Platelet-Active Drugs: The Relationships Among Dose, Effectiveness, and Side Effects. part 42

Both abciximab therapy and stenting were studied in the Controlled Abciximab (ReoPro) and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial of patients with MI. In this group of patients, who appeared to be at a relatively low risk (Table 8), abciximab had a beneficial effect in the PTCA group but did not affect death or reinfarction in the stent group.

Abciximab was compared to tirofiban as treatment for PCI in the TARGET study (Table 8). Abciximab treatment was found to be associated with a statistically significant lower rate of ischemic complications after 30 days, but at 6 months the differences were less appar

Five completed trials have examined the efficacy and safety of tirofiban, lamifiban (a nonpeptide GPIIb/IIIa blocker the development of which has been discontinued), and eptifibatide in approximately 25,000 patients with acute coronary syndromes without persistent ST-segment elevation who were randomized to receive a GPIIb/IIIa antagonist or placebo, in addition to conventional antithrombotic therapy (Table 9).i2,2 These studies demonstrated a 0 to 27% reduction in the RR of MI or death at 30 days. Both eptifibatide and tirofiban have received approval from the FDA for the treatment of acute coronary syndromes, including patients who are to be managed medically and those undergoing PCI. However, in the GUSTO IV-ACS trial, abciximab therapy (0.25 mg/kg bolus followed by a 0.125 g/kg/min infusion) for 24 or 48 h was not beneficial as a first-line medical treatment in patients with acute coronary syndromes. A meta-analysis of all major randomized clinical trials of GPIIb/IIIa antagonists in patients with acute coronary syndromes who were not routinely scheduled to undergo early coronary revascularization suggested a 9% reduction in the odds of death or MI at 30 days. However, the true size of the additional benefit resulting from short-term, high-grade blockade of GPIIb/IIIa combined with standard antithrombotic therapy is somewhat uncertain, since the 95% CI ranged from 2 to 16%. Moreover, the 1% absolute difference in death or MI was balanced by an absolute excess of 1% in major bleeding complications associated with GPIIb/IIIa antagonists vs control. The Platelet IIb/IIIa Antagonist for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON)-B Investigators have reported that dose-titrated lamifiban had no significant effects on clinical outcomes in patients with non-ST-segment elevation acute coronary syndromes and yet caused excess bleeding, thus reinforcing the uncertainty noted above. Of note, a subgroup analysis of these studies identified a consistent and significant mortality advantage for patients with diabetes, even in the GUSTO IV-ACS study, raising the possibility that platelets may play a more important role in the pathogenesis of the ischemic damage in diabetic patients.

Platelet-Active Drugs: The Relationships Among Dose, Effectiveness, and Side Effects. part 41

Eptifibatide received approval from the FDA for use in

 

PCI in 1998 based on data from the IMPACT-II and PURSUIT trials, and the dosing was modified based on the efficacy demonstrated in the ESPRIT trial. The c7E3 Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial demonstrated the efficacy of treatment with abciximab for 18 to 24 h prior to PCI in patients with unstable angina who were refractory to conventional antithrombotic and antianginal therapy. The Evaluation in PTCA to Improve Long-Term Outcome With Abciximab GP IIb/IIIa Blockade (EPILOG) trial demonstrated the efficacy of abciximab therapy in a broad population of patients undergoing PCI, not just in high-risk patients, as in the EPIC and CAPTURE trials. The Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trial demonstrated that abciximab therapy decreased the frequency of ischemic complications of PCI associated with stent insertion during the first 30 days, and that there also were fewer ischemic complications during this time period in patients who were treated with PCI and abcix-imab alone without stent insertion compared to those treated with stenting alone. Furthermore, the 1-year mortality rate difference was statistically significant between stenting alone (2.4%) and stenting plus abciximab therapy (1%), and this mortality rate difference was sustained for longer periods of time.

ED Findings From the Canada area Community Health Survey

Conceptual and methodological issues need to be addressed. First, the definition and measurement of Erectile Dysfunction varies from study to study. All definitions of ED, however, are based on patients’ self-report, which is typically assessed by single-item scales or questionnaire measures.

Some differences are evident among these scales, although studies show overall concordance in the prevalence rates and association with well- known comorbidities and risk factors. Early landmark studies, such as MMAS and National Health and Social Life Survey (NHSLS) used single-item scales, which assessed erection difficulties over several months or in the past year.

Subsequent studies used 5- or 15-item versions of the IIEF, a multidimensional, self-report scale that assesses male sexual function over a 4-week period.

Single-item instruments have the advantage of high completion rates and low patient burden. On the other hand, multidimensional scales provide broader and more complete assessment of disease severity. Despite such differences, largely similar results have been obtained across studies using these different measures.

A second, and potentially more challenging issue, concerns the complex and often bidirectional interactions between variables. For example, depression may be a cause or a consequence of ED in many studies.

These studies support a direct association between ED and mood. In other studies, the causal relationships among the major risk factors for ED are less evident. Biomedical, psychosocial, and lifestyle factors may interact in complex ways. Separating the effects of one risk factor or comorbidity from another and determining the direction of causality among these factors, can be difficult if not impossible to ascertain in cross-sectional studies alone.

More research is needed to elucidate these associations. The increased evidence of a link between ED and CVD with the potential for ED to serve as a sentinel marker of subclinical vascular disease has led to an increased awareness of Erectile Dysfunction as a “barometer” of vascular health and the early opportunity for primary prevention in at-risk men. The 2nd Princeton Consensus Conference has called for the routine assessment of cardiovascular risk in all ED patients and subsequent classification of ED patients into low, moderate, or high risk of CVD and recommendation for aggressive lifestyle modification in patients with ED and CV risk factors.

However, further understanding is needed of the link between endothelial dysfunction and Erectile Dysfunction and the specific role of endothelial dysfunction in the progression and remission of ED to:

1. Refine our understanding of pathophysiologicalprocesses of ED in human subjects;
2. Improve the identification of ED patients at higher risk of CVD who would benefit most from preventive interventions, such as statin therapy, perioperative beta blocker therapy, etc.;
3. Establish the primacy of endothelial dysfunction in ED incidence and progression and relationship to other predictors.