A randomized controlled study of combination therapy with alefacept and narrow band UVB phototherapy (UVB) for moderate to severe psoriasis: efficacy, onset, and duration of response.

BACKGROUND: Alefacept is an effective intermittent treatment for psoriasis that can provide long-lasting remissions. Combination therapy with narrow-band ultraviolet B (nbUVB) phototherapy may enhance treatment outcomes and accelerate the onset of clinical response. OBJECTIVE: To assess the efficacy of alefacept in combination with nbUVB phototherapy compared to alefacept alone in subjects with moderate to severe psoriasis. METHODS: Ninety-eight adults with moderate to severe psoriasis were randomized to treatment with alefacept 15 mg intramuscularly (i.m.) once weekly for 12 weeks alone or in combination with three times weekly nbUVB treatments in this prospective, open-label, assessor-blinded, randomized, multicenter, parallel-group, 36-week study. RESULTS: A statistically significantly greater proportion of subjects in the alefacept plus nbUVB arm achieved the primary endpoint of PASI 75 at week 16 compared to subjects in the alefacept alone arm (44.9% vs 22.5%, P=0.032). Secondary outcomes were also in favor of the alefacept plus nbUVB group, including the proportion of subjects achieving a Physician Global Assessment (PGA) score of clear or almost clear at any time during the study (59.2% vs 34.7%, P=0.026) and reduction in percent body surface area (BSA) involved with psoriasis at week 16 (13.4% vs 8.0%, P<0.001). The onset of clinical response was significantly faster in the combination therapy group compared to monotherapy (mean time to PASI 75: 82 vs 107 days, P=0.007). Both treatments were generally well tolerated. LIMITATIONS: Open-label, assessor-blinded study without a phototherapy-only treatment arm. CONCLUSION: The addition of nbUVB to treatment with alefacept significantly enhanced and accelerated the clinical benefits of alefacept therapy and was generally safe and well-tolerated.

Tolerability of 5 mg solifenacin once daily versus 5 mg oxybutynin immediate release 3 times daily: results of the VECTOR trial.

PURPOSE: Although antimuscarinic treatment is indicated for overactive bladder, many patients discontinue it because of dry mouth. Of available antimuscarinics oxybutynin is associated with the highest dry mouth rate. We compared the safety and tolerability of 5 mg solifenacin vs 15 mg oxybutynin immediate release. MATERIALS AND METHODS: At 12 Canadian centers a total of 132 patients with overactive bladder symptoms (greater than 1 urgency episode per 24 hours, and 8 or greater micturitions per 24 hours) were randomized to 5 mg solifenacin once daily or 5 mg oxybutynin 3 times daily for 8 weeks. The primary end point was the incidence and severity of dry mouth reported after direct questioning. Efficacy end points (3-day diary documented changes in urgency, frequency, incontinence, nocturia and voided volume), and changes on the Patient Perception of Bladder Condition scale and the Overactive Bladder Questionnaire were evaluated secondarily. RESULTS: Of patients on solifenacin vs oxybutynin immediate release 35% vs 83% reported dry mouth (p <0.0001). Of patients reporting dry mouth severity was graded moderate by 13% and 42% of those on solifenacin and oxybutynin immediate release, and severe by 13% and 28%, respectively (p = 0.001). Patients in each group showed improvements in efficacy end points, and Patient Perception of Bladder Condition scale and Overactive Bladder Questionnaire scores from baseline to treatment end. CONCLUSIONS: Significantly fewer patients on 5 mg solifenacin once daily reported dry mouth vs those receiving 5 mg oxybutynin immediate release 3 times daily. Significantly fewer patients on solifenacin reported moderate/severe dry mouth. Significantly fewer patients on solifenacin withdrew from study due to dry mouth and there were significantly fewer overall adverse events. Solifenacin and oxybutynin immediate release were efficacious in decreasing efficacy end points, and improved Patient Perception of Bladder Condition scale and Overactive Bladder Questionnaire results from baseline to treatment end.

Comparison of enoxaparin versus heparin during elective percutaneous coronary intervention performed with either eptifibatide or tirofiban (the ACTION Trial).

Limited data are available with regard to the pharmacodynamics and safety of combining enoxaparin with glycoprotein IIb/IIIa inhibition during elective percutaneous coronary interventions (PCIs). We randomized 200 patients to receive open-label enoxaparin (0.75 mg/kg intravenous bolus) or unfractionated heparin (60 U/kg intravenous bolus) and eptifibatide or tirofiban during PCI. This yielded 4 groups of combination therapy (50 patients/group). The first 10 patients per group had anti-Xa activity and inhibition of platelet aggregation measured at baseline, and at 5 minutes, 10 minutes, 4 hours, and 24 hours. All patients received aspirin and clopidogrel therapy before PCI. Patients who received enoxaparin and heparin achieved therapeutic peak anti-Xa activity observed shortly after drug administration. At 4 hours, a differential anticoagulant effect was observed, with patients who received enoxaparin having a more gradual decrease in anti-Xa activity. Patients who received eptifibatide achieved >80% inhibition of platelet aggregation soon after initiation of therapy more often than did those who received tirofiban. Type of heparin did not affect inhibition of platelet aggregation. Compared with patients who received heparin, periprocedural myocardial infarction and bleeding events occurred less frequently among those who received enoxaparin (14% vs 8% and 10% vs 5%); however, these differences were not statistically significant. Three cases of intraprocedural thrombus occurred among patients who received enoxaparin. Two patients received concomitant tirofiban therapy. Compared with unfractionated heparin, similar levels of anticoagulation and platelet inhibition are achieved with enoxaparin when concomitant therapy with eptifibatide or tirofiban is used during elective PCI, without an observed increase in early bleeding events or periprocedural ischemic complications.

The importance of in-hospital statin therapy for patients with acute coronary syndromes.

Starting lipid-lowering therapy in the hospital, especially with statins, has become an important component in the management of patients with acute coronary syndromes (ACS). It improves outcomes and increases patient motivation and long-term adherence. In addition, discontinuation of statin therapy in patients with ACS after hospital admission is associated with an increased risk of adverse outcomes. Recent non-ST elevation ACS guidelines recommend beginning statin therapy, along with dietary intervention, in patients whose low-density lipoprotein cholesterol levels exceed 130 mg/dl within 24-96 hours after hospital admission. Various strategies have been developed to aid in the implementation of in-hospital lipid-lowering therapy. Pharmacists can play a valuable role in optimizing drug therapy for dyslipidemia and ensuring long-term adherence.

Acute thrombocytopenia associated with eptifibatide therapy.

BACKGROUND: Platelet glycoprotein (GP) IIb/IIIa receptor blockade improves clinical outcomes in percutaneous coronary interventions and in acute coronary syndromes. Thrombocytopenia is a serious complication well described with the use of the prototype GPIIb/IIIa inhibitor abciximab. Its association with other agents of this class has been underemphasized. OBJECTIVES: To determine the incidence of thrombocytopenia in a cohort of patients treated with eptifibatide at a tertiary cardiac centre. PATIENTS AND METHODS: Chart review of consecutive patients treated with eptifibatide at the study institution. RESULTS: There were four (1.3%) cases of acute thrombocytopenia (platelet count less than 100 x 10(9)/L) among 305 patients reviewed. One patient had been previously exposed to eptifibatide. The other three patients are described. In each case, platelet counts declined within 6 h of receiving eptifibatide. Recovery of platelet counts was noted within 6 to 30 h after withdrawal of eptifibatide. No patient suffered an adverse clinical event related to thrombocytopenia. CONCLUSIONS: It is important to monitor platelet counts closely after initiation of GPIIb/IIIa inhibitor therapy, not only for abciximab, but also for small molecule inhibitors such as eptifibatide. Monitoring of platelet counts at 2 to 6 h and 24 h will detect most cases of acute thrombocytopenia. Adverse events may be prevented by prompt discontinuation of GPIIb/IIIa inhibitor therapy.

High mortality with ST elevation myocardial infarction in a nontrial setting.

BACKGROUND: Early mortality following ST elevation myocardial infarction (MI) is declining in trial and nontrial settings. Absolute rates in nontrial settings remain significantly higher than those seen in randomized controlled trials. It is unclear if this mortality difference is due to different patient characteristics or to less frequent use of reperfusion strategies. OBJECTIVES: To provide a descriptive analysis of contemporary management and outcome of ST elevation MI in a nontrial setting at a tertiary care hospital, and to compare the clinical characteristics and in-hospital mortality of patients with ST elevation MI who were or were not treated with reperfusion therapy. METHODS: A retrospective chart review of 115 patients with ST elevation MI from July 1999 to June 2000 was performed. RESULTS: Eighty-five of 109 (78%) eligible patients received reperfusion therapy--44% fibrinolysis, 27% primary percutaneous coronary intervention (PCI) and 7% rescue PCI. Twenty-two per cent of eligible patients received no form of reperfusion therapy. In-hospital mortality was higher among patients who received no reperfusion therapy than among those who had (50% versus 11%, respectively, P<0.001). Patients who did not receive reperfusion therapy were older, presented with a longer median duration of chest pain, had a higher incidence of Killip class III or IV, and had a higher mean Thrombolysis in Myocardial Infarction (TIMI) risk score; many had absolute or relative contraindications to fibrinolytic therapy, and a significant proportion presented with a duration of chest pain of 12 h to 24 h. CONCLUSIONS: Mortality in ST elevation MI is disproportionately higher among patients who receive no reperfusion therapy. Many of these patients have clinical characteristics that may affect the physician's decision to provide reperfusion therapy. Improving overall survival among patients with ST elevation MI will be contingent on optimizing the number of patients receiving reperfusion therapy.

Clopidogrel in interventional cardiology: questions answered and questions remaining.

Clopidogrel is appropriate as a replacement for ticlopidine when used in combination with acetylsalicylic acid in the setting of percutaneous coronary intervention (PCI). Compared with ticlopidine, clopidogrel has comparable efficacy in reducing adverse cardiac events and a lower risk of hematological toxicity; both medications have been associated with rare cases of the very serious syndrome of thrombotic thrombocytopenic purpura. Clopidogrel should preferably be initiated with a loading dose of 300 mg before PCI, because most cases of thrombotic stent occlusion occur shortly after stent implantation, and attainment of target platelet inhibition is delayed for several days if a loading dose is not given. Bypass surgery in patients recently treated with clopidogrel appears to be associated with a significant increase in hemorrhagic complications. Long term therapy with clopidogrel after PCI may decrease late thrombotic stent occlusion and late vascular events; this hypothesis is currently being evaluated in randomized trials. By inhibiting platelet activation, clopidogrel may have a mechanism of benefit that is independent of the potent inhibition of platelet aggregation produced by the glycoprotein IIb/IIIa inhibitors.

Thrombotic thrombocytopenic purpura associated with clopidogrel: further evaluation.

BACKGROUND: Eleven cases of thrombotic thrombocytopenic purpura (TTP) associated with clopidogrel therapy have been published. OBJECTIVES: To perform a comprehensive causality assessment of the 11 published cases of TTP to assess quantitatively the extent to which clopidogrel was the causative factor. METHODS: The 11 reports of TTP were analyzed using the Bayesian Adverse Reaction Diagnostic Instrument to calculate the posterior probability (PsP) that clopidogrel caused the TTP based on epidemiological and clinical trials data (expressed as prior odds) and the clinical characteristics of each case (expressed as likelihood ratios). RESULTS: Clopidogrel was implicated as the causative factor of the TTP (PsP>0.75) in only five of the 11 cases. The PsP for clopidogrel was lowered by concomitant use of a statin, a history of cancer and the occurrence of relapsing TTP (in the absence of clopidogrel) in the remaining six cases. CONCLUSIONS: This systematic analysis provides strong evidence, based on the case information reported, that clopidogrel was the causative factor in at least some cases of TTP.

Risk stratification, management and outcomes of patients with non-ST elevation acute coronary syndrome: a Canadian teaching hospital perspective.

BACKGROUND: Current guidelines for non-ST elevation acute coronary syndromes (NSTACS) recommend tailoring the intensity of therapeutic management according to the baseline risk of the patient. Although the clinical characteristics, risk stratification and therapeutic management of contemporary patients with NSTACS have been reported for other geographical regions, this information has not been documented from a Canadian perspective. OBJECTIVES: To describe the baseline clinical characteristics, therapeutic management and clinical outcomes of contemporary patients with NSTACS at a Canadian, tertiary care, teaching hospital, and to retrospectively risk stratify the patients with NSTACS according to the American College of Cardiology (ACC)/American Heart Association (AHA) and Thrombolysis in Myocardial Infarction (TIMI) risk guidelines to characterize management and outcomes according to the various risk classifications. METHODS: Baseline demographics, procedural variables and clinical outcome data were retrospectively collected in 380 patients with a diagnosis of NSTACS from July 1999 to July 2000. Patients were retrospectively categorized into high, intermediate and low risk categories using two classification schemes. RESULTS: According to the ACC/AHA guidelines, 10.3% and 89.7% of patients were intermediate and high risk, respectively. Applying the TIMI risk score, 20.0%, 52.4% and 27.6% of patients were low, intermediate and high risk, respectively. The use of antithrombotic, acetylsalicylic acid and beta-blocker therapy was very high both in hospital and at discharge. Glycoprotein IIb/IIIa inhibitors, angiotensin-converting enzyme inhibitors and lipid lowering agents were all underutilized. The use of pharmacological therapies and cardiovascular interventions did not appear to correlate with the level of risk of the patient, at least within these classification schemes. Adverse clinical events in hospital and length of hospital stay increased as the risk level of the patients increased. CONCLUSIONS: According to the ACC/AHA guidelines, patients with a discharge diagnosis of NSTACS in a nontrial setting are a high risk population, requiring prompt recognition and aggressive management. This study serves as an integral part of clinical practice to continually evaluate the quality of medical care.

A national survey of antimicrobial prophylaxis in adult cardiac surgery across Canada.

OBJECTIVE: To characterize national and regional patterns of antimicrobial prophylaxis in adult cardiac surgery across Canada. DESIGN: Retrospective, cross-sectional analysis. SETTING: Thirty-three adult cardiac surgical centres across Canada. INTERVENTIONS: A one-page questionnaire collecting information regarding institutional demographics and antimicrobial prophylaxis regimens for adult cardiac surgical procedures was mailed to all adult surgical centres across Canada. If a response was not received within one month, a second survey was mailed, followed by a telephone reminder within two weeks of the second mailing. MAIN RESULTS: The Overall response rate was 100%. Prophylactic antimicrobials were used in all the adult cardiac centres; single-agent prophylaxis was used in 97% (32 of 33) of centres; Single-dose antimicrobial prophylaxis was used in only 3% (one of 33) of centres. Preoperative and postoperative antimicrobial prophylaxis regimens varied both between provinces and within provinces across Canada. Cefazolin was the antimicrobial used in 88% (38 of 43) and 87% (33 of 38) of the reported pre-operative and post-operative prophylaxis regimens, respectively. Antimicrobial prophylaxis was initiated in the operating room 72% (26 of 36) of the time and intra-operative supplemental antimicrobial doses were administered for cardiac procedures longer than a median of 4 hours (range 4 to 8 hr). Overall, the median duration of antimicrobial prophylaxis was 36 hours (range 8 to 96 hr). CONCLUSIONS: Despite the availability of various published guidelines, our survey identified several areas for improvement with respect to antimicrobial prophylaxis in adult cardiac surgery across Canada.

Use of OTC and herbal products in patients with cardiovascular disease.

BACKGROUND: The use of nonprescription and herbal products by the public is rising, resulting in an increased potential for adverse reactions or drug interactions in cardiac patients. OBJECTIVE: To describe the utilization patterns for nonprescription medications and herbal products in patients with cardiovascular disease across Canada. METHODS: Patients admitted to 8 teaching hospitals during the winter of 1998/1999 were interviewed by a pharmacist using a structured survey instrument. RESULTS: Interviews were conducted with 306 patients (mean age 66 y; 60% men). The majority (74%) had coronary artery disease; however, hypertension, congestive heart failure, and arrhythmias were also common. The most common product categories used were pain relievers (51%), single-entity vitamin/mineral (38%), multivitamin/mineral (23%), antacids (21%), laxatives (17%), and herbals (17%). As compared with western (28%) and central Canada (26%), fewer patients in the Atlantic region (11%) reported daily use of multivitamin/mineral products. Overall, the usage of specific single-entity vitamin/mineral products was most commonly vitamin E (24%), vitamin C (16%), calcium (9%), and B vitamins (8%). Central Canada reported the highest rates (25%) of daily or weekly use of herbal products. The most common herbal products used were garlic (13%), cayenne pepper (2%), and ginseng (2%). More than half of the patients consulted with their pharmacist at least occasionally regarding the use of these products. CONCLUSIONS: Canadian patients with cardiovascular disease commonly report the use of herbal products and vitamins. Allied health professionals need to be aware of the widespread use of these products and their potential for adverse reactions and drug interactions.