Determining the efficacy of antiplatelet therapies for the individual: lessons from clinical trials

This article focuses on lessons learned from clinical trials of antiplatelet therapies-in particular, that the degree of inhibition of ex vivo platelet aggregation does not necessarily directly translate into clinical efficacy. As an example, the case of the oral platelet glycoprotein IIb/IIIa inhibitors is presented, in which despite consistent evidence of substantial inhibition of platelet aggregation, this class of drugs provided no clinical benefit in Phase III trials and, in fact, was harmful. Several hypotheses for these unexpected findings have been proposed, but none has been confirmed. The connection between ex vivo inhibition of platelet aggregation and clinical benefit of platelet P2Y(12) antagonists is also not straightforward and is currently being tested in large clinical trials. A link between inflammatory status and clinical benefit from antiplatelet agents continues to emerge and highlights the fact that biomarkers beyond ex vivo platelet aggregation may predict the clinical benefit of antiplatelet agents that can reduce platelet activation (i.e., aspirin and thienopyridines). Results of past and ongoing trials hold valuable clues to determining the appropriate targets for maximizing antiplatelet efficacy, but the current lack of a proven ex vivo assay that correlates with clinical outcomes hampers clinical investigation, drug development programs, and clinical practice.     

Atrial fibrillation: insights from clinical trials and novel treatment options

Atrial fibrillation (AF) is the most common encountered sustained arrhythmia in clinical practice. The last decade the result of large 'rate' versus 'rhythm' control trials have been published that have changed the current day practise of AF treatment. It has become clear that rate control is at least equally effective as a rhythm control strategy in ameliorating morbidity as well as mortality. Moreover, in each individual patient the risk of thromboembolic events should be assessed and antithrombotic treatment be initiated. There have also been great advances in understanding the mechanisms of AF. Experimental studies showed that as a result of electrical and structural remodelling of the atria, 'AF begets AF'. Pharmacological prevention of atrial electrical remodelling has been troublesome, but it seems that blockers of the renin angiotensin system, and perhaps statins, may reduce atrial structural remodelling by preventing atrial fibrosis. Clinical studies demonstrated that the pulmonary veins exhibit foci that can act as initiator and perpetuator of the arrhythmia. Isolation of the pulmonary veins using radiofrequency catheter ablation usually abolishes AF. The most promising advances in the pharmacological treatment of AF include atrial specific antiarrhythmic drugs and direct thrombin inhibitors. In the present review we will describe the results of recent experimental studies, discuss the latest clinical trials, and we will focus on novel treatment modalities.     

Increasing protection after tamoxifen: insights from the extended adjuvant aromatase inhibitor trials

For disease-free postmenopausal women with hormone-responsive breast cancer, a risk for relapse remains following 5 years of adjuvant therapy with tamoxifen. Additional therapy with tamoxifen beyond 5 years is not indicated due to a demonstrated lack of efficacy beyond this time frame. Thus, there is a need for other endocrine therapy options in the period beyond 5 years. The third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane) have emerged as at least as effective and somewhat better tolerated alternatives to tamoxifen. Three trials were initiated to evaluate the efficacy and tolerability of aromatase inhibitors in the extended adjuvant setting. Among these, the large, double-blind, randomized, placebo-controlled MA.17 trial has already demonstrated a significant benefit of letrozole when compared with placebo on disease-free survival in postmenopausal women previously treated for 4.5–6 years with tamoxifen. A smaller open-label trial, the Austrian Breast and Colorectal Cancer Study Group 6a has reported a significant benefit for anastrozole on recurrence when used as extended adjuvant therapy when compared with no treatment, and similar results have been seen with extended adjuvant exemestane in the National Surgical Adjuvant Breast and Bowel Project B-33 trial. The results of these trials have important clinical implications for the future of extended adjuvant hormonal therapy for breast cancer. Dr. Rose has served on advisory boards for Roche, AstraZeneca, Novartis, Eli Lilly, and Bristol Meyers Squibb and has participated in Speaker’s Bureau for AstraZeneca and Novartis.     

Asymmetric dimethylarginine (ADMA) and cardiovascular disease: insights from prospective clinical trials

Evidence has accumulated that asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthase. ADMA inhibits vascular NO production at concentrations found in pathophysiological conditions; it also causes local vasoconstriction when infused intra-arterially. ADMA is increased in the plasma of humans with hypercholesterolemia, atherosclerosis, hypertension, chronic renal failure, chronic heart failure, and other clinical conditions. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilation or reduced NO metabolite levels. In several prospective and cross-sectional studies, ADMA has evolved as a marker of cardiovascular risk. Moreover, prospective clinical studies have suggested that it may play a role as a novel cardiovascular risk factor. Zoccali and coworkers were the first to show that elevated ADMA is associated with a three-fold increased risk of future severe cardiovascular events and mortality in patients undergoing hemodialysis. Valkonen and coworkers demonstrated in a nested case-control study that elevated ADMA was associated with a four-fold increased risk for acute coronary events in clinically healthy, nonsmoking men. In patients with stable angina pectoris, preinterventional ADMA indicates the risk of developing restenosis or severe clinical events after coronary intervention. Furthermore, in humans with no underlying cardiovascular disease who are undergoing intensive care unit treatment, ADMA is a marker of the mortality risk. A number of additional prospective clinical trials are currently under way in diverse patient populations, among them individuals with congestive heart failure, cardiac transplantation patients, and patients with pulmonary hypertension. In summary, an increasing number of prospective clinical trials have shown that the association between elevated ADMA levels and major cardiovascular events and total mortality is robust and extends to diverse patient populations. However, we need to define more clearly in the future who will profit from ADMA determination, in order to use this novel risk marker as a more specific diagnostic tool.     

Interpreting clinical trials of diabetic dyslipidaemia: new insights

Current treatment guidelines highlight the importance of aggressive lipid-modifying therapy in reducing cardiovascular risk in patients with type 2 diabetes. Statins are established as the cornerstone of dyslipidaemia management in diabetic patients, based on their efficacy in lowering levels of low-density lipoprotein cholesterol (LDL-C). However, statins fail to address the high residual cardiovascular risk in treated patients, some of which may be attributable to low HDL cholesterol (HDL-C) and elevated triglycerides and to a preponderance of small, dense LDL particles, indicating the need for further intervention. Fibrates are effective against all components of atherogenic dyslipidaemia associated with type 2 diabetes. Clinical studies, most notably the Fenofibrate Intervention and Event Lowering in Diabetes, indicate that fibrates, most likely in combination with a statin, have a secondary role in reducing cardiovascular risk in patients with type 2 diabetes, particularly in those without prior cardiovascular disease or patients with low HDL-C. Results are awaited from the ongoing Action to Control Cardiovascular Risk in Diabetes trial to fully evaluate the outcome benefits of this combination strategy.     

Pulmonary artery catheterization in acute coronary syndromes: insights from the GUSTO IIb and GUSTO III trials

PURPOSE: To correlate pulmonary artery catheterization (PAC) use and 30-day outcomes and to characterize the use of pulmonary artery catheters among patients with acute coronary syndromes (ACS). SUBJECTS AND METHODS: We retrospectively studied 26437 ACS patients from two large multicenter, international randomized clinical trials. Multivariable and causal inference analyses were applied to adjust for differences in baseline risk. RESULTS: PAC was performed in 735 patients (2.8%), with a median time to insertion of 24 hours. Patients undergoing PAC were older (median, 67 vs. 64 years), more often diabetic (25.7% vs.16.2%), and more likely to present with ST-segment elevation (81.6% vs. 70.2%) or Killip class III or IV (7.9% vs. 1.4%). US patients were 3.8 times more likely than non-US patients to undergo PAC. Patients managed with PAC also underwent more procedures, including percutaneous intervention (40.7% vs. 18.1%), coronary artery bypass grafting (12.5% vs. 7.7%), and endotracheal intubation (29.3% vs. 2.2%). Mortality at 30 days was substantially higher among patients with PAC for both unadjusted (odds ratio [OR] 8.7; 95% confidence interval [CI] 7.3-10.2) and adjusted analyses (OR 6.4; 95% CI 5.4-7.6) in all groups except in patients with cardiogenic shock (OR 0.99; 95% CI 0.80-1.23). CONCLUSIONS: PAC was associated with increased mortality, both before and after adjustment for baseline patient differences and subsequent events that may have led to PAC use, except in patients with cardiogenic shock. The definitive role of PAC in managing patients with ACS is still to be determined.     

Differential effects of lipid-lowering therapies on stroke prevention: a meta-analysis of randomized trials

BACKGROUND: Previous overviews suggested that hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins), but not other lipid-lowering therapy (LLT), may reduce stroke incidence in coronary patients. OBJECTIVE: To investigate the amplitude and sources of heterogeneity of LLT effects on stroke prevention. METHODS: We searched the literature from 1966 to 2001 and then conducted a meta-analysis including randomized trials of primary and secondary coronary heart disease prevention, testing statins, nonstatin drugs, diet, or other interventions and providing data on stroke incidence. RESULTS: The meta-analysis (38 trials, 83 161 patients, mean follow-up of 4.7 years) showed a significant relative risk reduction (RRR) of strokes by LLT of 17% (P<.001), without significant heterogeneity between trials and between subgroups according to either the type of prevention (primary or secondary) or the type of LLT. The most substantial effects were obtained, however, with statins (RRR, 26%). Effect model analysis showed that treatment benefit appeared constant whatever the risk of stroke, suggesting that LLT may be effective in a population with a higher risk of stroke. Weighted regression showed a significant correlation between RRR of stroke and total cholesterol levels (baseline, final, and change). Only final cholesterol allowed clear separation between benefit (RRR>0) and no effect (RRR<0) of LLT on stroke incidence, with a cutoff for benefit of 232 mg/dL (6.0 mmol/L). CONCLUSION: Lipid-lowering therapy reduces stroke incidence in coronary patients, especially when total cholesterol level is lowered to less than 232 mg/dL (6.0 mmol/L), which explains the best results being obtained with statins.     

Aspiration thrombectomy in ST-Elevation myocardial infarction: Further insights from a network meta-analysis of randomized trials

BackgroundThe initial enthusiasm for thrombectomy during percutaneous coronary intervention (PCI) of ST-elevation myocardial infarction (STEMI) patients has given way to restraint. There has been some limited interest whether it is beneficial in a few selected subgroups. Hence, we performed a network meta-analysis to compare conventional PCI (cPCI), Aspiration or manual thrombectomy (AT) and Mechanical thrombectomy (McT) for clarification.MethodsElectronic databases were searched for randomized studies that compared AT, McT, or cPCI. A network meta-analysis was performed and odd’s ratio (OR) with 95% confidence intervals was generated for major adverse cardiac events (MACE), mortality, myocardial infarction (MI), target vessel revascularization (TVR), stent thrombosis (ST), stroke, left ventricular ejection fraction (LVEF), myocardial blush grade (MBG) and ST segment resolution (STR).ResultsA total of 43 randomized trials (n = 26,682) were included. The risk of MACE (OR 0.86 95% CI 0.73–1.00), Mortality (OR 0.85 95% CI 0.73–0.99), MI (OR 0.65, 95% CI: 0.44–0.95) and TVR (OR 0.86, 95% CI: 0.74–1.00) were lower with AT compared to cPCI. The risk of ST and stroke was no different with the use of adjunctive AT. MBG, STR, and LVEF improved with the use of AT while the infarct size was no different in the two groups.ConclusionsOur comprehensive network meta-analysis suggests conflicting outcomes with AT. While Mortality, MACE, MI seem better, there is a suggestion that, Stroke and ST might be worse. Whether AT can still be pursued in any select cases should be further scrutinized.     

A review of trials evaluating nonstatin lipid-lowering therapies

Recently reported clinical trials raise doubts on the effectiveness of nonstatin lipid-lowering therapies in reducing the residual risk of cardiovascular events after statin monotherapy. Addition of torcetrapib to statin therapy increased overall mortality in coronary patients despite a marked increase in high-density lipoprotein cholesterol. Combining ezetimibe with statin therapy neither further reduces carotid atherosclerosis nor slows aortic stenosis, and it has not been shown to be superior to statin monotherapy in reducing cardiovascular events. Clinical trials currently in progress will more clearly delineate the cardiovascular effects of adding either ezetimibe or extended-release niacin/laropiprant to statin therapy.