New femoral designs: do they influence stress shielding?

Virtually all contemporary cementless femoral hip stems are designed with the goals of achieving immediate and long-term stability, restoring hip mechanics, and minimizing thigh pain. However, the incorporation of features specifically intended to minimize stress-mediated bone resorption (stress shielding) has been variable. Attempts to reduce bone loss through stem design have yielded inconsistent results and, in certain instances, early and catastrophic failure. Prior beliefs regarding the determinants of stress shielding were based upon the qualitative assessment of bone loss using plain radiographs. These are being challenged, particularly with regard to the role of porous coating level. This is in large part due to the refinement and widespread availability of dual-energy xray absorptiometry (DEXA), which allows quantitative assessment of bone mineral density both pre- and postoperatively. The available evidence indicates stem stiffness plays a dominant role. Progressive bone loss through stress shielding has potentially dire consequences. While such problems have not manifested as severe or widespread clinical issues, the preservation of femoral bone stock is an important and desirable goal.

Selective serotonin reuptake inhibitors yield additional antiplatelet protection in patients with congestive heart failure treated with antecedent aspirin.

Clinical depression has been identified as an independent risk factor for increased mortality in patients with coronary artery disease. Enhanced platelet activity has been suggested as the mechanism responsible for this adverse association. Selective serotonin reuptake inhibitors (SSRIs) are known to inhibit platelets in patients undergoing coronary stenting. We sought to determine whether concomitant therapy with SSRIs would yield additional anti-platelet benefit in patients with congestive heart failure (CHF) already treated with antecedent aspirin. A total of 88 patients with left ventricular ejection fraction (LVEF) <40% or CHF symptoms in the setting of preserved systolic function and NYHA Class II-IV were analyzed. Of these, 23 patients (26%) were chronic SSRI users (SSRI+), and 65 patients were free from SSRI therapy (SSRI-). All patients received aspirin (325 mg) for at least 1 month prior to platelet studies. Platelets were assessed by aggregometry, flow cytometry and a rapid analyzer. The SSRI+ group exhibited a substantial decrease in platelet activity when compared with SSRI- patients, as manifested by a significant reduction in ADP- (P=0.001), and collagen-induced (P=0.02) aggregation, and the expression of PECAM-1 (P=0.03), GPIb (P=0.03), GP IIb/IIIa antigen (P=0.02) and GP IIb/IIIa activity with PAC-1 antibody (P=0.04) and P-selectin (P=0.02). Therapy with SSRIs also resulted in the reduced formation of platelet-leukocyte microparticles (P=0.01). Epinephrine-induced aggregation in plasma, collagen-induced whole blood aggregation, closure time and expression of vitronectin receptor, CD63, CD107a, CD107b and CD151 did not differ between groups. In patients with CHF already on aspirin, SSRI therapy was associated with further inhibition of platelet function. This observation may help to explain some of the clinical benefits associated with SSRI therapy. Further clinical trials may help to elucidate the potential outcome benefits of SSRIs in other potential thrombotic circumstances.

Depression and nicotine: preclinical and clinical evidence for common mechanisms.

Updated findings on the relationship between nicotine and depression are presented. Clinical and preclinical research on nicotine use and depression suggests that nicotine may have some properties in common with antidepressants. Updated findings involve the comorbidity of smoking and major depressive disorder (MDD), the influence of depression during withdrawal on failure to quit smoking, the course of MDD without nicotine and the neurobiology of smoking and depression.

Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death.

OBJECTIVE: The authors review the mechanisms and establish the risk of torsade de pointes and sudden death with antipsychotic drugs. METHOD: They present a review of original concepts, the distinction between familial and drug-induced cases of torsade de pointes, and the recognition of the role of noncardiac drugs in torsade de pointes and sudden death. They review the evidence linking QTc interval prolongation, potassium channels, and torsade de pointes from both the long QT syndrome and drugs. They examine the risk for torsade de pointes from antipsychotic drugs and estimate the frequency of sudden death on the basis of epidemiological data in normal and schizophrenic populations. RESULTS: All drugs that cause torsade de pointes prolong the QTc interval and bind to the potassium rectifier channel, but the relationships are not precise. Prediction of torsade de pointes and sudden death can be improved by examining dose dependency, the percent of QTc intervals higher than 500 msec, and the risk of drug-drug interactions. Although sudden unexpected death occurs almost twice as often in populations treated with antipsychotics as in normal populations, there are still only 10-15 such events in 10,000 person-years of observation. CONCLUSIONS: Although pimozide, sertindole, droperidol, and haloperidol have been documented to cause torsade de pointes and sudden death, the most marked risk is with thioridazine. There is no association with olanzapine, quetiapine, or risperidone. Ziprasidone does prolong the QT interval, but there is no evidence to suggest that this leads to torsade de pointes or sudden death. Only widespread use will prove if ziprasidone is entirely safe. To date, all antipsychotic drugs have the potential for serious adverse events. Balancing these risks with the positive effects of treatment poses a challenge for psychiatry.

Smoking cessation and the course of major depression: a follow-up study.

BACKGROUND: Smokers with a history of major depression who attempt to stop smoking have a higher risk of failure than non-depressed smokers. Anecdotal and post-hoc data suggest that those who successfully abstain are at increased risk of depression compared with individuals who continue to smoke. However, these studies confound effects of abstinence and history of depression. We aimed to assess whether there is an increased risk of depression and for how long that increase lasts. METHODS: We enrolled 100 smokers (>1 pack per day) with a history of major depression, but who were currently free from major depression and had not been on antidepressant medicine for at least 6 months, in a 2-month smoking-cessation trial. The primary outcome was recurrence of major depression, which we assessed by structured clinical interviews 3 and 6 months after the end of treatment. We verified smoking status by serum-sample cotinine concentrations. FINDINGS: 76 participants (42 successful abstainers, 34 smokers) were followed up. 13 abstainers and two smokers had an episode of major depression (odds ratio 7.17 [95% CI 1.5-34.5]; Kaplan-Meier survival curve, log-rank statistic 9.11 [p=003]). Risk of major depression was similar between the first and second 3 months of follow-up. INTERPRETATIONS: Smokers with a history of depression who abstain from smoking are at significantly increased risk of developing a new episode of major depression. This risk remains high for at least 6 months.

A low stiffness composite biologically fixed prosthesis.

The current authors addressed the question whether stress-induced adaptive bone remodeling of the proximal femur is a necessary consequence after total hip reconstruction with extensively biologically-fixed femoral components. A novel total hip femoral component was designed to simultaneously achieve stable skeletal fixation, structural durability, and reduced femoral stress shielding. This implant allowed for proximal and distal canal filling, yet was significantly less rigid than all-metallic femoral stems crafted of either cobalt chromium or titanium alloy. A cohort of 366 patients (386 hips) treated at 21 institutions worldwide now have been followed up a mean of 2.4 years postoperatively (range, 3 months-6 years). Two hundred sixty-eight patients have 2 years minimum followup. To date, no femoral implants have failed to achieve bone ingrowth and none have required revision. The implants appear radiographically well-fixed with no progressive radiolucencies or osteolysis. Radiostereometric analysis studies on one subset of patients showed stable initial fixation and minimal stem micromotion. Dual energy xray absorptiometry analysis on another subset of patients revealed excellent periprosthetic bone mineral density retention. Compared with more rigid metal implants, this design shows reduced proximal femoral bone loss secondary to stress-mediated bone resorption.

Advances in non-nicotine pharmacotherapy for smoking cessation.

Progress in understanding the pharmacological nature of tobacco addiction, along with the modest success rates achieved by the nicotine replacement therapies, has provided the major impetus for the development of non-nicotine drugs as smoking cessation aids. This article reviews evidence from controlled trials of several non-nicotine medications for the treatment of nicotine dependence. Clonidine was the first non-nicotine medication to show efficacy for smoking cessation in multiple studies, but its effect was found to be limited at best. Positive results across several trials have been consistently demonstrated for amfebutamone (bupropion). Encouraging results have also been observed for nortriptyline and moclobemide. Studies of combined treatments using non-nicotine medications (amfebutamone, mecamylamine, oral dextrose) with nicotine replacement therapy suggest increased efficacy relative to treatments using one or the other treatment strategy alone. Thus, available evidence indicates that non-nicotine drug treatments offer a promising panoply of therapeutic strategies for the addicted smoker.

An open-label preliminary trial of sertraline for treatment of major depression after acute myocardial infarction (the SADHAT Trial). Sertraline Anti-Depressant Heart Attack Trial.

BACKGROUND: Depression occurs frequently in patients with acute myocardial infarction and is associated with increased mortality rates. It is not known whether serotonin reuptake inhibitors would be safe and effective for patients with depression after myocardial infarction and whether such treatment would reduce mortality rates. METHODS AND RESULTS: We conducted a multicenter, open-label, pilot study of sertraline treatment in patients with major depressive disorder identified 5 to 30 days after admission for acute myocardial infarction. Outcome measures included cardiovascular and hemostatic function, adverse events, and mood ratings. Twenty-six patients were enrolled in the study. During treatment there were no significant changes in heart rate, blood pressure, cardiac conduction, or left ventricular ejection fraction, and there was a trend toward reduced ventricular ectopic activity. There were no changes in coagulation measures. Bleeding time increased in 12 patients, decreased in 4 patients, and was unchanged in 2 patients. Three (12%) patients withdrew from treatment prematurely because of adverse events. Significant improvements in mood ratings occurred over the course of treatment. CONCLUSIONS: Sertraline treatment was associated with clinical improvement and was well tolerated in >85% of the patients in this open-label treatment trial for patients with major depression after myocardial infarction. These results encourage further controlled trials to establish the effects of treatment for this high-risk population.

Naltrexone effects on short-term and long-term smoking cessation.

OBJECTIVES: This study examined the efficacy of naltrexone, a long-acting opiate antagonist, as a smoking cessation aid in a double-blind placebo-controlled randomized trial. It was hypothesized that naltrexone would result in higher quit rates at the end of treatment and six months later. METHODS: Subjects were 68 smokers aged 18 to 65 who smoked at least 20 cigarettes daily and wished to stop smoking. They took naltrexone or placebo daily for four weeks and were seen weekly for individual smoking cessation therapy. RESULTS: A statistical trend towards a higher overall cessation rate (cotinine < 15 ng/mL) at end-of-treatment was observed among subjects treated with naltrexone than placebo (46.7% vs. 26.3%, respectively, odds ratio = 2.5, p < .10); however, this difference was attenuated at six months (27% vs. 15%, respectively, odds ratio = 1.9, p = ns). Stratified analysis indicated the usefulness of naltrexone primarily for female smokers and those with a history of major depression. These effects remained six months later. CONCLUSION: These results provide, at best, mild promise for naltrexone as a smoking cessation drug and provide another instance of a differential response to nicotine dependence treatment according to gender and depression history.

Cardiovascular effects of antidepressant drugs: updated.

It has long been evident that the tricyclic antidepressants have serious cardiovascular effects. This becomes an increasingly important issue as patient populations age. In addition, there is now strong evidence that depression increases the incidence of ischemic heart disease. Taken together these issues make the safety of antidepressant drugs even more important. The tricyclic antidepressants have long been able to produce orthostatic hypotension and this propensity is increased in patients with cardiac disease. In addition, the tricyclics prolong conduction and in overdose this leads to serious cardiac complications. Although only a limited amount of data are available, the serotonin reuptake inhibitors show no evidence of harm. In fact, there is some evidence that the selective serotonin reuptake inhibitor drugs may be beneficial for patients with cardiovascular disease.

Cardiovascular effects of antidepressant drugs: updated.

The cardiovascular effects of tricyclic antidepressants (TCAs), including the propensity of these agents to be fatal in overdose, have been well described. It has been established further that even at therapeutic doses the TCAs may have untoward cardiovascular effects in the context of underlying ischemic heart disease. By comparison, the selective serotonin reuptake inhibitors (SSRIs) as a class are less likely to affect cardiovascular parameters in depressed patients who are otherwise healthy. Importantly, the SSRIs in overdose situations are enormously safer than TCAs and rarely have been associated with cardiotoxic effects when ingested alone. More recently, the safety and efficacy of several of the SSRIs have been evaluated in patients with existing ischemic heart disease. Although the studies have involved a limited number of patients, the available data suggest that SSRIs are not associated with adverse cardiovascular effects in these patients and are safer than TCAs in the treatment of depression in patients with heart disease. The prevalence of cardiovascular disease and the evidence that comorbid depression with cardiovascular disease (for example, following myocardial infarction) increases the risk of mortality underscore the importance of understanding the cardiac effects of antidepressants and the need for effective antidepressants that are free of adverse cardiovascular effects. At present, the SSRIs should be considered first-line agents for the treatment of depressed patients with cardiovascular illness, particularly ischemic heart disease. Among the SSRIs, those with a lower potential for causing pharmacokinetic drug interactions generally are preferred.

The use of antidepressant drugs in patients with heart disease.

Both depression and cardiovascular disease are common as people age and are, therefore, likely to coexist. It has become evident recently that the rate of this comorbidity exceeds substantially what is expected by chance. A major problem arises in that there is increasing evidence that the tricyclic antidepressants (TCAs) carry more risk than originally thought in patients with ischemic heart disease. This risk increases the importance of understanding both the safety and efficacy of the serotonin selective reuptake inhibitors (SSRIs) in this population. Three recent studies on safety data in patients with overt heart disease are now available: although the total of 94 patients limits the ability to make generalizations, the data that are available give little evidence of harm and even suggest that SSRIs may have beneficial effects in ischemic heart disease.

Cardiovascular effects of fluoxetine in depressed patients with heart disease.

OBJECTIVE: The purpose of this study was to determine the cardiovascular effects of fluoxetine in depressed patients with cardiac disease. METHOD: Twenty-seven depressed patients (26% of whom were female and whose average age was 73 years) who had congestive heart failure, conduction disease, and/or ventricular arrhythmia were studied in an open medication trial of fluoxetine, up to 60 mg/day, for 7 weeks. The main outcome measures were heart rate and rhythm measured by 24-hour ECG recordings, ejection fraction determined by radionuclide angiography, cardiac conduction intervals, and blood pressure. Baseline values were compared with those at weeks 2 and 7 of fluoxetine treatment. In 60 comparable patients, values of these same cardiovascular measures at baseline and after 3 weeks of treatment with a tricyclic antidepressant, nortriptyline, were also examined. RESULTS: Fluoxetine induced a statistically significant 6% decrease in heart rate, a 2% increase in supine systolic pressure, and a 7% increase in ejection fraction. There was no effect on cardiac conduction, ventricular arrhythmia, or orthostatic blood pressure. Overall, 4% of the fluoxetine patients had an adverse cardiovascular effect. In contrast, nortriptyline treatment caused a significant increase in heart rate and orthostatic hypotension, and 20% of the nortriptyline-treated patients had an adverse cardiovascular effect. CONCLUSIONS: In depressed patients with heart disease, fluoxetine treatment was not associated with the cardiovascular effects documented for the tricyclic antidepressants or with significant adverse cardiac events. However, limited conclusions about fluoxetine's cardiovascular effects and safety can be drawn from this study of only 27 patients monitored for 7 weeks.

Cigarette smoking and major depression.

The authors review recent literature that has demonstrated an association between cigarette smoking behavior and major depression. Persons with major depression are more likely to smoke and to have difficulty when they try to stop. When they manage to succeed in stopping, such persons are at increased risk of experiencing mild to severe states of depression, including full blown major depression. The period of vulnerability to a new depressive episode appears to vary from a few weeks to several months after cessation. This knowledge suggests a relationship between smoking and depression that is complex, pernicious, and potentially life-long. It is recommended that cessation treatments incorporate screening procedures that will identify those patients with a propensity to depression and monitor the emergence of postcessation depression, particularly in those with a history of depression.

Depression and the course of coronary artery disease.

Literature and folk wisdom have long linked depression and death; however, only recently have scientific studies examined the relation between them. Beginning in the 1970s, investigators compared mortality among patients treated for major depression and the general population. Nine of ten studies found an increased mortality from cardiovascular disease among depressed patients. However, such studies confound the relation between depression and its treatment. Community surveys circumvent this difficulty, but as these studies began to appear, other investigations revealed the strong association between depression and cigarette smoking, which made obvious a need to control for smoking. The first study to do this appeared in 1993, and not only did a relation between depression and mortality persist, but a relation between depression and the development of ischemic disease was revealed. In the past 2 years, six more community surveys have followed populations initially free of disease, and five have observed an increased risk of ischemic heart disease among depressed persons. Another research strategy is to start with subjects who have preexisting cardiovascular disease. Here, too, depression has consistently been associated with a worse outcome. In one well-designed study, patients with depression in the period immediately after a myocardial infarction were 3.5 times more likely to die than nondepressed patients. The basis of this association remains speculative. However, it is likely that the changes in the autonomic nervous system and platelets that are seen in depression account for a substantial portion of the association.