with evidence-based guidelines to providers substantially reduced glycated hemoglobin levels over 1 year.

Design of the multicenter study of hydroxyurea in sickle cell anemia

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia is a randomized double-blind placebo-controlled trial to test whether hydroxyurea can reduce the rate of painful crises in adult patients who have at least three painful crises per year. The sample size of 299 patients yields at least 90% power to detect a 50% or greater reduction in crisis rate. Dosage starts at 15 mg/kg/day and is titrated to the patients maximum tolerated dose up to 35 mg/kg/day. Placebo dosage is titrated in similar fashion to maintain blinding. Attempts are made to ascertain medical contacts for at least 2 years after study entry. The Core Laboratory, Treatment Distribution Center, and Data Coordinating Center collaborate to provide standardized monitoring for toxicity and dose adjustments. The Core Laboratory also reduces the possibility of inadvertent unmasking of treatment assignment during review of hematologic data in clinical centers. An independent Crisis Review Committee classifies clinical events to assure that outcome evaluations are standardized and unbiased by knowledge of treatment assignments. The Data and Safety Monitoring Board assures scientific integrity of the study, as well as the safety and ethical treatment of study patients. We expect the study to determine whether or not treatment with hydroxyurea can offer significant clinical benefit to patients with the most common hereditary disorder among African-Americans in the United States.

Long-Term Effects on Clinical Outcomes of Aggressive Lowering of Low-Density Lipoprotein Cholesterol Levels and Low-Dose Anticoagulation in the Post Coronary Artery Bypass Graft Trial

Background —The Post Coronary Artery Bypass Graft Trial, designed to compare the effects of 2 lipid-lowering regimens and low-dose anticoagulation versus placebo on progression of atherosclerosis in saphenous vein grafts of patients who had had CABG surgery, demonstrated that aggressive lowering of LDL cholesterol (LDL-C) levels to <100 mg/dL compared with a moderate reduction to 132 to 136 mg/dL decreased the progression of atherosclerosis in grafts. Low-dose anticoagulation did not significantly affect progression. Methods and Results —Approximately 3 years after the last trial visit, Clinical Center Coordinators contacted each patient by telephone to ascertain the occurrence of cardiovascular events and procedures. The National Death Index was used to ascertain vital status for patients who could not be contacted. Vital status was established for all but 3 of 1351 patients. Information on nonfatal events was available for 95% of surviving patients. A 30% reduction in revascularization procedures and 24% reduction in a composite clinical end point were observed in patients assigned to aggressive strategy compared with patients assigned to moderate strategy during 7.5 years of follow-up, P =0. 0006 and 0.001, respectively. Reductions of 35% in deaths and 31% in deaths or myocardial infarctions with low-dose anticoagulation compared with placebo were also observed, P =0.008 and 0.003, respectively. Conclusions —The long-term clinical benefit observed during extended follow-up in patients assigned to the aggressive strategy is consistent with the angiographic findings of delayed atherosclerosis progression in grafts observed during the trial. The apparent long-term benefit of low-dose warfarin remains unexplained.

Comparison of Clinical Outcomes for Women and Men after Acute Myocardial Infarction

Drugs Generic Name Brand Name alteplase Activase Abbreviations rt-PA = recombinant tissue plasminogen activator The decline in coronary heart disease-related deaths, which began in the mid-1960s [1-6], has been greater for men than for women [4]. Data from several large epidemiologic [7] and clinical [8-12] studies suggest that the prognosis after acute myocardial infarction is worse for women. Some investigators relate these differences to age, risk factor profile, and the severity of preexisting coronary disease [10-15], whereas others relate them to sex [8, 9, 12]. Epidemiologic research on coronary heart disease among women has been limited, particularly in the thrombolytic era. Although several population- and community-based studies have been done [7, 10, 14-16], different methods, diagnostic criteria, end points, and definitions have made direct comparisons between women and men difficult and unreliable. The Thrombolysis in Myocardial Infarction Phase II (TIMI-II) trial [17] provides a valuable opportunity to investigate the potential influence of sex on clinical outcome after myocardial infarction. In a secondary observational analysis, we assessed possible differences in morbidity and mortality between men and women with myocardial infarction treated with thrombolytic therapy. We also analyzed the relation of any differences to baseline patient characteristics and clinical features. Methods Patient Selection Details of the TIMI-II protocol have been reported before [17, 18]. Briefly, women and men younger than 76 years who had ischemic chest pain lasting 30 minutes or more, in whom treatment with recombinant tissue plasminogen activator (rt-PA) (alteplase; Activase, Genentech, South San Francisco, California) within 4 hours of symptom onset was feasible, were considered for the study. Exclusion criteria included a history of cerebrovascular disease; blood pressure greater than 180 mm Hg systolic or 110 mm Hg diastolic; systemic bleeding disorders; major surgery within the previous 2 weeks; recent prolonged cardiopulmonary resuscitation; percutaneous transluminal coronary angioplasty or severe trauma within the previous 6 months; previous coronary artery bypass grafting or prosthetic heart valve replacement; left bundle-branch block; dilated cardiomyopathy; and other serious illness. Thrombolytic Therapy The rt-PA used in the TIMI-II study was produced by the suspension culture method (G11044, supplied by Genentech). The total dosage of rt-PA used in the first 520 patients was 150 mg administered intravenously during a period of 6 hours. Because of an unacceptably high rate of intracranial hemorrhage [19], however, the dosage was reduced to 100 mg given during 6 hours in the remaining patients. Assigned Strategies and Beta-Blocker Treatment Patients were assigned randomly to receive one of two treatment regimens: 1) routine coronary angiography done 18 to 48 hours after study entry and percutaneous transluminal coronary angioplasty or coronary artery bypass grafting if angiography showed that the patients anatomy was suitable [invasive strategy]; or 2) conventional care without coronary angiography and percutaneous transluminal coronary angioplasty, unless evidence showed either spontaneous or exercise-induced myocardial ischemia (conservative strategy) [17]. Coronary artery bypass grafting was done in patients assigned to either group for appropriate clinical indications. In the TIMI-IIA substudy [18], 195 patients were assigned to receive an immediate invasive strategy and were excluded from the analysis. Enrollment of patients in TIMI-IIB (the -blocker substudy) [20] at the seven TIMI-IIA clinical sites did not begin until enrollment in TIMI-IIA was completed. In TIMI-IIB, patients assigned to receive immediate intravenous -blocker therapy were given 15 mg of metoprolol as three 5-mg intravenous injections at 2-minute intervals, followed by oral metoprolol. Those assigned to receive deferred -blocker therapy received 50 mg of oral metoprolol twice on day 6 and 100 mg twice each day thereafter. Concomitant Care Patients received intravenous lidocaine for 24 hours and intravenous heparin for 5 days. Aspirin (80 mg) was administered on the day of study entry according to the protocol in the first 488 patients and on the next day in the remaining patients; it was increased to 325 mg per day on day 6, when intravenous heparin was replaced by subcutaneous heparin. End Points The primary end point in TIMI-II was survival with no recurrent myocardial infarction at 42 days. Secondary end points included the ejection fraction at rest and during exercise at hospital discharge and at 6 weeks. Complications of therapy were also assessed. Follow-up examinations were conducted 6 weeks and 1 year after study entry. The vital status of all patients not individually examined was determined by telephone interview. Statistical Analysis Probability values and confidence intervals for percentages and proportions were calculated using standard methods to test differences between two independent proportions [21, 22]. Because of multiple comparisons in the TIMI-II secondary analyses, probability values between 0.01 and 0.001 for two-sided tests were considered to provide some evidence of differences, and values less than 0.001 were thought to provide strong evidence of differences. Comparisons between mortality and either mortality or myocardial infarction rates are based on Cox regression analysis [23, 24]. The Cox proportional-hazards model was examined for validity of assumptions using the Kaplan-Meier [23] estimates of survival (S[t]) for each covariate in graphs plotting the log (log[S(t)]) against time to events (death and death or myocardial infarction), and the assumptions were tested for the comparison of men with women by introducing time-dependent variables for interaction [24]. Adjustment, when appropriate, was made for assignment to conservative or invasive strategy, rt-PA dose, and the TIMI-II baseline patient characteristics (age, previous myocardial infarction, anterior myocardial infarction, history of diabetes, history of hypertension, time from onset of symptoms to study entry, ongoing chest pain when rt-PA infusion was begun, history of congestive heart failure, race, and history of angina). Crude event rates and Kaplan-Meier event rates for mortality and for death or myocardial infarction were almost identical because of the completeness of follow-up information. Tests of interaction were done using crude event rates and the Breslow-Day statistic [25]. This report is based on an analysis file prepared at the TIMI Coordinating Center in January 1991. Results Patient Characteristics Women were older than men, with mean ages of 62.2 and 56.6 years (P < 0.001), respectively, and more commonly had past medical histories that included congestive heart failure (P < 0.001), systemic hypertension (P < 0.001), or diabetes mellitus (P < 0.001). As a group, women were less likely than men to be classified as low risk (P < 0.001). The time from symptom onset to study entry was delayed in women compared with men (2.8 hours compared with 2.6 hours; P < 0.001). Fewer women than men were considered eligible for the -blocker study (P < 0.001) (Table 1). Invasive Procedures and Medical Treatments The frequency of invasive procedures done within 6 weeks of study entry is summarized in Table 2. No differences between men and women were found in either the invasive or conservative treatment groups. Throughout this period, women were less likely than men to receive -blockers, but calcium channel blockers were prescribed more frequently for women. Aspirin was used with similar frequency. Table 1. Baseline Characteristics and Clinical Features of Patients* Complications Coronary Angioplasty Although coronary arterial dissection was observed more frequently in women than in men (17.2% compared with 10.0%; P = 0.002), within 24 hours after percutaneous transluminal coronary angioplasty, the frequencies of recurrent myocardial infarction, death, or the need to do emergent coronary bypass surgery did not differ statistically between women and men assigned to receive invasive procedures. Sex was not associated with the frequency of successful percutaneous transluminal coronary angioplasty [26]. Left Ventricular Function More of the 597 women in the TIMI-II study had resting left ventricular ejection fractions greater than 55% on radionuclide ventriculography than did the 2742 men before hospital discharge (33.5% compared with 29.0%; P = 0.03) and at 6-week follow-up (32.8% compared with 27.1%; P = 0.005). However, a greater proportion of these women than men did not have radionuclide studies analyzed because of death or inability to measure ejection fraction at hospital discharge (24.0% compared with 16.6%; P < 0.001) and 6-week follow-up (34.2% compared with 25.5%; P < 0.001). Patient Outcome: Mortality and Morbidity One-year follow-up data were available for 3316 (99.3%) patients [27]. Event rates according to sex and treatment strategy are summarized in Table 3. The cumulative 6-week mortality rate was higher for women than for men (9% compared with 4%; P < 0.001). Combined reinfarction and death also was more common among women than men (15.9% compared with 9.5%; P < 0.001). These differences (for both the invasive and conservative treatments) persisted at 1-year follow-up (Figures 1 and 2). Table 2. Invasive Procedures and Medications at 6 Weeks from Study Entry according to Sex and Treatment Strategy* Figure 1. One-year Kaplan-Meier mortality curves for women and men. Figure 2. One-year Kaplan-Meier event rates for reinfarction in women and men. The occurrence of myocardial infarction or death was predictably lower for low-risk women and men. The mortality rate was 1.9% for women compared with 1.6% for men (P = 0.78) 6 weeks after study entry, and it was 3.1% compared with 2.5% (P = 0.66) 1 year after study entry. Among high

A pilot randomized trial comparing symptomatic vs. hemoglobin-level- driven red blood cell transfusions following hip fracture

BACKGROUND: The indications for transfusion have never been evaluated in an adequately sized clinical trial. A pilot study was conducted to plan larger clinical trials.