Jeremiah P. Depta

Atherothrombosis and atrial fibrillation: Important and often overlapping clinical syndromes

Atherothrombosis and atrial fibrillation: Important and often overlapping clinical syndromes -

Long-Term Outcomes With Use of Intravascular Ultrasound for the Treatment of Coronary Bifurcation Lesions

Percutaneous coronary intervention (PCI) of bifurcation lesions remains challenging with a higher risk of adverse outcomes. Whether adjunctive intravascular ultrasound (IVUS) imaging improves outcomes of PCI of bifurcation lesions remains unclear. This study sought to determine the long-term clinical outcomes associated with using IVUS for percutaneous treatment of coronary bifurcation lesions. From April 2003 through August 2010, 449 patients with 471 bifurcation lesions underwent PCI with (n = 247) and without (n = 202) the use of IVUS. Clinical outcomes (death, myocardial infarction [MI], periprocedural MI, stent thrombosis, target vessel revascularization [TVR], and target lesion revascularization [TLR]) were compared between patients undergoing PCI with and without IVUS using univariate and propensity score-adjusted analyses. Most patients (61%) presented with acute coronary syndrome and 89% of bifurcations lesions were Medina class 1,1,1. After propensity score adjustment, use of IVUS was associated with significantly lower rates of death or MI (odds ratio 0.38, 95% confidence interval 0.20 to 0.74, p = 0.005), death (odds ratio 0.40, 95% confidence interval 0.18 to 0.88, p = 0.02), MI (odds ratio 0.37, 95% confidence interval 0.14 to 0.98, p = 0.04), periprocedural MI (odds ratio 0.45, 95% confidence interval 0.20 to 0.97, p = 0.04), TVR (odds ratio 0.28, 95% confidence interval 0.14 to 0.53, p <0.0001), and TLR (odds ratio 0.27, 95% confidence interval 0.14 to 0.53, p = 0.0003) compared to no IVUS. In conclusion, IVUS-guided treatment of complex bifurcation lesions was associated with significantly lower rates of adverse cardiac events at late follow-up. Further study is warranted to evaluate the role of IVUS guidance in improving long-term outcomes after PCI of bifurcation lesions.

Omeprazole and clopidogrel: Should clinicians be worried?

The US Food and Drug Administration has issued a warning that omeprazole (Prilosec) reduces the antiplatelet activity of clopidogrel (Plavix) by about 50%. However, the warning is based largely on ex vivo data. Preliminary results from a randomized clinical trial revealed no effect on cardiovascular outcomes when omeprazole was given with clopidogrel. We recommend that physicians continue to prescribe a proton pump inhibitor for patients receiving dual antiplatelet therapy who are at risk of gastrointestinal bleeding or have an indication for use of a proton pump inhibitor. The FDA has warned of a possible interaction between omeprazole (Prilosec) and clopidogrel (Plavix), but for the time being we should not change the way we manage patients.

Risk model for estimating the 1-year risk of deferred lesion intervention following deferred revascularization after fractional flow reserve assessment

AIMS Although lesions deferred revascularization following fractional flow reserve (FFR) assessment have a low risk of adverse cardiac events, variability in risk for deferred lesion intervention (DLI) has not been previously evaluated. The aim of this study was to develop a prediction model to estimate 1-year risk of DLI for coronary lesions where revascularization was not performed following FFR assessment. METHODS AND RESULTS A prediction model for DLI was developed from a cohort of 721 patients with 882 coronary lesions where revascularization was deferred based on FFR between 10/2002 and 7/2010. Deferred lesion intervention was defined as any revascularization of a lesion previously deferred following FFR. The final DLI model was developed using stepwise Cox regression and validated using bootstrapping techniques. An algorithm was constructed to predict the 1-year risk of DLI. During a mean (±SD) follow-up period of 4.0 ± 2.3 years, 18% of lesions deferred after FFR underwent DLI; the 1-year incidence of DLI was 5.3%, while the predicted risk of DLI varied from 1 to 40%. The final Cox model included the FFR value, age, current or former smoking, history of coronary artery disease (CAD) or prior percutaneous coronary intervention, multi-vessel CAD, and serum creatinine. The c statistic for the DLI prediction model was 0.66 (95% confidence interval, CI: 0.61-0.70). CONCLUSION Patients deferred revascularization based on FFR have variation in their risk for DLI. A clinical prediction model consisting of five clinical variables and the FFR value can help predict the risk of DLI in the first year following FFR assessment.

Clinical Outcomes Using a Platelet Function-Guided Approach for Secondary Prevention in Patients With Ischemic Stroke or Transient Ischemic Attack

Background and Purpose— Antiplatelet therapy nonresponse is associated with worse clinical outcomes. We studied the clinical outcomes associated with platelet function-guided modifications in antiplatelet therapy in patients with ischemic stroke or transient ischemic attack. Methods— From January 2005 to August 2007, 324 patients with ischemic stroke underwent platelet function testing using platelet aggregometry. Aspirin nonresponse was defined as a mean platelet aggregation ≥20% with 0.5 mg/mL arachidonic acid and/or ≥70% with 5 &mgr;mol/L adenosine diphosphate. Clopidogrel nonresponse was defined as a mean platelet aggregation ≥40% with 5 &mgr;mol/L adenosine diphosphate. A modification was any increase in antiplatelet therapy occurring after testing. Clinical outcomes were compared between patients with and without platelet function-guided antiplatelet therapy modifications using univariate and propensity score-adjusted analyses. Results— In patients with ischemic stroke or transient ischemic attack, 43% (n=128) and 35% (n=54) were nonresponders to aspirin and clopidogrel, respectively. After platelet function testing, antiplatelet therapy was increased in 23% of patients (n=73). After propensity score matching (n=61 in each group), antiplatelet therapy modification was associated with significantly increased rates of death, ischemic events, or bleeding (hazard ratio, 2.24; 95% CI, 1.12–4.47; P=0.02) compared with no modification in antiplatelet therapy and a trend toward increased bleeding (hazard ratio, 3.56; 95% CI, 0.98–12.95; P=0.05). No differences in ischemic events were observed. Conclusions— Platelet function-guided modification in antiplatelet therapy after an ischemic stroke or transient ischemic attack was associated with significantly higher rates of adverse clinical outcomes.

New Approaches to Inhibiting Platelets and Coagulation

Ischemic heart disease and stroke are major causes of death and morbidity worldwide. Coronary and cerebrovascular events are a consequence of thrombus formation caused by atherosclerotic plaque rupture or embolism, both of which result from platelet activation and aggregation and thrombin-mediated fibrin generation via the coagulation cascade. Current and emerging antiplatelet and anticoagulant agents are evolving rapidly. The use of aspirin for primary prevention continues to be controversial, as are the doses appropriate for secondary prevention. Development of new oral and intravenous adenosine diphosphate P2Y12 inhibitors and novel antiplatelet agents continues to transform the landscape of antiplatelet therapy. Oral anticoagulation has advanced with the use of direct thrombin and factor Xa inhibitors that do not require therapeutic monitoring. In this review, we discuss the pharmacology and growing clinical evidence for traditional and new antiplatelet and anticoagulant therapies.

Aspirin and platelet adenosine diphosphate receptor antagonists in acute coronary syndromes and percutaneous coronary intervention: role in therapy and strategies to overcome resistance.

Platelet activation and aggregation are key components in the cascade of events causing thrombosis following plaque rupture. Antiplatelet therapy is essential in the treatment of patients with acute coronary syndromes (ACS) and for those requiring percutaneous coronary intervention (PCI). Aspirin (acetylsalicylic acid) is a well established antiplatelet therapy and is mandated for secondary prevention of cardiovascular events following ACS. In patients with ACS, the addition of clopidogrel to aspirin is more effective than aspirin alone. For patients undergoing PCI, dual antiplatelet therapy with aspirin and clopidogrel is warranted. Aspirin should be continued indefinitely after PCI. Pretreatment of patients with clopidogrel prior to PCI lowers the incidence of cardiovascular events, yet the optimum timing of drug administration and dose are still being investigated, as is the duration of therapy following PCI. Late-stent thrombosis with drug-eluting stents has pushed the recommendation for duration of clopidogrel therapy up to 1 year and perhaps beyond, in patients without risks for bleeding. The concepts of aspirin and clopidogrel resistance are important clinical questions. No uniform definition exists for aspirin or clopidogrel resistance. Measurements of resistance are often highly variable and do not necessarily correlate with clinical resistance. Noncompliance remains the most prominent mode of resistance. Screening of selected patient populations for resistance or pharmacologic intervention of those patients termed ‘resistant’ warrants further study.

Cytochrome P450 Gene Variants, Race, and Mortality Among Clopidogrel-Treated Patients After Acute Myocardial Infarction

Background—Clopidogrel is recommended after acute myocardial infarction but has variable efficacy and safety, in part related to the effect of cytochrome P450 (CYP) polymorphisms on its metabolism. The effect of CYP polymorphisms on cardiovascular events among clopidogrel-treated patients after acute myocardial infarction remains controversial, and no studies to date have investigated the association of CYP variants with outcomes in black patients. Methods and Results—Subjects (2732: 2062 whites; 670 blacks) hospitalized with acute myocardial infarction enrolled in the prospective, multicenter TRIUMPH study were genotyped for CYP polymorphisms. The majority of whites (79%) and blacks (64.4%) were discharged on clopidogrel. Among whites, carriers of the loss-of-function CYP2C19*2 allele had significantly increased 1-year mortality (adjusted hazards ratio [HR]: 1.70; confidence interval [CI]: 1.01–2.86; P=0.046) and a trend toward increased rate of recurrent MI (adjusted HR: 2.10; CI: 0.95–4.63; P=0.066). Among blacks, increased 1-year mortality was associated with the gain-of-function CYP2C19*17 allele (adjusted HR for *1/*17 versus *1/*1: 2.02; CI: 0.92–4.44; *17/*17 versus *1/*1: 8.97; CI: 3.34–24.10; P<0.0001) and the CYP1A2*1C allele (adjusted HR for *1/*1C versus *1/*1: 1.89; CI: 0.85–4.22; *1C/*1C versus *1/*1: 4.96; CI: 1.69–14.56; P=0.014). Bleeding events were significantly more common among black carriers of CYP2C19*17 or CYP1A2*1C. Conclusions—Both loss-of-function and gain-of-function CYP polymorphisms affecting clopidogrel metabolism are associated with increased mortality among clopidogrel-treated patients after acute myocardial infarction; the specific polymorphism and the putative mechanism vary according to race.

Patient Characteristics Associated With the Choice of Triple Antithrombotic Therapy in Acute Coronary Syndromes

Evidence regarding the use of dual antiplatelet therapy and oral anticoagulation (i.e., triple therapy) in acute coronary syndromes (ACS) is limited. We evaluated the characteristics associated with the choice of triple therapy in ACS. Using the Get With The Guidelines (GWTG) Coronary Artery Disease national registry, we studied patients with ACS at 361 sites in the United States from 2004 to 2007. Both univariate analysis and multivariate logistic regression analysis were used to assess the factors associated using triple therapy on discharge. The Generalized Estimating Equation method was used to account for within-hospital clustering in modeling. A total of 86,304 patients presented with ACS during the study period. At discharge, 3,933 patients (4.6%) were prescribed triple therapy, 60,716 patients (70.4%) received dual antiplatelet therapy, 2,348 patients (2.7%) received single antiplatelet therapy plus oral anticoagulation, 19,065 patients (22.1%) received antiplatelet monotherapy, and 242 patients (0.3%) received oral anticoagulation alone. Patients with a history of atrial fibrillation (odds ratio 7.01, 95% confidence interval 6.06 to 8.12; p <0.001), documented new-onset atrial fibrillation (odds ratio 3.76, 95% confidence interval 2.87 to 4.93; p <0.001), or history of atrial flutter (odds ratio 3.38, 95% confidence interval 2.15 to 5.32; p <0.001) were more frequently discharged with triple therapy. In conclusion, for patients with ACS, atrial fibrillation and atrial flutter were most strongly associated with the use of triple therapy; however, this therapy was used less often than dual or single antiplatelet therapy.

Clinical outcomes associated with proton pump inhibitor use among clopidogrel-treated patients within CYP2C19 genotype groups following acute myocardial infarction.

We examined clinical outcomes with proton pump inhibitors (PPI) use within CYP2C19 genotype groups during clopidogrel treatment following acute myocardial infarction (AMI). 2062 patients were genotyped for CYP2C19*2 and *17 variants in TRIUMPH. 12 month clinical outcomes were analyzed among patients discharged on clopidogrel within CYP2C19*2 carrier, CYP2C19*17 carrier, and CYP2C19*1 homozygote genotype groups. PPI use was not associated with a difference in mortality. Among clopidogrel-treated Caucasians following AMI, PPI use was associated with a significantly higher rate of cardiac rehospitalization (HR 1.62, 95% CI 1.19–2.19; P=0.002) compared with no PPI use. PPI users who were carriers of the CYP2C19*17 variant experienced significantly higher rates of cardiac rehospitalization (HR 2.05, 95% CI 1.26–3.33; P=0.003), carriers of the CYP2C19*2 variant had a trend toward increased 1-year cardiac rehospitalization (HR 1.69, 95% CI 0.95–2.99; P=0.07), while no significant differences were observed among CYP2C19*1 homozygotes. These results indicate that the risks associated with PPI use among clopidogrel-treated Caucasian post-MI patients are impacted by CYP2C19 genotype, and suggest knowledge of genotype may be useful for personalizing PPI use among patients following AMI to reduce rehospitalization.