Steven R. Steinhubl

Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease : the STRADIVARIUS randomized controlled trial

CONTEXT Abdominal obesity is associated with metabolic abnormalities and increased risk of atherosclerotic cardiovascular disease. However, no obesity management strategy has demonstrated the ability to slow progression of coronary disease. OBJECTIVE To determine whether weight loss and metabolic effects of the selective cannabinoid type 1 receptor antagonist rimonabant reduces progression of coronary disease in patients with abdominal obesity and the metabolic syndrome. DESIGN, SETTING, AND PATIENTS Randomized, double-blinded, placebo-controlled, 2-group, parallel-group trial (enrollment December 2004-December 2005) comparing rimonabant with placebo in 839 patients at 112 centers in North America, Europe, and Australia. INTERVENTIONS Patients received dietary counseling, were randomized to receive rimonabant (20 mg daily) or matching placebo, and underwent coronary intravascular ultrasonography at baseline (n = 839) and study completion (n = 676). MAIN OUTCOME MEASURES The primary efficacy parameter was change in percent atheroma volume (PAV); the secondary efficacy parameter was change in normalized total atheroma volume (TAV). RESULTS In the rimonabant vs placebo groups, PAV (95% confidence interval [CI]) increased 0.25% (-0.04% to 0.54%) vs 0.51% (0.22% to 0.80%) (P = .22), respectively, and TAV decreased 2.2 mm3 (-4.09 to -0.24) vs an increase of 0.88 mm3 (-1.03 to 2.79) (P = .03). In the rimonabant vs placebo groups, imputing results based on baseline characteristics for patients not completing the trial, PAV increased 0.25% (-0.04% to 0.55%) vs 0.57% (0.29% to 0.84%) (P = .13), and TAV decreased 1.95 mm3 (-3.8 to -0.10) vs an increase of 1.19 mm3 (-0.73 to 3.12) (P = .02). Rimonabant-treated patients had a larger reduction in body weight (4.3 kg [-5.1 to -3.5] vs 0.5 kg [-1.3 to 0.3]) and greater decrease in waist circumference (4.5 cm [-5.4 to -3.7] vs 1.0 cm [-1.9 to -0.2]) (P < .001 for both comparisons). In the rimonabant vs placebo groups, high-density lipoprotein cholesterol levels increased 5.8 mg/dL (4.9 to 6.8) (22.4%) vs 1.8 mg/dL (0.9 to 2.7) (6.9%) (P < .001), and median triglyceride levels decreased 24.8 mg/dL (-35.4 to -17.3) (20.5%) vs 8.9 mg/dL (-14.2 to -1.8) (6.2%) (P < .001). Rimonabant-treated patients had greater decreases in high-sensitivity C-reactive protein (1.3 mg/dL [-1.7 to -1.2] [50.3%] vs 0.9 mg/dL [-1.4 to -0.5] [30.9%]) and less increase in glycated hemoglobin levels (0.11% [0.02% to 0.20%] vs 0.40% [0.31% to 0.49%]) (P < .001 for both comparisons). Psychiatric adverse effects were more common in the rimonabant group (43.4% vs 28.4%, P < .001). CONCLUSIONS After 18 months of treatment, the study failed to show an effect for rimonabant on disease progression for the primary end point (PAV) but showed a favorable effect on the secondary end point (TAV). Determining whether rimonabant is useful in management of coronary disease will require additional imaging and outcomes trials, which are currently under way. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00124332.

Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU-Assessing Ultegra) multicenter study☆

Background—The optimal level of platelet inhibition with a glycoprotein (GP) IIb/IIIa antagonist necessary to minimize thrombotic complications in patients undergoing a percutaneous coronary intervention (PCI) is currently unknown. Methods and Results—Five hundred patients undergoing a PCI with the planned use of a GP IIb/IIIa inhibitor had platelet inhibition measured at 10 minutes, 1 hour, 8 hours, and 24 hours after the initiation of therapy with the Ultegra Rapid Platelet Function Assay (Accumetrics). Major adverse cardiac events (MACEs: composite of death, myocardial infarction, and urgent target vessel revascularization) were prospectively monitored, and the incidence correlated with the measured level of platelet function inhibition at all time points. One quarter of all patients did not achieve ≥95% inhibition 10 minutes after the bolus and experienced a significantly higher incidence of MACEs (14.4% versus 6.4%, P =0.006). Patients whose platelet function was <70% inhibited at 8 hours after the start of therapy had a MACE rate of 25% versus 8.1% for those ≥70% inhibited (P =0.009). By multivariate analysis, platelet function inhibition ≥95% at 10 minutes after the start of therapy was associated with a significant decrease in the incidence of a MACE (odds ratio 0.46, 95% CI 0.22 to 0.96, P =0.04). Conclusions—Substantial variability in the level of platelet function inhibition is achieved with GP IIb/IIIa antagonist therapy among patients undergoing PCI. The level of platelet function inhibition as measured by a point-of-care assay is an independent predictor for the risk of MACEs after PCI.

Lack of Adverse Clopidogrel-Atorvastatin Clinical Interaction From Secondary Analysis of a Randomized, Placebo-Controlled Clopidogrel Trial

Background—Statins primarily metabolized by cytochrome P450 3A4 (CYP3A4) reportedly reduce clopidogrel’s metabolism to active metabolite, thus attenuating its inhibition of platelet aggregation ex vivo. However, the clinical impact of this interaction has not been evaluated. Methods and Results—Clopidogrel for the Reduction of Events During Observation (CREDO) was a double-blind, placebo-controlled, randomized trial comparing pretreatment (300 mg) and 1-year (75 mg/d) clopidogrel therapy (clopidogrel) with no pretreatment and 1-month clopidogrel therapy (75 mg/d) (control) after a planned percutaneous coronary intervention. All patients received aspirin. The 1-year primary end point was a composite of death, myocardial infarction, and stroke. We performed a post hoc analysis to evaluate the clinical efficacy of concomitant clopidogrel and statin administration, categorizing baseline statin use to those predominantly CYP3A4-metabolized (atorvastatin, lovastatin, simvastatin, and cerivastatin) (CYP3A4-MET) or others (pravastatin and fluvastatin) (non-CYP3A4-MET). Of the 2116 patients enrolled, 1001 received a CYP3A4-MET and 158 a non-CYP3A4-MET statin. For the overall study population, the primary end point was significantly reduced in the clopidogrel group (8.5% versus 11.5%, RRR 26.9%; P =0.025). This clopidogrel benefit was similar with statin use, irrespective of treatment with a CYP3A4-MET (7.6% clopidogrel, 11.8% control, RRR 36.4%, 95% CI 3.9 to 57.9; P =0.03) or non-CYP3A4-MET statin (5.4% clopidogrel, 13.6% control, RRR 60.6%, 95% CI −23.9 to 87.4; P =0.11). Patients given atorvastatin or pravastatin had similar 1-year event rates. Additionally, concomitant therapy with statins had no impact on major or minor bleeding rates. Conclusions—Although ex vivo testing has suggested a potential negative interaction when coadministering a CYP3A4-metabolized statin with clopidogrel, this was not clinically observed statistically in a post hoc analysis of a placebo-controlled study.

Rapid Platelet-Function Assay An Automated and Quantitative Cartridge-Based Method

BACKGROUND The platelet glycoprotein (GP) IIb/IIIa receptor is important in mediating platelet thrombus formation, and the GP IIb/IIIa antagonist abciximab (c7E3 Fab; ReoPro) is effective in preventing thrombotic ischemic cardiovascular complications of unstable angina and percutaneous coronary interventions. Small-molecule antagonists of GP IIb/IIIa based on the Arg-Gly-Asp (RGD) sequence show similar benefit, and some of these agents are orally active. However, there may be significant interindividual variation in response to such antagonists, especially with chronic oral therapy. It will be essential to balance the beneficial antithrombotic effect of these drugs with their potential for causing bleeding. In response to this need, we have developed a rapid platelet-function assay (RPFA), a point-of-care system that provides a quantitative measure of the competence of the GP IIb/IIIa receptor as reflected in the ability of platelets to agglutinate fibrinogen-coated beads. METHODS AND RESULTS Polystyrene beads were coated with fibrinogen and placed in a cartridge along with a lyophilized peptide that activates the thrombin receptor. Anticoagulated whole blood was added to the cartridge, and then a microprocessor-controlled operation mixed the reagents and detected agglutination between platelets and coated beads. Quantitative digital results were displayed within 3 minutes. Because there is no dilution of the blood, the assay can be used to measure platelet activity in samples that have been treated with GP IIb/IIIa antagonists with high dissociation rates. RPFA results of whole-blood samples treated with different GP IIb/IIIa antagonists correlated well with both conventional turbidimetric platelet aggregation (r2=0.95) and the percentage of free GP IIb/IIIa molecules in the sample (r2=0.96). The mean difference in measurements between RPFA and aggregometry was -4% (+/-4% SD), and the mean difference in measurements between RPFA and free GP IIb/IIIa receptors was -2% (+/-6% SD). CONCLUSIONS The RPFA provides rapid information on platelet function that mirrors turbidimetric platelet aggregation and reflects GP IIb/IIIa receptor blockade.

Why have antioxidants failed in clinical trials

Antioxidant therapies have been evaluated in placebo-controlled trials involving tens of thousands of patients. Despite pathophysiologic, epidemiologic, and mechanistic data suggesting otherwise, these clinical trial results have been, to date, mostly negative in the setting of chronic preventative therapy. On the other hand, a much smaller number of trials involving handfuls of patients have been much more encouraging in terms of the acute benefit of antioxidants reflected by the data on N-acetylcysteine. However, the seemingly overwhelmingly data not supporting a role for antioxidants in the chronic suppression of atherosclerosis must be kept in perspective. Most antioxidant therapies that have been tested were not chosen because they were proved to be the best antioxidants, but rather because of their easy availability. An excellent example is vitamin E. Although easily available, it has many limitations as an antioxidant. In fact, in some studies, vitamin E has been shown to have some prooxidant effects. Another possible explanation for the lack of benefit in clinical trials is that the trials have not lasted long enough. It may be impossible to show the benefits of antioxidant therapy over several years if the therapy is trying to reverse the results of several decades of oxidative stress. It is critical to remember that the lack of benefits seen in clinical trials to date does not disprove the central role of oxidative stress in atherosclerosis. Rather, these results challenge us to evaluate optimal antioxidant therapies, the ideal study patients to study, and the appropriate trial duration.

Early and Sustained Dual Oral Antiplatelet Therapy Following Percutaneous Coronary Intervention

CONTEXT Following percutaneous coronary intervention (PCI), short-term clopidogrel therapy in addition to aspirin leads to greater protection from thrombotic complications than aspirin alone. However, the optimal duration of combination oral antiplatelet therapy is unknown. Also, although current clinical data suggest a benefit for beginning therapy with a clopidogrel loading dose prior to PCI, the practical application of this therapy has not been prospectively studied. OBJECTIVES To evaluate the benefit of long-term (12-month) treatment with clopidogrel after PCI and to determine the benefit of initiating clopidogrel with a preprocedure loading dose, both in addition to aspirin therapy. DESIGN, SETTING, AND PARTICIPANTS The Clopidogrel for the Reduction of Events During Observation (CREDO) trial, a randomized, double-blind, placebo-controlled trial conducted among 2116 patients who were to undergo elective PCI or were deemed at high likelihood of undergoing PCI, enrolled at 99 centers in North America from June 1999 through April 2001. INTERVENTIONS Patients were randomly assigned to receive a 300-mg clopidogrel loading dose (n = 1053) or placebo (n = 1063) 3 to 24 hours before PCI. Thereafter, all patients received clopidogrel, 75 mg/d, through day 28. From day 29 through 12 months, patients in the loading-dose group received clopidogrel, 75 mg/d, and those in the control group received placebo. Both groups received aspirin throughout the study. MAIN OUTCOME MEASURES One-year incidence of the composite of death, myocardial infarction (MI), or stroke in the intent-to-treat population; 28-day incidence of the composite of death, MI, or urgent target vessel revascularization in the per-protocol population. RESULTS At 1 year, long-term clopidogrel therapy was associated with a 26.9% relative reduction in the combined risk of death, MI, or stroke (95% confidence interval [CI], 3.9%-44.4%; P =.02; absolute reduction, 3%). Clopidogrel pretreatment did not significantly reduce the combined risk of death, MI, or urgent target vessel revascularization at 28 days (reduction, 18.5%; 95% CI, -14.2% to 41.8%; P =.23). However, in a prespecified subgroup analysis, patients who received clopidogrel at least 6 hours before PCI experienced a relative risk reduction of 38.6% (95% CI, -1.6% to 62.9%; P =.051) for this end point compared with no reduction with treatment less than 6 hours before PCI. Risk of major bleeding at 1 year increased, but not significantly (8.8% with clopidogrel vs 6.7% with placebo; P =.07). CONCLUSIONS Following PCI, long-term (1-year) clopidogrel therapy significantly reduced the risk of adverse ischemic events. A loading dose of clopidogrel given at least 3 hours before the procedure did not reduce events at 28 days, but subgroup analyses suggest that longer intervals between the loading dose and PCI may reduce events.

Incidence, prognostic impact, and influence of antithrombotic therapy on access and nonaccess site bleeding in percutaneous coronary intervention

OBJECTIVES The aim of this study was to evaluate the relative frequency of access and nonaccess site bleeding, the association of these events with 1-year mortality, and the impact of randomized antithrombotic therapy. BACKGROUND Post-percutaneous coronary intervention (PCI) bleeding has been strongly associated with subsequent mortality. The extent to which access versus nonaccess site bleeding contributes to this poor prognosis and the role of antithrombotic therapies remains poorly understood. METHODS The incidence and impact of Thrombolysis In Myocardial Infarction (TIMI) major/minor 30-day bleeding and randomized antithrombotic therapy were examined in a combined dataset from the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events), Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY), and HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trials in 17,393 PCI patients. RESULTS The TIMI major/minor bleeding occurred in 5.3% of patients, 61.4% of which (3.3%) were nonaccess site bleeds. After multivariable adjustment, TIMI bleeding was associated with an increased risk of 1-year mortality (hazard ratio [HR]: 3.17, 95% confidence interval [CI]: 2.51 to 4.00, p < 0.0001). The HR of a nonaccess site bleed was approximately 2-fold that of an access site bleed: HR: 3.94, 95% CI: 3.07 to 5.15, p < 0.0001 versus HR: 1.82, 95% CI: 1.17 to 2.83, p = 0.008, respectively. Randomization to bivalirudin versus heparin + a glycoprotein IIb/IIIa inhibitor resulted in 38% and 43% relative reductions in TIMI major/minor and TIMI major bleeding, respectively (p < 0.0001 for both), with significant reductions in both access and nonaccess site bleeding. CONCLUSIONS Nonaccess site bleeding after PCI is common, representing approximately two-thirds of all TIMI bleeding events, and is associated with a 4-fold increase in 1-year mortality. Use of bivalirudin rather than heparin + a glycoprotein IIb/IIIa inhibitor significantly decreases both nonaccess site as well as access site bleeding events by approximately 40%.

Platelet aggregation and its association with stent thrombosis and bleeding in clopidogrel-treated patients: initial evidence of a therapeutic window.

To the Editor: Platelet response to clopidogrel is characterized by large interindividual response variability ([1][1]). Numerous studies have linked low responsiveness to clopidogrel with the occurrence of thrombotic events, and more recently, data have emerged linking an enhanced response to

Can Mobile Health Technologies Transform Health Care

There is substantial enthusiasm for the concept of mobile health (mHealth), a broad term typically used to describe the use of mobile telecommunication technologies for the delivery of health care and in support of wellness. In 2011, US Secretary of Health and Human Services Kathleen Sebelius referred to mHealth as “the biggest technology breakthrough of our time” and maintained that its use would “address our greatest national challenge.”1 This level of exuberance for mHealth is driven by the convergence of 3 powerful forces. First is the unsustainability of current health care spending and the recognition of the need for disruptive solutions. Second is the rapid and ongoing growth in wireless connectivity— there now are more than 3.2 billion unique mobile users worldwide—and the remarkable capability this brings for the bidirectional instantaneous transfer of information. Third is the need for more precise and individualized medicine; a refinement in phenotypes that mandates novel, personal data streams well beyond the occasional vital sign or laboratory data available through intermittent clinic visits. But there are multiple obstacles to the acceptance and widespread utilization of mHealth technologies. Foremost are the complexities of the health care system, especially the current drivers of reimbursement. In addition, clinicians are concerned about the possible further weakening of the patient-physician relationship and the possible increase in their workload. Also, and somewhat paradoxically, the unbridled enthusiasm of the mHealth technology development community, coupled with consumers’ appetite for alternative health and wellness resources, can create challenges to the appropriate use and validation of mHealth technologies. For example, there are tens of thousands (estimates vary between 30 000 to more than 90 000) health care– related apps available for download, in contrast to the US Food and Drug Administration estimate of the approximately 100 it has reviewed. This lack of oversight is worrisome and contributes to the increasingly high likelihood of useless and possibly even dangerous apps being downloaded by unsuspecting consumers.2 When such a high level of interest and promise coexists with such a paucity of evidence, there is potential for hype to dominate the discussion around mHealth. To move beyond that, in this Viewpoint we offer examples of how mHealth technologies can transform health care by addressing inefficient practices and challenges faced by consumers and clinicians in the current system.

Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: Determinants and effect on cardiovascular risk

Background— Incomplete inhibition of platelet thromboxane generation, as measured by elevated urinary 11-dehydro thromboxane B2 concentrations, has been associated with an increased risk of cardiovascular events. We aimed to determine the external validity of this association in aspirin-treated patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial and to determine whether there are any modifiable factors or interventions that lower urinary 11-dehydro thromboxane B2 concentrations that could thereby reduce cardiovascular risk. Methods and Results— Urinary 11-dehydro thromboxane B2 concentrations were measured in 3261 aspirin-treated patients at least 1 month after they had been randomly assigned to placebo or clopidogrel. Baseline urinary 11-dehydro thromboxane B2 concentrations in the highest quartile were associated with an increased risk of stroke, myocardial infarction, or cardiovascular death compared with the lowest quartile (adjusted hazard ratio 1.66, 95% CI 1.06 to 2.61, P=0.03). Increasing age, female sex, history of peripheral artery disease, current smoking, and oral hypoglycemic or angiotensin-converting enzyme inhibitor therapy were independently associated with higher urinary concentrations of 11-dehydro thromboxane B2, whereas aspirin dose ≥150 mg/d, history of treatment with nonsteroidal antiinflammatory drugs, history of hypercholesterolemia, and statin treatment were associated with lower concentrations. Randomization to clopidogrel (versus placebo) did not reduce the hazard of cardiovascular events in patients in the highest quartile of urinary 11-dehydro thromboxane B2 levels. Conclusions— In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B2 are an externally valid and potentially modifiable determinant of stroke, myocardial infarction, or cardiovascular death in patients at risk for atherothrombotic events.