Clinical Trials News

Bivalirudin during Primary PCI in Acute Myocardial Infarction

2008-05-26T01:29:00.000-07:00

Image via WikipediaPrimary percutaneous coronary intervention (PCI) in patients with evolving ST-segment elevation myocardial infarction decreases infarct size and the rates of recurrent ischemia, reinfarction, and stroke and improves survival, as compared with pharmacologic reperfusion therapy.1,2 Nonetheless, the prognosis after primary PCI has remained essentially unchanged over the past decade, with neither stents nor other novel devices or drugs improving survival beyond that achievable with balloon angioplasty alone.3,4,5,6,7,8 Treatment with glycoprotein IIb/IIIa inhibitors may decrease the short- and long-term risk of death,9,10 and these agents are used in more than 90% of patients who undergo primary PCI in the United States and in the majority of such patients in Europe.11,12 Nonetheless, glycoprotein IIb/IIIa inhibitors increase the risk of hemorrhagic complications and thrombocytopenia,3,10,13,14,15 which have been strongly associated with early and late mortality.15,16,17,18,19

The direct thrombin inhibitor bivalirudin (Angiomax, the Medicines Company), when used instead of heparin plus glycoprotein IIb/IIIa inhibitors, has been shown in large-scale, randomized trials to reduce major and minor bleeding and thrombocytopenia while resulting in similar rates of ischemia after PCI in patients with stable angina, those with unstable angina, and those with non–ST-segment elevation myocardial infarction.20,21,22,23 Whether bivalirudin is safe and effective for patients with ST-segment elevation myocardial infarction who are undergoing primary PCI has not, to our knowledge, been studied. We therefore performed a large-scale study to evaluate the clinical value of bivalirudin in patients with ST-segment elevation myocardial infarction.

Clinical Outcomes

At 30 days, patients who were assigned to receive bivalirudin alone, as compared with those who were assigned to receive heparin plus a glycoprotein IIb/IIIa inhibitor, had a significantly reduced rate of net adverse clinical events (9.2% vs. 12.1%; relative risk, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P=0.005), owing to a lower rate of major bleeding (4.9% vs. 8.3%; relative risk, 0.60; 95% CI, 0.46 to 0.77; P<0.001), with similar rates of major adverse cardiovascular events (5.4% and 5.5%, respectively; relative risk in the bivalirudin group, 0.99; 95% CI, 0.76 to 1.30; P=0.95) (Table 3 and Figure 2). In a post hoc analysis, with the exclusion of large hematomas from the protocol definition, the rate of major bleeding was reduced from 7.8% with heparin plus glycoprotein IIb/IIIa inhibitors to 4.7% with bivalirudin (P<0.001). Bivalirudin, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, also reduced hemorrhagic complications as defined by the TIMI and GUSTO scales, thrombocytopenia, and the need for blood transfusions (Table 3). Among patients in the control group, the peak activated clotting time did not differ significantly between those with major bleeding and those without major bleeding (median, 273 seconds and 263 seconds, respectively; P=0.12).
Treatment with bivalirudin, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, resulted in significantly lower 30-day rates of death from cardiac causes (1.8% vs. 2.9%; relative risk, 0.62; 95% CI, 0.40 to 0.95; P=0.03) and death from all causes (2.1% vs. 3.1%; relative risk, 0.66; 95% CI, 0.44 to 1.00; P=0.047); rates of reinfarction, target-vessel revascularization, and stroke were not significantly different (Table 3 and Figure 2). There were no significant differences in the peak creatine kinase level or creatine kinase MB fraction between the bivalirudin group and the group that received heparin plus glycoprotein IIb/IIIa inhibitors (median peak creatine kinase level, 1433.0 U per liter and 1428.5 U per liter, respectively; P=0.79; median peak creatine kinase MB fraction, 162.8 U per liter and 160.1 U per liter, respectively; P=0.98). There were no significant interactions between the treatment assignment and either preprocedural unfractionated-heparin use or clopidogrel loading dose with respect to major adverse cardiovascular events or major bleeding (Table 4).
Among 3124 patients in whom stents were successfully implanted, the overall rate of stent thrombosis at 30 days did not differ significantly between the group that received bivalirudin and the group that received heparin plus a glycoprotein IIb/IIIa inhibitor (2.5% and 1.9%, respectively; P=0.30). However, in a prespecified analysis, within the first 24 hours, stent thrombosis occurred in 17 more patients in the bivalirudin group than in the group receiving heparin plus a glycoprotein IIb/IIIa inhibitor (1.3% vs. 0.3%, P<0.001), whereas between 24 hours and 30 days, stent thrombosis occurred in 7 fewer patients in the bivalirudin group (1.2% vs. 1.7%, P=0.28). Nonetheless, patients in whom PCI was performed and who were assigned to receive bivalirudin rather than heparin plus a glycoprotein IIb/IIIa inhibitor had lower 30-day rates of death from cardiac causes (1.8% vs. 2.8%; relative risk, 0.63; 95% CI, 0.40 to 0.99; P=0.045), major bleeding (5.1% vs. 8.5%; relative risk, 0.59; 95% CI, 0.46 to 0.77; P<0.001), and net adverse clinical events (9.2% vs. 12.2%; relative risk, 0.75; 95% CI, 0.62 to 0.92; P=0.005).

Among the 25 patients in whom stent thrombosis developed within 24 hours, 2 patients died (8.0%), including 1 in each randomized group. In the entire study cohort, of the 93 patients who died within 30 days, death was preceded by major bleeding in 26 patients, 8 of whom were in the bivalirudin group (hazard ratio for death among patients with vs. those without major bleeding, 9.12; 95% CI, 5.73 to 14.52; P<0.001) and by definite stent thrombosis in 5 patients, 1 of whom was in the bivalirudin group (hazard ratio for death among patients with vs. those without definite stent thrombosis, 5.54; 95% CI, 2.24 to 13.69; P<0.001).
Discussion

In this prospective, randomized trial involving patients with ST-segment elevation myocardial infarction who were undergoing primary PCI, treatment with the direct thrombin inhibitor bivalirudin (with glycoprotein IIb/IIIa inhibitors administered in 7.2% of the patients because of suboptimal results of the PCI), as compared with treatment with heparin plus the routine use of glycoprotein IIb/IIIa inhibitors, improved event-free survival at 30 days, owing to a significant reduction in major bleeding. The rates of major adverse cardiovascular events were similar in the two treatment groups. Bivalirudin reduced the rate of major bleeding, as classified not only by the protocol definition but also by the laboratory-based TIMI scale and the clinical GUSTO scale, and in addition reduced the rates of thrombocytopenia and blood transfusion, despite the significantly higher peak activated clotting time among patients treated with bivalirudin. Moreover, random assignment to bivalirudin alone as compared with heparin plus glycoprotein IIb/IIIa inhibitors significantly reduced the rates of death from cardiac causes and from all causes at 30 days.

The reduction in mortality with bivalirudin as compared with heparin plus glycoprotein IIb/IIIa inhibitors in the present trial may be attributable to the prevention of iatrogenic hemorrhagic complications. Previous trials have documented the independent relationship between major bleeding (with or without blood transfusions) and subsequent death.16,17,18,19 Major bleeding was a more powerful predictor of death than periprocedural myocardial infarction after PCI in the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events 2 (REPLACE-2) trial, and the reduction in bleeding with bivalirudin as compared with heparin plus glycoprotein IIb/IIIa inhibitors resulted in a trend toward reduced late mortality after PCI among the relatively low-risk patients in that study.27 In the present trial, more deaths occurred after major bleeding (26 deaths) than after reinfarction (10) or definite stent thrombosis (5). The 40% relative reduction in major bleeding in the bivalirudin group as compared with the group that received heparin plus a glycoprotein IIb/IIIa inhibitor, with similar rates of ischemic complications, may thus explain the observed improvement in survival with bivalirudin in patients with ST-segment elevation myocardial infarction, who are at higher risk than the patients in the REPLACE-2 trial. Moreover, anticoagulation with bivalirudin reduced the occurrence of severe thrombocytopenia, which has also been strongly associated with death among patients with ST-segment elevation myocardial infarction and with PCI.14,15

Among patients in whom a stent was successfully implanted, assignment to bivalirudin, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, resulted in 17 more episodes of stent thrombosis within the first 24 hours, representing a significant 1.0% absolute increase, which was partially offset by 7 fewer events in the patients treated with bivalirudin between 24 hours and 30 days (absolute reduction, 0.5%). The early increase in stent thrombosis with bivalirudin alone may be explained by adenosine diphosphate–induced platelet activation before maximal thienopyridine blockade of the P2Y12 receptor28 or by residual thrombin activity after the discontinuation of bivalirudin. However, although the increase in acute thrombotic events probably underlies the increased risk of major adverse cardiovascular events that was noted on the first day among patients treated with bivalirudin, the overall 30-day rates of reinfarction were not increased — 1.8% in each group — and only 2 of the 93 deaths in the study occurred after acute stent thrombosis (1 in each randomized group). The prognostic implications of acute stent thrombosis that occurs early in the hospital phase in closely monitored patients who have undergone primary PCI for ST-segment elevation myocardial infarction and that affects a previously infarcted myocardial territory may thus differ from the implications of subacute stent thrombosis or acute thrombosis that occurs after discharge from the hospital in patients who have undergone elective PCI and whose left ventricular function was well preserved. Most important, the rate of death from cardiac causes (including deaths due to stent thrombosis) among patients who were treated with heparin plus a glycoprotein IIb/IIIa inhibitor surpassed that among patients treated with bivalirudin by day 7, and by 30 days, a significant 37.9% relative reduction in death from cardiac causes (an absolute decrease of 1.1%) was seen in the group treated with bivalirudin. Further investigation is warranted to determine whether the risk of early stent thrombosis can be mitigated by treatment with more rapidly acting and potent thienopyridine agents,29,30 a longer course of bivalirudin, or both, without increasing the risk of bleeding. Pending such studies, the 1% incremental risk of stent thrombosis within the first 24 hours, with no significant difference in the rates at 30 days, must be placed in the context of the decrease in the rate of major bleeding and the subsequent 1% absolute reduction in mortality from cardiac causes that were achieved with the abbreviated use of bivalirudin (i.e., only during PCI) as compared with heparin plus glycoprotein IIb/IIIa inhibitors.

The present study has several strengths, including the enrollment of a broad cross section of patients. Nonetheless, several limitations should be noted. First, the logistic complexities of the trial necessitated an open-label design, introducing potential bias. However, compliance with the protocol procedure and the study medications was high, and the rate of provisional use of glycoprotein IIb/IIIa inhibitors in the bivalirudin group was low and similar to that in the double-blind REPLACE-2 trial.20 The relative reductions in hemorrhagic complications with bivalirudin as compared with heparin plus glycoprotein IIb/IIIa inhibitors in the present trial were also similar to those in the REPLACE-2 trial.20 Potential bias was further mitigated by the use of blinded core laboratories and a clinical-event adjudication committee that required original-source documentation for event verification. Second, a heparin bolus was administered in the emergency room to approximately two thirds of the patients, with bivalirudin most commonly started in the cardiac catheterization laboratory 30 minutes later, before PCI. Interaction testing, however, showed that administration of bivalirudin significantly reduced major bleeding independently of preprocedural administration of heparin, and preprocedural administration of heparin before bivalirudin was associated with a weak trend toward reduced major adverse cardiovascular events at 30 days. Third, the trial was underpowered for low-frequency end points, including death. However, the mechanistic underpinnings for the observed reduction in the rate of death with bivalirudin (i.e., reduced risks of bleeding, transfusion, and thrombocytopenia), in concert with the consistency of our results with those of earlier studies,20,21,22,23 provide reassurance that this finding is probably valid. Fourth, reinfarction may be difficult to detect after primary PCI, although the nearly identical peak levels of cardiac enzymes after PCI in the two treatment groups suggest that there was no difference in the rate of reinfarction. Finally, although an independent, unblinded statistical monitoring group has found no interactions between the type of stent used and the randomly assigned study drug for the primary 30-day end points, longer-term follow-up, including unblinding of the stent randomization data at 1 year, is required to evaluate thoroughly the effect of bivalirudin in patients with ST-segment elevation myocardial infarction who are undergoing primary PCI.

In conclusion, our trial shows that in patients with evolving ST-segment elevation myocardial infarction who are undergoing primary PCI, the use of bivalirudin alone, as compared with heparin plus a glycoprotein IIb/IIIa inhibitor, results in significantly reduced 30-day rates of major bleeding and increased event-free survival.

Supported by the Cardiovascular Research Foundation, with grant support from Boston Scientific and the Medicines Company.

Dr. Stone reports receiving consulting fees from Medtronic, GlaxoSmithKline, Eli Lilly, and Bristol-Myers Squibb and grant support from Boston Scientific, the Medicines Company, and Abbott Vascular. Dr. Guagliumi reports receiving consulting fees from or serving on advisory boards for Abbott Vascular and Boston Scientific and receiving grant support from Medtronic and Boston Scientific. Dr. Dudek reports receiving lecture fees from Nycomed. Dr. Gersh reports receiving consulting fees from or serving on advisory boards for AstraZeneca, Bristol-Myers Squibb, Abbott Laboratories, and Boston Scientific and having equity interest in CV Therapeutics. Dr. Pocock reports receiving consulting fees from and serving on an advisory board for the Medicines Company. Dr. Kirtane reports receiving consulting fees from or serving on advisory boards for Abbott Vascular, Medtronic, and Boston Scientific and receiving lecture fees from the Medicines Company and Alphamedica. Dr. Mehran reports receiving lecture fees from Boston Scientific and the Medicines Company. Dr. Parise reports being employed by the Cardiovascular Research Foundation. No other potential conflict of interest relevant to this article was reported.

* The investigators, institutions, and research organizations participating in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) Trial are listed in the Appendix.

Source Information

From Columbia University Medical Center and the Cardiovascular Research Foundation, New York (G.W.S., G.D., A.J.K., H.P., R.M.); Charité Campus Benjamin Franklin, Berlin (B.W.); Ospedali Riuniti di Bergamo, Bergamo, Italy (G.G.); Silesian Center for Heart Disease, Lodz, Poland (J.Z.P.); LeBauer Cardiovascular Research Foundation and Moses Cone Hospital, Greensboro, NC (B.R.B.); Jagiellonian University, Krakow, Poland (D.D.); Rabin Medical Center, Petach Tikva, Israel (R.K.); Universitätsklinikum Schleswig-Holstein, Lübeck, Germany (F.H.); Mayo Clinic, Rochester, MN (B.J.G.); London School of Hygiene and Tropical Medicine, London (S.J.P.); and New York–Presbyterian Hospital/Weill Cornell Medical Center, New York (S.C.W.).

Address reprint requests to Dr. Stone at Columbia University Medical Center, Cardiovascular Research Foundation, 111 E. 59th St., 11th Fl., New York, NY 10022, or at gs2184@columbia.edu.

References

1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361:13-20. [CrossRef][ISI][Medline]
2. Schömig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:1084-1089. [Free Full Text]
3. Stone GW, Grines CL, Cox DA, et al. Comparison of angioplasty with stenting with or without abciximab, in acute myocardial infarction. N Engl J Med 2002;346:957-966. [Free Full Text]
4. De Luca G, Suryapranata H, Ottervanger JP, et al. Comparison between stenting and balloon in elderly patients undergoing primary angioplasty for ST-segment elevation myocardial infarction. Int J Cardiol 2007;119:306-309. [CrossRef][Medline]
5. De Luca G, Suryapranata H, Stone GW, Antoniucci D, Neumann FJ, Chiarello M. Adjunctive mechanical devices to prevent distal embolization in patients undergoing mechanical revascularization for acute myocardial infarction: a meta-analysis of randomized trials. Am Heart J 2007;153:343-353. [CrossRef][Medline]
6. Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). J Am Coll Cardiol 2005;45:1775-1780. [Free Full Text]
7. Armstrong PW, Granger CB, Adams PX, et al. Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial. JAMA 2007;297:43-51. [Free Full Text]
8. Alexander JH, Reynolds HR, Stebbins AL, et al. Effect of tilarginine acetate in patients with acute myocardial infarction and cardiogenic shock: the TRIUMPH randomized controlled trial. JAMA 2007;297:1657-1666. [Free Full Text]
9. De Luca G, Suryapranata H, Stone GW, et al. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials. JAMA 2005;293:1759-1765. [Free Full Text]
10. Kandzari DE, Hasselblad V, Tcheng JE, et al. Improved clinical outcomes with abciximab therapy in acute myocardial infarction: a systematic overview of randomized clinical trials. Am Heart J 2004;147:457-462. [CrossRef][ISI][Medline]
11. Dauerman HL, Frederick PD, Miller D, French WJ. Current incidence and clinical outcomes of bivalirudin administration among patients undergoing primary coronary intervention for stent thrombosis elevation acute myocardial infarction. Coron Artery Dis 2007;18:141-148. [CrossRef][ISI][Medline]
12. Fox KA, Steg PG, Eagle KA, et al. Decline in rates of death and heart failure in acute coronary syndromes, 1999-2006. JAMA 2007;297:1892-1900. [Free Full Text]
13. Montalescot G, Barragan P, Wittenberg O, et al. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 2001;344:1895-1903. [Free Full Text]
14. Kereiakes DJ, Berkowitz SD, Lincoff AM, et al. Clinical correlates and course of thrombocytopenia during percutaneous coronary intervention in the era of abciximab platelet glycoprotein IIb/IIIa blockade. Am Heart J 2000;140:74-80. [CrossRef][ISI][Medline]
15. Nikolsky E, Grines CL, Cox DA, et al. Impact of baseline platelet count in patients undergoing primary percutaneous coronary intervention in acute myocardial infarction (from the CADILLAC trial). Am J Cardiol 2007;99:1055-1061. [CrossRef][ISI][Medline]
16. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006;114:774-782. [Free Full Text]
17. Kinnaird TD, Stabile E, Mintz GS, et al. Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions. Am J Cardiol 2003;92:930-935. [CrossRef][ISI][Medline]
18. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004;292:1555-1562. [Free Full Text]
19. Manoukian SV, Feit F, Mehran R, et al. Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: an analysis from the ACUITY trial. J Am Coll Cardiol 2007;49:1362-1368. [Free Full Text]
20. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853-863. [Erratum, JAMA 2003;289:1638.] [Free Full Text]
21. Lincoff AM, Kleiman NS, Kereiakes DJ, et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA 2004;292:696-703. [Erratum, JAMA 2006;296:46.] [Free Full Text]
22. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203-2216. [Free Full Text]
23. Stone GW, Ware JH, Bertrand ME, et al. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management: one-year results from the ACUITY trial. JAMA 2007;298:2497-2506. [Free Full Text]
24. Stone GW, Bertrand M, Colombo A, et al. Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial: study design and rationale. Am Heart J 2004;148:764-775. [CrossRef][ISI][Medline]
25. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344-2351. [Free Full Text]
26. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc [B] 1995;57:289-300.
27. Feit F, Voeltz MD, Attubato MJ, et al. Predictors and impact of major hemorrhage on mortality following percutaneous coronary intervention: an analysis of the REPLACE-2 trial. Am J Cardiol 2007;100:1364-1369. [CrossRef][Medline]
28. Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the Clopidogrel Loading with Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study. Circulation 2005;111:1153-1159. [Free Full Text]
29. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-2015. [Free Full Text]
30. Greenbaum AB, Ohman EM, Gibson CM, et al. Preliminary experience with intravenous P2Y12 platelet receptor inhibition as an adjunct to reduced-dose alteplase during acute myocardial infarction: results of the Safety, Tolerability and Effect on Patency in Acute Myocardial Infarction (STEP-AMI) angiographic trial. Am Heart J 2007;154:702-709. [CrossRef][ISI][Medline]

Landmark ATHENA Study With Dronedarone (Multaq(R)) Shows 24% Reduction In Cardiovascular Hospitalisation Or Death In Patients With Atrial Fibrillation

2008-05-19T12:34:00.000-07:00

Sanofi-aventis (EURONEXT: SAN and NYSE: SNY) announced that findings from the landmark ATHENA study showed dronedarone (Multaq®), a potential therapy for the treatment of patients with atrial fibrillation or atrial flutter, decreased the risk of cardiovascular hospitalisations or death from any cause by a statistically significant 24% (p=0.00000002), meeting the study primary endpoint.

The ATHENA results will be presented at the late breaking clinical trial session of Heart Rhythm 2008, the Heart Rhythm Society's 29th Annual Scientific Sessions in San Francisco, USA.

For the first time in twenty years of clinical drug trials in atrial fibrillation, an investigational medicine, dronedarone, showed a significant decrease in the risk of cardiovascular death by 30% (p=0.03) on top of standard therapy, including rate control and antithrombotic drugs, in patients with atrial fibrillation or atrial flutter. Dronedarone also significantly decreased the risk for arrhythmic death by 45% (p=0.01) and there were numerically less deaths (16%) from any cause in the dronedarone group compared to placebo (p=0.17). First cardiovascular hospitalisation was reduced by 25% (p=0.000000009) in the dronedarone group.

"The ATHENA results have the potential to change the face of atrial fibrillation management. For atrial fibrillation patients, who together with their physicians struggle on a daily basis to manage the dramatic consequences of this complex disease, Multaq®carries hope for patients" said Marc Cluzel, sanofi-aventisSenior Vice President, R&D. "This milestone is indicative of sanofi-aventis' commitment to bringing innovative therapies to market, and of our ongoing commitment to provide patients, physicians and public health stakeholders with breakthrough medicines in those therapeutic areas where there are major healthcare needs and limited solutions".

Atrial fibrillation is a major cause of hospitalisation and mortality and affects about 2.5 million people in the United States, as well as 4.5 million people in the European Union and is emerging as a growing public health concern because of the aging of the population. Patients suffering from atrial fibrillation have twice the risk of death, an increased risk of stroke and cardiovascular complications, including congestive heart failure. Furthermore atrial fibrillation considerably impairs patients' lives, mainly because of their inability to perform normal daily activities due to complaints of palpitations, chest pain, dyspnoea, fatigue or light-headedness, without consideration of the cumbersome and sometime serious constraints imposed by current therapies of atrial fibrillation.

"In atrial fibrillation where treatment morbidity-mortality benefit still needed to be demonstrated, ATHENA is a unique trial using clinically relevant outcomes such as cardiovascular hospitalisation or death as the primary endpoint. In this regard, the trial has clearly achieved these safety and efficacy endpoints," said Dr Stefan H. Hohnloser, J.W. from the Goethe University, Division of Clinical Electrophysiology, Frankfurt, Germany, who served as co-principal investigator of the ATHENA study. "As a consequence, dronedarone is the first treatment for atrial fibrillation which has been demonstrated to reduce cardiovascular hospitalisation or mortality in patients with AF."

The most frequently reported adverse events of dronedarone vs placebo induced gastro-intestinal effect (26% vs 22%), skin disorder (10% vs 8%, mainly rash) and increased blood creatinine (4.7% vs 1%). The mechanism of blood creatinine increase (inhibition of creatinine secretion at the renal tubular level) is well defined. Compared to placebo, dronedarone showed low risk of pro-arrhythmia and no excess of hospitalisations for congestive heart failure. There was a similar rate of study drug discontinuation between the two study groups.

"ATHENA is truly a landmark trial, that marks a paradigm change for the management of atrial fibrillation," said Dr Christopher Cannon, a Senior Investigator in the TIMI Study Group at Brigham and Women's Hospital, who was not involved in the study. "Atrial fibrillation is a very common disease, and our prior treatment options have been focused only on symptom relief and a hope to not do harm, which has been the problem with prior antiarrhythmic drugs. Now, with a highly significant reduction in death or hospitalisation, as well as a 45% reduction in arrhythmic death or 30% cardiovascular death, dronedarone may become a first line treatment of atrial fibrillation".

ATHENA, the largest double blind randomised study in patients with atrial fibrillation, was conducted in more than 550 sites in 37 countries and enrolled a total of 4,628 patients. The ATHENA landmark trial is the first morbidity-mortality study as part of the dronedaronephase III clinical development program, which also included five other multinational clinical studies, an initial study in severe cardiac heart failure and a recent decompensationpatients ANDROMEDA, and a total of 4 international studies in atrial fibrillation: EURIDIS/ADONIS, ERATO, and the ongoing DIONYSOS trial.

Based upon this new clinical data, sanofi-aventis plans to submit a registration dossier to the European Medicines Agency (EMEA), and a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) during the 3rd quarter of 2008.

Telmisartan, Ramipril, or Both in Patients at High Risk for Vascular Events

2008-04-11T04:18:00.000-07:00

Randomized, controlled trials involving about 150,000 patients have convincingly demonstrated that angiotensin-converting–enzyme (ACE) inhibitors reduce rates of death, myocardial infarction, stroke, and heart failure among patients with heart failure,1 left ventricular dysfunction,2,3,4 previous vascular disease alone,5,6,7 or high-risk diabetes.8 ACE inhibitors do not block the production of all angiotensin II, so direct receptor blockade might be more effective. ACE inhibitors reduce bradykinin degradation, which enhances vasodilatation, but increase the rates of angioedema and cough. In patients with heart failure, angiotensin II levels may increase and symptoms worsen, despite the use of ACE inhibitors.9 The use of an angiotensin-receptor blocker (ARB), as compared with placebo, reduced the rate of death or hospitalization for heart failure in patients with a low ejection fraction and heart failure who either could not tolerate an ACE inhibitor10 or were already receiving one.11,12 As compared with beta-blockers, ARBs also reduced vascular events in high-risk patients with hypertension and left ventricular hypertrophy.13 Nevertheless, in other high-risk populations, the role of ARBs as an alternative or in addition to ACE inhibitors to prevent cardiovascular outcomes is not known.

Discussion

ACE inhibitors have been convincingly shown to reduce rates of death, myocardial infarction, stroke, heart failure, and revascularization among patients with previous cardiovascular disease and high-risk diabetes. Therefore, to provide clinically relevant information, trials evaluating ARBs in these patients must include proven doses of an ACE inhibitor, either as background therapy or as a comparator.

In our study, we evaluated both approaches in a population similar to the one studied in the HOPE trial. Telmisartan was clearly not inferior to ramipril for both the prespecified primary outcome of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure and for the primary outcome in the HOPE trial (death from cardiovascular causes, myocardial infarction, or stroke). Similarities in the telmisartan group and the ramipril group in the proportions of patients who had heart failure, underwent revascularization, or had renal dysfunction (outcomes that were reduced by ramipril in the HOPE trial) and the high rates of adherence to both drug regimens provided additional confidence in establishing the noninferiority of telmisartan. As compared with the ramipril group, the telmisartan group had significantly fewer episodes of cough or angioedema, but this benefit was partially offset by higher rates of hypotensive symptoms (but not syncope). Higher rates of hypotension-related symptoms are consistent with the slightly lower blood-pressure levels associated with telmisartan, although the lower levels did not lead to further benefit. The benefits of ARBs are being evaluated in three other placebo-controlled trials that are expected to be completed in 2008.14,18,19

Our results parallel the findings of the Valsartan in Acute Myocardial Infarction Trial (VALIANT),20 which established the noninferiority of valsartan, as compared with captopril, in patients with left ventricular dysfunction or heart failure after myocardial infarction. The upper boundaries of the confidence intervals and the noninferiority margins were almost identical in the two studies, even though they enrolled different patient populations. The side effects in our study were similar to those in the VALIANT study, which showed lower rates of cough and angioedema in the valsartan group than in the captopril group but higher rates of hypotension-related symptoms. There were more dose reductions (but not discontinuations) because of renal complications in the valsartan group than in the captopril group, an association that was not observed in our study.

In order to establish noninferiority, a rigorous trial design is required that includes a patient population similar to that in the reference trial, a similar drug regimen, high adherence rates, outcomes that the comparator is known to affect, and high statistical power to exclude clinically important differences. All these criteria were satisfied in our study. The entry criteria for our study and the event rates in the ramipril group were similar to those in the HOPE trial, with high follow-up rates in both trials. Moreover, the adherence rate was higher in the ramipril group (89.4% at 2 years and 84.7% at the end of the study among patients receiving either ramipril or an open-label ACE inhibitor) than that in the HOPE trial (85.0% and 78.8%, respectively). A sensitivity analysis that was restricted to patients who adhered to their allocated drug regimen for more than 50% of the study period showed the consistency of our results and confirmed the robustness of noninferiority.

In our study, we confirmed the statistical noninferiority of telmisartan, as compared with ramipril, since the upper boundary of the 97.5% confidence interval (1.09) was lower than the predefined margin of 1.13 for both the primary outcome (P=0.004) and the primary outcome used in the HOPE trial (P=0.001). Telmisartan preserved about 95% (95% CI, 83.2 to 106.3) of the benefits of ramipril over placebo with respect to the primary outcome and preserved 105% (95% CI, 91.6 to 119.0) of the benefits with respect to the outcome of death from cardiovascular causes, myocardial infarction, or stroke that were observed in the HOPE trial. Use of the method of Hasselblad and Kong21 to impute effects of telmisartan versus placebo (based on the benefits of ramipril over placebo in the HOPE trial) indicates a relative risk of 0.79 (95% CI, 0.70 to 0.89) for the primary outcome. The number of patients who discontinued therapy was significantly smaller in the telmisartan group than in the ramipril group, although the absolute difference in the discontinuation rate was modest, because we used an active run-in phase that selected patients for randomization only if they tolerated both medications. After randomization, we vigorously reinforced adherence and encouraged patients who stopped medications to restart them. In clinical practice, the rates of discontinuation might be higher.

We also evaluated whether the combination of telmisartan and ramipril (with both drugs targeted to the full dose) would be superior to ramipril alone. Surprisingly, despite a reduction in systolic blood pressure of 2 to 3 mm Hg in the combination-therapy group, as compared with the ramipril group — a decrease that should have translated into a risk reduction of 4 to 5% — no significant benefit was seen in the primary outcome among patients receiving the two-drug therapy. However, combination therapy significantly increased the risk of hypotension, syncope, renal dysfunction, and hyperkalemia, with a trend toward an increased risk of renal dysfunction requiring dialysis. These results are similar to the analysis of the combined effects of an ARB and an ACE inhibitor, as compared with an ACE inhibitor alone, in four previous trials.22 Therefore, even though combination therapy had a larger biologic effect (as suggested by greater blood-pressure lowering and changes in potassium), dual blockade did not produce any additional clinical benefit in this population.

In this regard, our results are also similar to those of the VALIANT study, in which the combination of a full dose of captopril plus valsartan (the latter at a dose of 80 mg per day, which was lower than the 160 mg per day used in the valsartan-only group) did not significantly reduce the occurrence of the primary outcome but did increase hypotension.20 Taken together, these two studies showed no additive effect for an ARB in conjunction with a full dose of a proven ACE inhibitor.

However, our findings contrast with those of two other studies. In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) study,12 which involved patients who had symptomatic heart failure and had been hospitalized in the previous 6 months, candesartan, when added to existing therapy with any ACE inhibitor used at variable doses (with less than half the patients receiving full doses), was superior to placebo in reducing death or hospitalization for heart failure. Similarly, a reduction in hospitalization for heart failure was observed in the Valsartan Heart Failure Trial,11 which compared valsartan with placebo in patients with heart failure, with about 90% of patients receiving background therapy with ACE inhibitors at variable doses. Both trials differed from both our study and the VALIANT study in that decisions regarding the dose and choice of an ACE inhibitor were left to individual physicians, and there was no attempt to titrate the ACE inhibitor to the maximum dose. Furthermore, patients had symptomatic heart failure despite receiving an ACE inhibitor.

The lack of an additional benefit of a substantial lowering of blood pressure is puzzling, both in our study and in the VALIANT study. These results may have been due to previous successful treatment of patients with other drugs so that little further clinical benefit was possible with the addition of full doses of multiple drugs that block the renin–angiotensin system. Alternatively, some harm from combined therapy with ACE inhibitors and ARBs used at full doses may offset any potential gains. Further information is expected regarding the role of ARBs as compared with placebo in patients after stroke,18 in high-risk patients with vascular disease who are unable to tolerate an ACE inhibitor,14 and in patients with atrial fibrillation.19

In conclusion, our data show that in patients who have vascular disease or high-risk diabetes but do not have heart failure, telmisartan is an equally effective alternative to ramipril and is less likely to cause angioedema. The choice between the two agents will depend on the preferences of patients and physicians and the individual patient's susceptibility to specific adverse events. There is no additional advantage (and there is some harm) from the combination of telmisartan and ramipril used in full doses in this population, as compared with ramipril alone.

Supported by a grant from Boehringer Ingelheim, the Heart and Stroke Foundation of Ontario, and a Senior Scientist Award from the Canadian Institutes of Health Research (to Dr. Yusuf).

Dr. Yusuf reports receiving consulting and lecture fees and research grants from Boehringer Ingelheim, AstraZeneca, Sanofi-Aventis, Servier, Bristol-Myers Squibb, and GlaxoSmithKline; Dr. Teo, receiving consulting and lecture fees and grant support from Boehringer Ingelheim; Dr. Schumacher, being an employee of Boehringer Ingelheim; Dr. Dagenais, receiving consulting and lecture fees from Boehringer Ingelheim and Sanofi-Aventis and grant support from Sanofi-Aventis; Dr. Sleight, receiving consulting and lecture fees from Boehringer Ingelheim and lecture fees from AstraZeneca and Sanofi-Aventis; and Dr. Anderson, receiving consulting fees from Boehringer Ingelheim, Servier, Novo Nordisk, and AstraZeneca, lecture fees from Boehringer Ingelheim, Servier, AstraZeneca, and Sanofi-Aventis, and grant support from Boehringer Ingelheim. No other potential conflict of interest relevant to this article was reported.
NEJM

Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia Did Not Result In A Difference I In Intima–Media Thickness

2008-04-04T14:22:00.000-07:00

A reduction in levels of low-density lipoprotein (LDL) cholesterol constitutes one of the cornerstones in the prevention of cardiovascular disease. In recent trials comparing various statins or the same statin at various doses, aggressive therapy to lower LDL cholesterol levels was associated with a reduction in rates of cardiovascular events.1,2,3,4 However, administration of the highest approved statin dose offers only limited additional lowering of LDL cholesterol at the expense of an increased incidence of side effects.5 Therefore, novel compounds that further reduce LDL cholesterol levels when added to statin therapy are of interest. A recently introduced compound, ezetimibe, selectively inhibits cholesterol absorption by binding to the Niemann–Pick C1-like 1 (NPC1L1) protein. The latter is located at the brush-border membrane of the enterocyte, where it contributes substantially to the intestinal uptake and cellular transport of cholesterols and noncholesterol sterols.6,7 Combined therapy with ezetimibe and a statin provides an incremental reduction in LDL cholesterol levels of 12 to 19%.8,9

In this study, we sought to determine whether the daily administration of 10 mg of ezetimibe in combination with 80 mg of simvastatin could reduce the progression of atherosclerosis in patients with familial hypercholesterolemia, as assessed by measurement of arterial intima–media thickness. The rationale for studying patients with familial hypercholesterolemia is that such patients have a greatly increased risk of premature coronary artery disease10 and an increased rate of progression of intima–media thickness starting in childhood.11 In our study, called the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, we used B-mode ultrasonographic imaging of the intima–media thickness in the carotid and femoral arteries as a surrogate measure to assess the progression of atherosclerosis

The results of our study showed that the addition of ezetimibe to the highest recommended dose of simvastatin did not reduce the intima–media thickness of the carotid-artery wall in this cohort of patients with familial hypercholesterolemia, despite significant incremental reductions in levels of both LDL cholesterol and C-reactive protein. The primary outcome, the change in the mean intima–media thickness, did not differ significantly between the two study groups, nor did the secondary outcome measures.

There are at least three possible explanations for the absence of an incremental reduction in the intima–media thickness in patients receiving ezetimibe: the lack of vascular benefit conferred by ezetimibe despite the observed reduction in LDL cholesterol level, the inability of the measurement technique to accurately reflect changes in atherosclerotic burden, and the possibility that the study population had too low a risk, which would limit our ability to detect a differential response to the two interventions.

The first explanation to consider is that the lowering of LDL cholesterol levels by a drug other than a statin might be ineffective for slowing atherosclerosis. Thus, the fact that ezetimibe-induced lowering of LDL cholesterol levels was not associated with an incremental effect on carotid-artery intima–media thickness could be due to the different mechanisms of action of ezetimibe, as compared with those of statins. In addition to the capacity of statins to lower LDL cholesterol levels, the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase also leads to a plethora of lipid-independent effects involving antiinflammatory action and improvement in endothelial function.15 A direct comparison between ezetimibe and statins revealed differential effects on endothelial function favoring statin therapy despite similar reductions in LDL cholesterol,16,17 although this finding has not been consistent in all studies.18 Also, dose intensification of statins in patients with familial hypercholesterolemia resulted in a further reduction in the progression of intima–media thickness in the carotid artery.19 Thus, it can be argued that certain lipid-independent effects of statins that are not shared by ezetimibe are involved in the production of a vascular benefit.

However, several facts argue against the concept that ezetimibe-induced lowering of LDL cholesterol levels does not produce additional vascular benefit beyond that of statins. First, a recent regression meta-analysis showed that the lipid-independent effects of statins did not confer an additional risk reduction beyond that expected from the degree of the lowering of the LDL cholesterol level.20 Second, data from the Program on Surgical Control of the Hyperlipidemias (POSCH) trial showed that reductions in levels of LDL cholesterol after ileocecal bypass were associated with significant reductions in cardiovascular mortality and event rates similar to those observed in statin-prevention trials.21,22 In view of the controversy regarding the lipid-independent effects of statins, the results of ongoing clinical trials comparing statins with combined therapy with ezetimibe and a statin are eagerly awaited to resolve this issue.

Large epidemiologic studies have provided strong associations between intima–media thickness and stroke, angina pectoris, and myocardial infarction.10,11 In the Atherosclerosis Risk in Communities (ARIC) study involving 15,800 adults, an increase of 0.2 mm in the mean carotid-artery intima–media thickness was associated with an increase in relative risk for myocardial infarction and stroke of 33% and 28%, respectively.23 This close relationship between intima–media thickness and cardiovascular risk has subsequently been corroborated in several other studies.24

One of the principal determinants of atherosclerosis progression has proved to be LDL cholesterol levels, as confirmed by the linear relationship between the level of LDL cholesterol and intima–media thickness.25 This finding is further supported by the observation that progression in intima–media thickness is significantly attenuated in statin intervention studies in both adult and pediatric patients with familial hypercholesterolemia.11,19,26,27,28,29,30,31,32 On the basis of this information, the measurement of intima–media thickness can be considered as a validated surrogate marker for atherosclerotic vascular disease. Also, in view of the precision of the measurements in our study, as exemplified by the high intraclass correlation coefficient and the small standard deviations, it seems unlikely that we were unable to detect a truly significant change in arterial-wall measures using our measurement technique.

Patients with familial hypercholesterolemia are known to be at greatly increased risk for premature coronary artery disease,10 accompanied by accelerated progression of intima–media thickness starting in childhood.11 However, the treatment of patients with familial hypercholesterolemia has witnessed profound changes. Currently, the majority of patients with familial hypercholesterolemia are treated with high-dose statins starting at an early age. Such therapy can be expected to attenuate the progression of intima–media thickness, as was shown in the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) study.19 Thus, it is not unexpected that the baseline carotid intima–media thickness in our study was lower than that observed in earlier trials involving patients with familial hypercholesterolemia33 and in most other previous lipid-modifying trials,26,27,31 with the exception of the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 1 (ARBITER-1) study.31 Among patients who received 80 mg of simvastatin only in our study, the progression of intima–media thickness was 0.0029 mm per year, as compared with 0.018 mm per year in patients with familial hypercholesterolemia who received 40 mg of simvastatin in the ASAP study — a reduction by a factor of 6 among patients receiving the higher dose. In further support of the influence of previous statin therapy, progression of intima–media thickness in the carotid artery decreased to 0.005 mm per year during long-term daily therapy with 80 mg of atorvastatin in the ASAP extension study,34 a finding that contrasts with the substantial reductions in intima–media thickness seen during the first 2 years of the trial. In the Rating Atherosclerotic Disease Change by Imaging with a New CETP [Cholesteryl Ester Transfer Protein] Inhibitor (RADIANCE 1) study,35 the most recent study involving a similar group of patients with familial hypercholesterolemia, the pattern of change in intima–media thickness after a mean daily dose of 57 mg of atorvastatin was very similar to that observed in both groups in our study. These data raise the possibility that there may be limits to the extent to which the lowering of LDL cholesterol levels can result in a further decrease in the progression of intima–media thickness in the context of previous statin therapy and a modest baseline intima–media thickness.

In conclusion, the reduction of LDL cholesterol by the addition of ezetimibe to simvastatin did not reduce intima–media thickness of the carotid-artery wall in patients with familial hypercholesterolemia in our study. The reason for the failure to observe an incremental effect on intima–media thickness despite a reduction in levels of LDL cholesterol remains unknown.

Supported by Merck and Schering-Plough.

Final Data From The SEISMIC Trial Suggest Safety, Efficacy Of Autologous Stem Cell Therapy For Treating Congestive Heart Failure

2008-04-02T00:49:00.000-07:00

Final six-month, follow-up patient data presented during the late-breaking clinical trial sessions at the American College of Cardiology, suggest MyoCell(R) myoblast clinical cell therapy is a safe and potentially effective alternative treatment to standard medical therapy alone for improving heart function among patients with previously implanted cardiac devices who are experiencing congestive heart failure.

The findings from the SEISMIC(1) Trial, a 40-patient, randomized, multicenter, controlled, Phase II-a study conducted in Europe, evaluated MyoCell myoblast clinical cell therapy delivered via the MyoCath(R), endoventricular needle-injection catheter in patients previously fitted with implanted cardiac defibrillators(ICDs), receiving standard medical therapy and who are experiencing congestive heart failure. On admission to the trial, patients were randomized on a two-to-one ratio into the treatment versus control groups with 26 patients receiving MyoCell therapy and 14 patients in the control group. All patients were experiencing congestive heart failure and were previously fitted with ICDs and receiving standard medical therapy. Both the MyoCell biologic therapy and the MyoCath needle-injection catheter, developed by Bioheart, Inc., are currently being studied as investigational products.

"The results from the SEISMIC Trial are encouraging," said Prof. Patrick W. Serruys, MD, PhD, Principal Investigator and Chief, Department of Interventional Cardiology, Thoraxcenter, Erasmus Medical Center - Rotterdam, the Netherlands. "While the study was specifically designed to show safety, the findings also suggest positive trends in clinical benefits when evaluating the treated group versus the control group at six months."

Patients in both groups were evaluated at three- and six-month intervals using a variety of tests, including digital imaging and standard quality of life measurement such as the six-minute walking test, New York Heart Association (NYHA) heart failure classification and Minnesota Living with Heart (MLHF) questionnaire. Final six-month results observed in the SEISMIC Trial include:

-- 84 percent of treated patients experienced improved or unchanged six- minute walking test scores compared to 16 percent of the control group

- 69 percent of the control group's results worsened, versus only 16 percent of the treated group

-- 94 percent of treated patients experienced improved or unchanged NYHA classification compared to 58 percent of the control group

- 42 percent of the control group's results worsened, versus only 6 percent of the treated group

Prof. Serruys also noted that reports of arrhythmia among the patients evaluated in SEISMIC, both in terms of total number of episodes as well as timing of episodes, were no different between the treatment and control arms in the study. This suggests that MyoCell is not associated with a higher prevalence of arrhythmias; rather, that arrhythmias are an expected occurrence for this subset of heart failure patients.

"These data support the need for a randomized, double-blind, placebo- controlled study involving the MyoCell technology," said Prof. Serruys. "We look forward to applying our learning from this trial to the larger, more comprehensive MARVEL(2) Trial currently underway in the U.S. and Europe." The MARVEL Trial, a randomized, double-blind, placebo-controlled, multi-center Phase II/III Trial involving 330 patients in North America and Europe, is the largest trial of its kind to date. Enrollment in the MARVEL Trial began in October 2007, targeting patients who fall into Class II or III heart failure. The MARVEL Trial will further study the safety and efficacy of the minimally invasive MyoCell autologous stem-cell therapy in the treatment of congestive heart failure delivered via a MyoStar(TM) injection catheter(3), in combination with the NOGA(R) XP Cardiac Navigation System. The Principal Investigator for the MARVEL Trial is Warren Sherman, MD, Director, Cardiac Cell-based Endovascular Therapies, Columbia University Medical Center, New York.

ABOUT MYOCELL CLINICAL CELL THERAPY

MyoCell clinical cell therapy, developed by Bioheart, Inc., is currently being studied as an investigational product in Europe and the U.S. MyoCell clinical cell therapy is intended to be used to improve cardiac function months or even years after a patient has suffered severe heart damage due to a heart attack. The procedure involves a physician removing a small amount of muscle obtained from the patient's thigh. From this muscle specimen, autologous myoblasts (muscle stem cells) are then isolated, grown using Bioheart's proprietary cell-culturing process, and injected directly into the scar tissue of the patient's heart. The myoblast cells are delivered via an endoventricular needle-injection catheter during a minimally invasive procedure performed by an interventional cardiologist or vascular surgeon. The myoblast-based muscle formation in the newly populated regions of scar tissue are intended to improve cardiac function by helping the heart muscle beat more efficiently.

ABOUT HEART DISEASE

Approximately nine million European patients and 5.2 million Americans(4) suffer from congestive heart failure, a progressively degenerative condition in which the heart is unable to adequately pump blood throughout the body resulting in fluid accumulation in the lungs, kidneys, and other body tissues. Patients suffering from this disease fatigue easily, and become increasingly less capable of normal activity as they progress through the various stages of the disease. Current standard of care typically involves drug therapy and/or the implantation of a pacemaker and/or defibrillator device to regulate heart function.

ABOUT BIOHEART, INC.

Bioheart, Inc. is a biotechnology company focused on the discovery, development and, subject to regulatory approval, commercialization of autologous cell therapies for the treatment of chronic and acute heart damage. Its lead product candidate, MyoCell, is an innovative clinical cell therapy designed to populate regions of scar tissue within a patient's heart with autologous muscle cells, or cells from the patient's body, for the purpose of improving cardiac function in chronic heart failure patients. The company's pipeline includes multiple product candidates for the treatment of heart damage, including Bioheart Acute Cell Therapy, an autologous, adipose cell treatment for acute heart damage, and MyoCell SDF-1, a therapy utilizing autologous cells genetically modified to express additional growth factors.

References

(1) SEISMIC: Safety and Effects of Implanted (Autologous) Skeletal Myoblasts (MyoCell(R)) using an Injection Catheter

(2) MARVEL: A Phase II/III, Double-Blind, Randomized, Placebo-Controlled Multi-center study to Assess the Safety and Cardiovascular Effects of MyoCell Implantation by a Catheter Delivery System in Congestive Heart Failure Patients Post-Myocardial Infarction(s)

(3) The MYOSTAR(TM) Injection Catheter is not available for sale in the U.S. It is in use in IND investigations

(4) Heart Association Heart Disease Statistics - 2007 Update

MyoCell and MyoCell SDF-1 are trademarks of Bioheart, Inc.

MyoStar and NOGA XP are trademarks of Cordis Corporation, a Johnson & Johnson company

For more information, visit http://www.bioheartinc.com

Bioheart, Inc.
http://www.bioheartinc.com

Anti-Ischemic Therapy Ranexa(R) Significantly Reduces Cardiac Chest Pain Symptoms And Recurrent Ischemia In MERLIN-TIMI 36 Patients

2008-04-02T00:45:00.000-07:00

CV Therapeutics, Inc. (Nasdaq: CVTX) announced new data presented at the 57th Annual Scientific Sessions of the American College of Cardiology shows that Ranexa(R) (ranolazine extended release tablets) significantly reduced the risk of recurrent ischemia (p=0.002), worsening angina (p=0.048) and intensification of antianginal therapy (p=0.009) in angina patients (n=3,565) in the MERLIN- TIMI 36 study.

Additionally, Ranexa significantly improved all measures of exercise performance compared to placebo, including reductions in the time to onset of angina (p=0.002) and time to the onset of 1 mm ST segment depression (p=0.002), a signal of ischemia, in these MERLIN-TIMI 36 angina patients.

"MERLIN-TIMI 36 is the largest study of ranolazine in patients with established coronary artery disease," said David Morrow, M.D., MPH, of Brigham & Women's Hospital at Harvard Medical School and lead investigator of the MERLIN-TIMI 36 study. "This new subgroup analysis shows consistent safety and efficacy across a broader group of angina patients than those studied previously and reaffirms ranolazine as an option for treating chronic angina."

Study Design

MERLIN-TIMI 36 (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) was a multi-national, double-blind, randomized, placebo-controlled, parallel-group clinical trial designed to evaluate the efficacy and safety of Ranexa during acute and long-term treatment in 6,560 patients (3,279 received ranolazine, 3,281 received placebo) with non-ST elevation ACS treated with standard therapy.

Previously published data from the MERLIN-TIMI 36 study has shown that Ranexa was safe in this population of patients with coronary artery disease, which included nearly 1,100 patients with prior heart failure. Ranolazine had no effect on the risk of CV death or MI in the study.

About Angina

Chronic angina is a serious and debilitating heart condition, usually associated with coronary artery disease and marked by repeated and sometimes unpredictable attacks of chest pain. Approximately 8.9 million people in the United States have chronic angina, and 400,000 new cases are diagnosed annually, according to the American Heart Association. Ranexa has anti- ischemic effects which do not depend on changes in heart rate or blood pressure.

About CV Therapeutics

CV Therapeutics, Inc., headquartered in Palo Alto, California, is a biopharmaceutical company primarily focused on applying molecular cardiology to the discovery, development and commercialization of novel, small molecule drugs for the treatment of cardiovascular diseases.

CV Therapeutics' approved product, Ranexa(R) (ranolazine extended-release tablets), is indicated for the treatment of chronic angina in patients who have not achieved an adequate response with other antianginal drugs, and should be used in combination with amlodipine, beta-blockers or nitrates.

CV Therapeutics' clinical and preclinical drug development candidates and programs include regadenoson, which is being developed for potential use as a pharmacologic stress agent in myocardial perfusion imaging studies. Regadenoson has not been determined by any regulatory authorities to be safe or effective in humans for any use.

Except for the historical information contained herein, the matters set forth in this press release, including statements as to research and development and commercialization of products, are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially, including operating losses and fluctuations in operating results; capital requirements; regulatory review and approval of our products; special protocol assessment agreement; the conduct and timing of clinical trials; commercialization of products; market acceptance of products; product labeling; concentrated customer base; reliance on strategic partnerships and collaborations; uncertainties in drug development; uncertainties regarding intellectual property and other risks detailed from time to time in CV Therapeutics' SEC reports, including its Quarterly Report on Form 10-Q for the quarter ended September 30, 2007. CV Therapeutics disclaims any intent or obligation to update these forward-looking statements.

CV Therapeutics, Inc.
http://www.cvt.com

Merck/Schering-Plough Pharmaceuticals Comments On Results Of The ENHANCE Study

2008-03-31T03:26:00.000-07:00

Results of ENHANCE (Ezetimibe aNd simvastatin in Hypercholesterolemia enhANces atherosClerosis rEgression), an imaging trial in 720 patients with heterozygous familial hypercholesterolemia (HeFH), a rare genetic condition that causes very high levels of LDL "bad" cholesterol and greatly increases the risk for premature coronary artery disease, were presented at the 57th annual scientific sessions of the American College of Cardiology and also were published on-line in The New England Journal of Medicine.i

As previously reported on Jan. 14, 2008, despite the fact that ezetimibe/simvastatin 10/80 mg (VYTORIN® *) significantly lowered LDL "bad" cholesterol more than simvastatin 80 mg alone, there was no significant difference between treatment with ezetimibe/simvastatin and simvastatin alone on the pre-specified primary endpoint, a change in the thickness of carotid artery walls over two years as measured by ultrasound. There also were no significant differences between treatment with ezetimibe/simvastatin and simvastatin on the four pre-specified key secondary endpoints: percent of patients manifesting regression in the average carotid artery intima-media thickness (CA IMT); proportion of patients developing new carotid artery plaques >1.3 mm; changes in the average maximum CA IMT; and changes in the average CA IMT plus in the average common femoral artery IMT.

In ENHANCE, when compared to simvastatin alone, ezetimibe/simvastatin significantly lowered LDL "bad" cholesterol, as well as triglycerides and C-reactive protein (CRP). Ezetimibe/simvastatin is not indicated for the reduction of CRP. In the ENHANCE study, as previously reported, the overall safety profile of ezetimibe/simvastatin in the study was generally consistent with the product label.

"LDL cholesterol remains the primary target of lipid-modifying therapy and physicians should continue to lower patients' elevated LDL cholesterol and get their patients to their goals based on guidelines," said Michael Davidson, M.D., professor, director of preventive cardiology, The University of Chicago, Pritzker School of Medicine.

In the ENHANCE publication, the authors provided three theoretical explanations why, despite ezetimibe/simvastatin significantly lowering LDL "bad" cholesterol more than simvastatin (56 percent vs. 39 percent, p<0.01), there was no significant difference between treatment groups on the primary endpoint and four key secondary endpoints: (1) lowering of LDL cholesterol with non-statin therapy, such as ezetimibe, might affect IMT differently than statin therapy, (2) the imaging technology selected was not sensitive enough to detect a difference, or (3) that these HeFH patients were extensively pretreated with lipid-lowering therapy, thereby limiting the amount that CA IMT could change with further LDL cholesterol-lowering therapy, consequently limiting the ability to detect a differential response to the two treatments. The authors concluded that the reason for the failure to observe an incremental effect on CA IMT thickness in spite of a reduction of level of LDL cholesterol remains unknown.

In the publication, the authors addressed the premise that the lack of a difference in change of mean CA IMT between ezetimibe/simvastatin and simvastatin despite greater LDL cholesterol-lowering could be attributed to lipid-independent effects of statins on arteries. The authors presented several facts that argued against this concept, including a discussion of clinical studies involving statin and non-statin therapeutic approaches that demonstrated that cardiovascular risk reductions were associated with the degree of LDL-cholesterol lowering. The authors suggested that clinical outcomes data are needed to answer this question.

As for the hypothesis that the results may reflect the imaging technology, the authors noted this seems unlikely given the precision of the imaging measurement results seen in the ENHANCE trial.

With respect to the hypothesis that the ENHANCE results were due to the characteristics of the patients studied, the authors pointed out that in an earlier imaging study (extension of ASAP or Atorvastatin vs. Simvastatin on Atherosclerosis Progression study) use of potent lipid-lowering therapy in HeFH patients produced "regression" or "thinning" of CA IMT during the first one to two years of therapy, but further decreases during the following two years on the same therapy were not seen. In ENHANCE, approximately 80 percent of the enrolled patients reported taking statin treatment at the time of screening for the study, and had a mean baseline CA IMT of 0.69 to 0.70 mm. In another recent IMT study in HeFH patients (RADIANCE 1 or Rating Atherosclerotic Disease Change by Imaging with A New CETP Inhibitor study), the baseline CA IMT was also lower than in the earlier IMT study and similar to ENHANCE and, importantly, the pattern of change in CA IMT in this IMT study was very similar to that observed in both treatment groups in the ENHANCE study.

The authors noted that "these data raise the possibility that there may be limits to the extent to which the lowering of LDL cholesterol levels can result in a further decrease in the progression of intima-media thickness in the context of previous statin therapy and a modest baseline intima-media thicknessii."

"Although a definitive explanation is never possible with a finding like this, we believe that the most likely explanation for the failure to see a significant difference between treatment groups in ENHANCE relates to the behavior of IMT in this population of HeFH patients," noted Thomas Musliner, M.D., executive director, Cardiovascular Disease, Clinical Research, Merck Research Laboratories. "The large majority of these patients were previously treated with LDL cholesterol-lowering therapy and presumably experienced an effect on CA IMT from that treatment, as reflected in the patients' relatively low CA IMT values when they began the study. The findings of the ASAP extension, RADIANCE 1 and ENHANCE suggest there are limits to how much IMT can be decreased in HeFH study cohorts in the context of the widespread and prolonged use of effective LDL cholesterol-lowering treatment starting at an earlier age, which is now the standard of care for these patients."

Endpoint data and cardiovascular events

ENHANCE investigators found no statistically significant difference between the two treatment groups on the primary endpoint, the change in the average CA IMT at three carotid artery locations. The change from baseline in the mean (average) CA IMT in the ezetimibe/simvastatin group was 0.0111 mm, which did not significantly differ from the simvastatin group's change of 0.0058 mm (P=0.29). The median data for the primary endpoint, which also showed no statistical difference between treatments, was 0.0058 mm in the ezetimibe/simvastatin group and 0.0095 mm for the simvastatin group. The treatment groups also did not have statistically significant differences for each of the three carotid artery locations that comprised the primary endpoint: the common carotid, the internal carotid and the carotid bulb. The data for these analyses, key secondary endpoints and cardiovascular events are included in the attachment.

The ENHANCE study was not designed nor powered to evaluate cardiovascular clinical events. IMPROVE-IT is underway and is designed to provide cardiovascular outcomes data for ezetimibe/simvastatin in patients with acute coronary syndrome. No incremental benefit of ezetimibe/simvastatin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.

Lipid parameters of LDL cholesterol, triglycerides and HDL cholesterol; and C-reactive protein Over the two-year period of the ENHANCE study based upon the "last observation carried forward" endpoint approach, the group treated with ezetimibe/simvastatin had a 56 percent mean reduction of LDL cholesterol (from a baseline of 319 mg/dL) that was significantly greater than the 39 percent mean reduction of LDL cholesterol (from a baseline of 318 mg/dL) in the group treated with simvastatin alone (P<0.01). The LDL cholesterol-lowering observed in patients treated with ezetimibe/simvastatin in the ENHANCE trial was generally consistent with the LDL cholesterol-lowering of ezetimibe/simvastatin seen in separate head-to-head studies vs. simvastatin, vs. Crestor® and vs. Lipitor®.

In addition, by study completion, the ezetimibe/simvastatin group had a 30 percent median reduction in triglycerides (from baseline 157 mg/dL), significantly more than the 23 percent median reduction (from baseline 160 mg/dL) in the simvastatin group (P<0.01). Also, the ezetimibe/simvastatin group had a 49 percent median reduction in CRP (from baseline 1.70 mg/L), significantly more than the 24 percent median reduction in CRP (from baseline 1.70 mg/L) in the simvastatin group (P<0.01). The ezetimibe/simvastatin group had a 10 percent increase (from baseline 46.7 mg/dL) in HDL "good" cholesterol; the simvastatin group had an 8 percent increase from baseline 47.4 mg/dL (P=0.05, no statistical significance).

Safety data

As previously reported, the overall safety profiles of ezetimibe/simvastatin and simvastatin alone were similar and generally consistent with their product labels. Both medicines were generally well tolerated. Also, the overall incidence rates of treatment-related adverse events were 34 percent for ezetimibe/simvastatin (122/357) and 29 percent (107/363) for simvastatin only; the incidence rates for discontinuations due to adverse events were 8.1 percent for ezetimibe/simvastatin (29/357) and 9.4 percent for simvastatin only (34/363). Additional adverse event data are included in the attachment.

About the study design and methodology

The ENHANCE study was an international two-year, randomized, double-blind, controlled trial in 720 HeFH patients between the ages of 30 to 75. All of the ENHANCE patients had HeFH, which affects approximately 0.2 percent of the population. The rationale for studying HeFH patients is that these patients are known to be at increased risk for premature coronary artery disease and, if untreated, exhibit increased IMT progression rates beginning in childhood. Prior LDL cholesterol-lowering therapy of any kind was not an exclusion criterion for ENHANCE, although such therapies were discontinued at the start of the study. Also, there wasn't a minimum value for CA IMT specified for inclusion in study. Following a six-week, single blind, placebo lead-in/drug "wash-out" period, patients were randomized to receive either daily ezetimibe/simvastatin 10/80 mg (N=357) or daily simvastatin 80 mg (N=363).

ENHANCE investigators took digitized single-frame CA IMT images at the three locations of the patients' right and left carotid arteries, the main arteries in the neck that provide blood to the brain. These images were taken at several time points: study baseline, 6, 12, 18 and 24 months.

"Examination of the CA IMT collected during ENHANCE proved to be a far more challenging process than originally anticipated when the study design was drawn up. Therefore, preparation of the images for entry into a database took significantly longer than expected, as the blinded investigators and CA IMT evaluators took numerous steps in 2006 and 2007 to address image quality control and finalize the analysis," said Enrico P. Veltri, M.D., co-author of the ENHANCE study publication and group vice president, Global Clinical Research, Cardiovascular and Metabolic Diseases, Schering-Plough Research Institute. "Our companies acted with integrity and good faith in connection with the trial," he said.

Important information about VYTORIN

Ezetimibe/simvastatin is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, Apo B, triglycerides and non-HDL cholesterol and to increase HDL cholesterol in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia.

Ezetimibe/simvastatin is also indicated for the reduction of elevated total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.

Ezetimibe/simvastatin is a prescription medicine and should not be taken by people who are hypersensitive to any of its components. Ezetimibe/simvastatin should not be taken by anyone with active liver disease or unexplained persistent elevations of serum transaminases. Women who are of childbearing age (unless highly unlikely to conceive), are nursing or who are pregnant should not take ezetimibe/simvastatin.

Selected cautionary information for VYTORIN

Muscle pain, tenderness or weakness in people taking ezetimibe/simvastatin should be reported to a doctor promptly because these could be signs of a serious side effect. Ezetimibe/simvastatin should be discontinued if myopathy is diagnosed or suspected. To help avoid serious side effects, patients should talk to their doctor about medicine or food they should avoid while taking ezetimibe/simvastatin.

In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (>3 X ULN) in serum transaminases were 1.7 percent overall for patients treated with ezetimibe/simvastatin and 2.6 percent for patients treated with ezetimibe/simvastatin 10/80 mg. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations (>3 X ULN) in serum transaminases was 1.8 percent overall and 3.6 percent for patients treated with ezetimibe/simvastatin 10/80 mg. These elevations in transaminases were generally asymptomatic, not associated with cholestasis and returned to baseline after discontinuation of therapy or with continued treatment. Doctors should perform blood tests before, and periodically during treatment with ezetimibe/simvastatin when clinically indicated to check for liver problems. People taking ezetimibe/simvastatin 10/80 mg should receive an additional liver function test prior to and three months after titration and periodically during the first year.

Due to the unknown effects of increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, ezetimibe/simvastatin is not recommended in these patients. The safety and effectiveness of ezetimibe/simvastatin with fibrates have not been established; therefore, co-administration with fibrates is not recommended. Caution should be exercised when initiating ezetimibe/simvastatin in patients treated with cyclosporine and in patients with severe renal insufficiency.

Ezetimibe/simvastatin has been evaluated for safety in more than 3,800 patients in clinical trials and was generally well tolerated at all doses (10/10 mg, 10/20 mg, 10/40 mg, 10/80 mg). In clinical trials, the most commonly reported side effects, regardless of cause, included headache (6.8 percent), upper respiratory tract infection (3.9 percent), myalgia (3.5 percent), influenza (2.6 percent) and extremity pain (2.3 percent).

About Merck/Schering-Plough Pharmaceuticals

Merck/Schering-Plough Pharmaceuticals is a joint venture between Merck & Co., Inc. and Schering-Plough Corporation formed to develop and market in the United States new prescription medicines in cholesterol management. The collaboration includes worldwide markets (excluding Japan). VYTORIN is also marketed as INEGY outside the U.S.

Merck Forward-looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2007, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.

American College Of Cardiology Annual Scientific Session

2008-03-31T03:20:00.000-07:00

Doctors announce findings in new drug therapy, gender disaparities

Penn experts present research findings that could come to define new standards of cardiovascular diagnostics and care at the conference of the American College of Cardiology, the foremost professional society representing heart specialists throughout the world. These experts gathered in Chicago to present and discuss the latest advances in cardiovascular medicine, science and education.

The Effect of Darapladib on Plasma Lipoprotein-Associated Phospholipase A2 Activity and Cardiovascular Biomarkers in Patients with Coronary Heart Disease or Risk Equivalent

Emile R. Mohler, MD, Director of Vascular Medicine and Associate Professor of Medicine
Sunday, March 30

Dr. Mohler presented results of a trial that may herald a new class of medications to prevent heart attack and stroke. Researchers at Penn and several other sites around the world studied the safety and efficacy of the drug darapladib (manufactured by GlaxoSmithKline) on Lp-PLA, an enzyme associated with inflammatory activity and increased risk for heart attack and stroke.

The drug was tested among patients already taking a cholesterol-lowering statin drug. After 12 weeks on a daily regimen of 160 mg of darapladib, blood tests revealed a decrease in two important circulating biomarkers, suggesting a possible reduction in systemic inflammatory burden.

While the drug doesn't necessarily act to shrink plaque, Mohler says the research suggests that darapladib may reduce plaque inflammation and therefore lower rates of clot formation and heart attacks among patients with coronary heart disease.

These findings will be published in an upcoming issue of JACC, the Journal of the American College of Cardiology.

Under-Referral of Women for Atrial Fibrillation Ablation: Can This Be Explained by Gender Differences in Outcome?

Andrea M. Russo, MD, Electrophysiology Laboratory Director and Clinical Associate Professor of Medicine
Sunday, March 30

Dr. Russo and her colleagues from the division of cardiovascular medicine at Penn presented research on disparities in treatment of women suffering atrial fibrillation, one of the most common abnormal heart rhythms.

Although women represent more than half of patients with this serious rhythm problem, they are less likely to be referred for atrial fibrillation ablation - a therapy that uses radiofrequency energy to cauterize the heart tissue around each pulmonary vein to keep abnormal electrical signals from reaching the rest of the heart and triggering the faulty rhythm - than men.

Russo studied 1,165 women and men who underwent ablation at Penn and found that both groups had similar arrhythmia control at 24 months after the procedure (84 percent of women and 89 percent of men), suggesting that more women should be referred for ablation therapy.

Women Face Higher Risk for Decline in Left Ventricular Ejection Fraction Following Orthotopic Liver Transplant

James N. Kirkpatrick, MD, Assistant Professor of Medicine
10 a.m., Tuesday, April 1

Chronic liver disease patients often have low systemic vascular resistance that causes low blood pressure before liver transplant, but after receiving a new liver, they may suffer post-operative heart problems that leave the left ventricle unable to pump out an adequate amount of blood. This situation puts patients at a greater risk of organ failure and death.

Dr. Kirkpatrick and his colleagues studied 80 patients who received an orthotopic liver transplant - the procedure in which the patient's native liver is removed and replaced with a donor organ in the same spot - to determine who would be more likely to suffer post-transplant complications of the left ventricle.

Researchers found that female patients were more likely to exhibit a left ventricular ejection fraction depression following transplant, with 36.7 percent of women suffering the complication, compared to 16 percent of men.

Kirkpatrick believes that careful pre-operative ventricular assessment may help identify patients who could benefit from careful monitoring of blood pressure, heart rate and volume status, and, possibly, serial echocardiograms. Some of these patients may benefit from aggressive treatment with medications like ACE-inhibitors and beta blockers. The Penn researchers plan to test newer echocardiographic techniques before and after transplant to refine ways to identify these patients.

TRITON TIMI 38 Stent Analysis Favors Prasugrel

2008-03-30T04:26:00.000-07:00

Prasugrel has been shown to block platelet activity in patients with acute coronary syndromes (ACS) more effectively than clopidogrel, and to cut by more than half the risk of thrombosis, or blood clotting, inside the coronary stent. Now a new analysis of data from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38) reveals that the investigational drug maintains its edge over clopidogrel regardless of the type of stent, the amount of time since the stenting procedure, or the way stent thrombosis is defined.

The results of the TRITON-TIMI 38 analysis are being reported in a Late-Breaking Clinical Trials session at the SCAI Annual Scientific Sessions in Partnership with ACC i2 Summit (SCAI-ACCi2) in Chicago. SCAI-ACCi2 is a scientific meeting for practicing cardiovascular interventionalists sponsored by the Society for Cardiovascular Angiography and Interventions (SCAI) in partnership with the American College of Cardiology (ACC). The study will be simultaneously published online in The Lancet.

For the main TRITON-TIMI 38 study, researchers recruited 13,608 patients with ACS who needed stenting from 707 medical centers in 30 countries. Patients were randomly assigned to anti-platelet therapy consisting of either a 300-mg loading dose of clopidogrel before the procedure, followed by a maintenance dose of 75 mg daily for one year, or to a loading dose of 60 mg of prasugrel, followed by 10 mg daily for one year. Both medications prevent unwanted blood clotting by inhibiting the ability of platelets to clump together.

Stephen D. Wiviott, MD, Brigham and Women's Hospital, Boston, led the new stent analysis. Of the 12,844 patients who ultimately were treated with at least one coronary stent, 6,461 patients received only bare-metal stents (BMS), and 5,743 patients received only drug-eluting stents (DES). Overall, prasugrel reduced both early stent thrombosis -- within 30 days of stenting -- when compared with clopidogrel (0.64 percent vs. 1.56 percent, hazard ratio 0.41, p<0.001) -- and late stent thrombosis -- more than 30 days after stenting (0.49 percent vs. 0.82 percent, hazard ratio 0.60, p=0.035). For bare-metal stents, the respective rates of stent thrombosis with prasugrel and clopidogrel were 1.3 percent vs. 2.4 percent, hazard ratio 0.52, p=0.009, and for drug-eluting stents, 0.8 percent vs. 2.3 percent, hazard ratio 0.36, p<0.001. Prasugrel's advantage remained highly statistically significant across a broad array of patient and procedural characteristics.

Dr. Wiviott will present the results of the "Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel" (TRITON-TIMI 38) stent substudy on Saturday, March 29 at 9:00 a.m. CDT in the Grand Ballroom, S100. The study will be simultaneously published online in The Lancet.

TAXUS(R) Express(TM) Stent Shows Similarly Low Re-intervention Rates In Diabetic Patients Compared To Non Diabetics In ARRIVE 1 And 2 Registries

2008-03-30T04:25:00.000-07:00

Boston Scientific Corporation (NYSE: BSX) announced results from an analysis of 4,772 patients from its TAXUS ARRIVE 1 and 2 registries, designed to assess the performance of the TAXUS(R) Express2(TM) Paclitaxel-Eluting Coronary Stent System in real-world practice. The one-year pooled ARRIVE data confirmed the known higher mortality rate for diabetics versus non-diabetics with cardiovascular disease(1), but showed that the TAXUS Stent had similarly low rates of stent-related cardiac death, myocardial infarction (MI), stent thrombosis, and major cardiac events (MCE) across those two patient subsets. The study also showed similar rates of target vessel re-intervention (TVR) and TAXUS-related TVR in indicated patients(2) per the European Union (EU) label, whether or not they had diabetes. Analysis of the data was presented by D. Lynn Morris, M.D., at the SCAI Annual Scientific Sessions in Partnership with the ACC/i2 Summit in Chicago.

The pooled analysis included one-year data on 1,530 medication-requiring diabetic patients and 3,242 non-diabetic patients from the ARRIVE registry program. Due to significant disparity in baseline characteristics between diabetic and non-diabetic patients, propensity score analysis was used to allow for adjustment of baseline differences (other than the presence of diabetes) between the two groups.

The results showed diabetic patients had the well-known higher overall adjusted one-year mortality rate than patients without diabetes (3.7% vs. 2.3%, respectively, p=0.016), with the difference being driven by the cardiac death rate (2.3% vs. 1.2%, p=0.014), and reflecting the more advanced cardiac disease associated with diabetes. However, this difference was not related to the TAXUS Stent as the TAXUS Stent-related cardiac death rates at one-year were comparable in diabetics and non-diabetics, respectively (1.0% vs. 0.7%, p=0.29) in this patient population(2). Additionally, TAXUS Stent-related MCE rates (cardiac death, MI, and re-intervention) at one year were comparable (5.7% vs. 5.6%, p=0.80), as was the incidence of TAXUS Stent-related MI (1.6% vs. 1.2%, p=0.26), in both groups. Stent thrombosis at one year was low and showed no significant difference between diabetics and non-diabetics under Protocol definition (1.5% vs. 1.3%, p=0.59) or ARC Definite/Probable (1.7% vs. 1.2%, p=0.29). Unadjusted one-year rates of TAXUS Stent-related cardiac death, TAXUS Stent-related MCE, TAXUS Stent-related MI, and protocol-defined stent thrombosis showed no differences between the two populations (p-values of 0.30, 0.74, 0.31, and 0.65, respectively), suggesting that the safety profile is comparable for the two groups despite increased underlying risk in patients with diabetes.

Additionally, the ARRIVE analysis confirmed that the TAXUS Stent maintained comparable re-intervention rates in the diabetic and non-diabetic patient populations in ARRIVE 1 and 2. Rates of one-year TVR, whether adjusted or unadjusted, were similar between the patient groups (6.1% vs. 6.0%, p=0.80, adjusted). TAXUS Stent-related re-intervention of a target vessel (equivalent to target lesion revascularization, or TLR) was also similar between the patient groups (4.3% vs. 4.5%, p=0.70), despite the known higher risk for re-intervention in diabetic patients.

"The ARRIVE diabetic subset data demonstrated that the TAXUS Stent mitigated the adverse effect of diabetes as a risk factor for restenosis and repeat procedures in the patients studied," said Dr. Morris of the Albert Einstein Medical Center in Philadelphia, PA. "While the diabetic patients had more cardiac risk factors and co-morbidities than non-diabetics, the TAXUS- related cardiac death, MI and stent thrombosis in the ARRIVE 1 and 2 registries were similar in both groups, even without adjustment for risk factors."

"Our extensive ARRIVE registries provide valuable insights into diabetic patients who are often at higher risk for mortality and repeat stenting procedures," said Paul LaViolette, Chief Operating Officer at Boston Scientific. "The ARRIVE data demonstrated that the TAXUS Stent neutralized diabetes as a risk factor for clinical restenosis in the patients studied."

The growing diabetic subset accounts for more than one-quarter of all coronary interventional procedures in the United States. Diabetes is generally associated with an increased risk of cardiovascular events and patients with diabetes are more likely than non-diabetic patients to require repeat procedures due to a higher incidence of restenosis following angioplasty and stenting.

The safety and effectiveness of the TAXUS Express Stent has not been established in patients with diabetes in the United States.

Boston Scientific is a worldwide developer, manufacturer and marketer of medical devices whose products are used in a broad range of interventional medical specialties. For more information, please visit: http://www.bostonscientific.com.

Prasugrel, Cuts Risk Of Stent-Related Clots By More Than Half Versus Clopidogrel

2008-03-30T04:23:00.001-07:00

The investigational antiplatelet drug prasugrel plus aspirin produced a marked and highly statistically significant reduction in the risk of coronary stent thrombosis (ST) - a major concern for physicians and patients with potentially fatal consequences - in patients who received a stent as compared to standard therapy with clopidogrel (Plavix(R)) plus aspirin (1.13 percent vs. 2.35 percent, p<0.0001), according to a stent analysis from the head-to-head TRITON-TIMI 38 trial.

The findings were presented today by Dr. Stephen Wiviott, an assistant professor of medicine at Harvard Medical School and investigator with the Thrombolysis in Myocardial Infarction (TIMI) Study Group, at the Society for Cardiovascular Angiography and Interventions Scientific Sessions with the American College of Cardiology's Innovation in Intervention: i2 Summit, in Chicago. In addition, the manuscript was simultaneously published online by the British medical journal, The Lancet.

In the TRITON-TIMI 38 trial, whose overall results were previously published, 12,844 of the 13,608 enrolled patients received at least one intracoronary stent. Of those patients, 6,461 received a bare metal stent (BMS), 5,743 patients received a drug-eluting stent (DES), and 640 patients received both BMS and DES at the time of enrollment. Stent thrombosis was a pre-defined secondary endpoint in the trial.

Prasugrel reduced the relative risk of coronary stent thrombosis (a new clot at the implanted stent site) over clopidogrel by 52 percent (1.13 percent vs. 2.35 percent, p<0.0001). In patients who received drug-eluting stents (DES), treatment with prasugrel reduced relative risk by 64 percent over clopidogrel (0.84 percent vs. 2.31 percent, p<0.0001), and by 48 percent in patients who received bare metal stents (BMS) (1.27 percent vs. 2.41 percent, p=0.0009).

In the analysis, prasugrel was consistent in reducing stent thrombosis, compared to clopidogrel, whether assessment occurred early or late (<30 days and greater than or equal to 30 days, out to 450 days, the median duration of therapy), regardless of the type of stent used (bare metal or drug-eluting), and regardless of which academic research consortium (ARC) definition of stent thrombosis was used - definite/confirmed stent thrombosis, definite/confirmed plus probable stent thrombosis, and definite/confirmed plus probable plus possible stent thrombosis. Definite/probable stent thrombosis was reduced by 59 percent in prasugrel-treated patients within 30 days of stent placement (0.64 percent vs. 1.56 percent, p<0.0001), and by 40 percent after 30 days (out to 450 days, 0.49 percent vs. 0.82 percent, p=0.03).

"Stent thrombosis is very serious, given the high risk of mortality. In TRITON, among 210 patients with definite or probable stent thrombosis, 186 (89 percent) either died or experienced an MI as a result of the event," said Francis Plat, M.D., vice president, clinical development, Daiichi Sankyo Company, Limited. "We were excited by the results of this study and the possibility that prasugrel may someday provide an alternative treatment for ACS patients undergoing PCI and receiving coronary stents."

A 19 percent reduction in risk was observed with prasugrel compared with clopidogrel among all patients receiving a stent (9.7 percent vs. 11.9 percent, p=0.0001) in TRITON's primary endpoint of cardiovascular death, non- fatal heart attack, or non-fatal stroke. A 20 percent relative reduction favoring prasugrel was observed in the primary endpoint in patients who received only a bare metal stent (10.0 percent vs. 12.2 percent, p=0.003), and in patients who received only a drug-eluting stent, results showed an 18 percent relative reduction in the primary endpoint favoring prasugrel (9.0 percent vs. 11.1 percent, p=0.019). Fatal stent thrombosis occurred in 18 (0.28 percent) patients treated with prasugrel and 29 (0.46 percent) patients treated with clopidogrel (p=0.10). Of note, of the 210 patients with stent thrombosis, 89 percent either died or had a myocardial infarction associated with the event.

The rate of major bleeding was higher in all patients receiving a stent treated with prasugrel vs. clopidogrel (2.4 percent vs. 1.9 percent, p=0.06). Major bleeding in both DES and BMS prasugrel-treated groups when compared to clopidogrel-treated patients was 3 percent vs. 2 percent (p=0.34 DES) and 2 percent vs. 2 percent (p=0.09 BMS).

In addition to a reduction in the primary endpoint (CV death, non-fatal heart attack, or non-fatal stroke), a significantly lower rate of the composite endpoint of cardiovascular death, heart attack or urgent target vessel revascularization (UTVR) was observed with prasugrel vs. clopidogrel for both bare metal stents (10 percent vs. 12 percent, p=0.009) and for drug- eluting stents (9 percent vs. 11 percent, p=0.004). A significant reduction was also seen in heart attack alone (8 percent vs. 10 percent, p=0.003, BMS and 7 percent vs. 9 percent, p=.006, DES). In DES-implanted patients, regardless of those receiving only sirolimus-eluting or paclitaxel-eluting stents, there was a similar magnitude of event reduction with prasugrel compared to clopidogrel.

For the entire cohort, sub-acute stent thrombosis (24 hours to 30 days) was 0.36 percent in prasugrel-treated patients vs. 1.19 percent in clopidogrel-treated patients (p<0.0001). DES-implanted patients had lower rates of stent thrombosis compared to BMS-implanted patients, and prasugrel was shown to significantly reduce stent thrombosis in DES-implanted patients within the first three days compared to clopidogrel (0.14 percent vs. 0.63 percent, p=0.003) as well as for thromboses that occurred >30 days following the DES implantation (0.42 percent vs. 0.91 percent, p=0.04).

"The reduction in risk seen in patients in this analysis treated with prasugrel over patients treated with clopidogrel is encouraging for high-risk patients with acute coronary syndrome being managed with PCI," said J. Anthony Ware, M.D., Lilly vice president for cardiovascular/acute care.

Vytorin : Not Better Than Cheaper Generic

2008-03-24T16:50:00.000-07:00

The tough times for the cholesterol drugs Vytorin and Zetia may be just beginning.

Full results of a controversial artery-imaging study are due to be presented March 30 at the annual meeting of the American College of Cardiology (ACC), following an unusual 18-month delay in releasing the negative results of the study by drug makers Schering-Plough (nyse: SGP - news - people ) and Merck (nyse: MRK - news - people ). The resulting controversy drew a congressional investigation and caused prescriptions for both drugs to slump 17%.

Shares of Schering and Merck plunged as investors fretted over the threat to a $5.2 billion cholesterol franchise. Zetia is a unique drug for lowering cholesterol; Vytorin combines it in one pill with the generic drug Zocor.

The problem: The delayed study couldn't prove that Vytorin prevents artery disease that leads to heart attacks and strokes any better than Zocor does, although it costs four times as much. A trial actually measuring whether the Vytorin combo prevents heart attacks better than Zocor won't be out until 2011. In the meantime, the lack of clear data could leave the companies in a long, slow battle to hold on to their sales.

They argue the controversy is "media-driven," and Wall Street analysts have expressed hopes that a scientific discussion of data will convince doctors, quiet doubters and stabilize sales of Zetia and Vytorin. But critics will be on hand, including Harlan Krumholz of Yale University, who will be among the top cardiologists discussing the data at the ACC meeting.

Cardiologists are torn about what to think of the imaging study, called ENHANCE. Prediman K. Shah, at Cedars Sinai Medical Center, says the results are "inconclusive." But he cautions, "It's not an unimportant study. It certainly raises questions, but doesn't answer them."

If it turns out that Zetia doesn't prevent heart attacks in the 2011 study, Merck and Schering are conducting, "we have some explaining to do," Shah says.

William Boden, a top cardiologist at the University of Buffalo, still uses the Zetia in rare cases and expects the big trial due in 2011 may vindicate it. But he warns his patients, "We don't really know if putting you on this additional drug will do anything more than make your numbers look better." He says the companies have "gotten a long-overdue pass on marketing a drug where there was no outcomes data."

Zetia, approved in 2002, works completely differently from drugs like Lipitor, Zocor and Crestor. The other medicines, called statins, work in the liver to lower blood levels of LDL, the "bad cholesterol." They also seem to have other benefits. Zetia works by preventing the absorption of cholesterol in food. Adding it to the other pills gives them an added LDL-lowering wallop with few side effects.

But some prominent doctors have questioned whether they can be sure that Zetia confers the same benefit as statins. Now, the ENHANCE study has given doubters ammunition.
Mounting Evidence

The first real convincing trial came in 1984, a test of the cholesterol-lowering drug Questran. It took seven years to prove a benefit from lowering LDL 12%. Sales of cholesterol drugs remained pretty low. Lopid, a cholesterol drug from Warner-Lambert, generated only $200 million in 1988. Merck introduced the first statin, Mevacor, in mid-1987; it generated $260 million in its first full year on the market.

"People regarded cholesterol as a major risk factor," says Boden. "But we didn't have very good treatments to lower it."

It was giant studies of the statins that finally convinced many doctors that lowering cholesterol saved lives. Mevacor and other statins were developed from genetic insights gleaned from patients with familial hypercholesterolemia. In 1994 and 1995, studies of Merck's Zocor, a Mevacor replacement, and Bristol-Myers Squibb's (nyse: BMY - news - people ) new Pravachol showed a striking 30% reduction in the risk of death for patients with established heart disease.

In 1998, cholesterol drugs were reportedly a $5 billion market. By 2000, that had tripled, according to drug data company IMS Health (nyse: RX - news - people ), and by 2002 they were the best-selling drug class in the world. The top dog was Pfizer's (nyse: PFE - news - people ) Lipitor. It was approved in 1996, getting a fast review because of its unprecedented ability to lower cholesterol in patients with the FH disorder that causes cholesterol levels of 300 or more. Within two years, Pfizer already had presented data showing that Lipitor prevented heart attacks and strokes.

But big studies to prove a statin reduces heart attacks and deaths are expensive and can take half a decade. So drug companies also pursued the approach of using ultrasound to measure the thickness of the wall of the carotid artery in the neck. Mevacor, Pravachol and Novartis' (nyse: NVS - news - people ) Lescol all have such ultrasound data in their product labels. A 2005 analysis in Current Controlled Trials in Cardiovascular Medicine concluded these imaging studies predicted how well the drugs would prevent heart attacks, strokes and deaths.
"No Valid Evidence"

When Zetia was approved in October 2002, cardiologists were starting to think that the lower they could get cholesterol with statins, the better. The refrain in studies, in company press releases and at medical meetings was that lower cholesterol is better. Some cardiologists argued that LDL levels should be brought down to levels seen most often in rural China. But many doctors were statin-shy because patients didn't like the muscle achiness and liver testsrequired with Lipitor, Zocor, and Pravachol.

Zetia seemed to represent a solution. Added to a low dose of a statin, Zetia lowers LDL as much as the top dose, with fewer side effects. Vytorin, approved in 2004, provided such a combo in a single pill, allowing patients to get it for one insurance co-payment. Sales ramped up fast. Zetia had annual sales of $900 million in 2004; Vytorin hit the same mark in 2005.

But that year, Rodney Hayward, a clinical researcher at the University of Michigan's School of Public Health, wrote that cardiologists may have gone too far in assuming lower is actually better. Patients at high risk of heart attacks do better on high doses of statins, he wrote in a 2005 issue of Annals of Internal Medicine, but it hasn't been proved that how low their LDL goes predicts their risk of heart attacks or strokes.

He also warned, "There is no valid clinical evidence to suggest that using treatments other than statins to pursue proposed LDL cholesterol goals is safe or effective."

Pfizer conducted 12 big studies to prove Lipitor's benefit, and AstraZeneca (nyse: AZN - news - people ) started three imaging trials and three trials measuring hard outcomes like heart attack and stroke. Merck and Schering started only one imaging study and three outcomes trials. A second imaging trial, with Steven Nissen of the Cleveland Clinic, was planned but never begun.

The most important study, due in 2011, is a 12,500-person trial to show whether adding Zetia to Zocor predicts heart attacks, strokes and heart procedures. The study was announced two years after Zetia was approved and started one year after that.
The Problem With ENHANCE

ENHANCE, involving 720 patients, began immediately in June 2002 and was modeled on an imaging study that had worked for Pfizer, called ASAP, conducted by John Kastelein of the University of the Netherlands. The patients in ASAP had FH, the genetic cholesterol disease. LDL, the bad cholesterol, was cut 50% on Lipitor, compared with 41% on Zocor. But while artery thickness increased by 0.036 millimeters on Zocor, it actually decreased by 0.031 millimeters on Lipitor.

ENHANCE was supposed to repeat that success, this time comparing Zocor and Vytorin. But it didn't. After delaying the release of the results for more than 18 months, the companies finally revealed data showing no statistically significant benefit in using the more expensive Vytorin. One explanation is that the patients in ENHANCE had been better treated and had less atherosclerosis, making it harder to prevent plaque buildup. Another is that lowering cholesterol with Zetia in addition to Zocor didn't provide a benefit in terms of slowing atherosclerosis.

"The full data will hopefully put in full perspective that there weren't any harmful effects at all," says A. Michael Davidson, executive medical director at Radiant Research. "This was a population that was so well treated that there wasn't really any opportunity to see any difference."

He says that FH patients are no longer a good population to use in these studies. He points out that LDL lowering is a main driver of the benefit of these drugs.

The danger to Merck and Schering this week isn't simply that the full data from the study will cause doctors to decide Zetia doesn't work. More doctors may decide they don't have enough data and use other drugs instead while they wait for the big trial the companies are conducting. Zetia and Vytorin will remain blockbusters, almost certainly. But if a significant minority of doctors find the ENHANCE results unconvincing, the drug makers will face strong headwinds, and a fast-growing brand could not only stagnate but also shrink.

This is what was happening to Vioxx, because of safety concerns, before Merck yanked it. And it's what happened with the schizophrenia drug Zyprexa, from Eli Lilly (nyse: LLY - news - people ), as prescriptions in the U.S. dropped because of concerns about weight gain and high blood sugar. And the companies spent a lot of their time defending these franchises when they needed to look for new opportunities for growth.

One person who won't be convinced by ENHANCE: Eric Topol, the noted chief of translational medicine at Scripps Health in La Jolla, Calif. He still wants to see clear data on how Zetia affects heart attacks, strokes and deaths, and doesn't understand why it took so long to embark on a big study to prove it.

Doctors have been "hanging in suspense for years, unnecessarily," Topol says. "It's still conceivable there would be improvement in outcomes. Until we have that data, the jury is out."

Cook Medical Announces First Enrolment In European Arm Of Global Trial Of Unique Device To Treat Aortic Dissection

2008-03-23T09:03:00.000-07:00

German patient is first in Europe to receive the first-of-its-kind Zenith Dissection Endovascular System in the STABLE trial.

Christoph A. Nienaber M.D., Ph.D., site investigator at the University of Rostock in Germany, has just completed the first European case in a global clinical trial designed to evaluate the Cook Zenith® Dissection Endovascular System for the treatment of Type B thoracic aortic dissections. This is the first device designed specifically to treat aortic dissections, the aortic tearing condition that took the life of American actor John Ritter. The technologically advanced device is the first of its kind worldwide and was designed to treat the unique morphology of this under-diagnosed disease, a major cause of mortality worldwide that often can be misdiagnosed as a heart attack based on its symptoms.

Dr. Nienaber, who serves as head of cardiology at the University of Rostock, Rostock, Germany, was assisted during the procedure by colleagues Huseyin Ince, M.D., Ph.D.; Thomas Korber, M.D.; and Stephan Kische, M.D. The global principal investigator for the trial is Joseph Lombardi, M.D., assistant professor at Thomas Jefferson University Hospital in Philadelphia, Penn., USA.

"This is the first real dissection-specific endovascular approach to this condition," Dr. Nienaber said of his experience with the Cook Zenith Dissection Endovascular System. "It stabilises the entire dissection with a 'petticoat' (stent graft and bare stent) without compromising important abdominal side branches."

The first European patient found suitable for inclusion in the STABLE dissection clinical trial was a 71-year-old male diagnosed with a Type B dissection of his thoracic aorta. The patient was treated with the Cook Zenith Dissection Endovascular System, which is comprised of the new Cook Zenith Dissection Stent, used in conjunction with the Cook Zenith TX2® Endovascular Graft. A Zenith TX2 Proximal Tapered Component stent graft sealed the entry tear in the thoracic aortic arch, and a bare Zenith Dissection Endovascular Stent was placed in the region where the aorta's true lumen had collapsed.

"We are proud to announce the enrolment of the fist European patient in the STABLE trial as it marks our continued effort to treat thoracic aortic dissections worldwide," said Phil Nowell, global director of Cook's Aortic Intervention strategic business unit. "We anticipate that the STABLE trial will confirm the success of the Cook Zenith Dissection Endovascular System and highlight the positive outcomes for our patients. We are delighted to have Dr. Nienaber as an investigator in the study as he plays an integral role in Cook's mission to offer patients the least invasive treatment options, ultimately leading to a successful and speedy recovery."

The Cook Zenith Dissection Endovascular System is used in the endovascular treatment of descending thoracic aortic dissection in patients with anatomies appropriate for endovascular repair. The device has unique Z-stents that exert pressure allowing gradual apposition of the dissection septum and re-expansion of the true lumen, while keeping important arteries exposed that supply the spinal cord with blood.

Endovascular aortic repair (EVAR) may potentially offer a solution that will eliminate the need for highly invasive, traumatic open surgery for thoracic aneurysms and dissections. Rather than opening the chest cavity and clamping off the aorta to surgically implant a graft to treat the damaged section of the thoracic aorta, physicians insert a catheter loaded with a self-expanding, fabric covered stent-graft through a surgical opening in the femoral artery. The catheter is guided through the patient's blood vessels under fluoroscopy until the device is positioned across the dissected section of the aorta. The stent-graft then expands upon deployment from the catheter to reopen the original path through the aorta and reduces blood flow into the false pathway in the damaged vessel wall, thereby restoring normal aortic blood flow. The uncovered Zenith Dissection Stent is used to expand the true lumen in the distal thoracic aorta where preservation of the side branch artery blood flow is critical.

The Cook Zenith Dissection Endovascular System is an investigational device not available in the European Union or United States. The Cook Zenith TX2 Endovascular Graft is approved in Europe, Australia and New Zealand for the treatment of thoracic aortic aneurysms and dissections.

Happily Marrieds Have Lower Blood Pressure Than Social Singles

2008-03-21T05:41:00.000-07:00

New research shows that happily married adults have lower blood pressure than singles with supportive social networks, suggesting marriage may literally be a matter of the heart.

Brigham Young University professor Julianne Holt-Lunstad found that men and women in happy marriages scored four points lower on 24-hour blood pressure than single adults. Having a network of supportive friends did not translate into improved blood pressure for singles or unhappily marrieds, which surprised Holt-Lunstad and her two student collaborators.

"There seem to be some unique health benefits from marriage," said Holt-Lunstad, whose findings will be published March 20 in the Annals of Behavioral Medicine. "It's not just being married that benefits health - what's really the most protective of health is having a happy marriage."

The study also found, unsurprisingly, that unhappily married adults have higher blood pressure than both happily married and single adults.

Holt-Lunstad, a psychologist who studies relationships and health, arranged for 204 married and 99 single adults to wear portable blood pressure monitors, mostly concealed by their clothes, for 24 hours.

The monitors recorded blood pressure at random intervals throughout the day even while participants slept. Each participant's blood pressure level was recorded about 72 times.

"We wanted to capture participants' blood pressure doing whatever they normally do in everyday life," Holt-Lunstad said. "Getting one or two readings in a clinic is not really representative of the fluctuations that occur throughout the day."

All participants completed a roster of friends in their social network and answered questions about the quality of those relationships. Married participants also completed questionnaires on the quality of the relationship with their spouses.

With the monitors recording blood pressure both day and night, the researchers could see that blood pressure for married adults especially those happily married dipped more during sleep than happens with singles.

"Research has shown that people whose blood pressure remains high throughout the night are at much greater risk of cardiovascular problems than people whose blood pressure dips," Holt-Lunstad said.

Holt-Lunstad said that spouses can promote healthy habits, such as encouraging each other to see a doctor and to eat healthy. The marriage relationship is also a source of emotional support in good and bad times. Sharing good news, for example, generates positive emotions, which in turn boosts the body's functioning.

The study was funded by the Anthony Marchionne Foundation, which supports research on the well-being of the never-married. Funding also came from BYU's Family Studies Center.

A next step in the research for Holt-Lunstad is to study couples participating in marriage counseling to see if improvement in the marriage translates into improved health.

The two co-authors on the study, Wendy Birmingham and Brandon Jones, worked on the project as undergraduate students at BYU. Jones is now in medical school at George Washington University, while Birmingham is now pursuing a Ph.D. in social psychology with an emphasis in behavioral medicine at the University of Utah.

The study is titled "Is There Something Unique about Marriage? The Relative Impact of Marital Status, Relationship Quality, and Network Social Support on Ambulatory Blood Pressure and Mental Health."

Brigham Young University
C-327 ASB
Provo, UT 84602
United States
http://www.byu.edu

Medtronic Introduces Improvement To Minimally Invasive Treatment Of Aortic Aneurysms In Europe

2008-03-13T04:07:00.000-07:00

Continuing its record of innovation in endovascular therapies for aortic aneurysms, Medtronic, Inc. (NYSE: MDT), today announced the European market launch of the Talent™ Abdominal Stent Graft on the new Xcelerant® Hydro Delivery System, which features a hydrophilic coating designed to aid navigation of the device through tight and tortuous arteries by reducing friction with the artery wall.

"The Xcelerant Hydro Delivery System is a significant innovation that will make endovascular repair (EVAR) using the Talent Stent Graft a treatment option for more patients with abdominal aortic aneurysms," said Dr. Dierk Scheinert, MD, PhD, of Park-Hospital and University of Leipzig - Heartcenter in Germany, and the leader of the first team worldwide to implant the device using the new delivery system. "It will simplify the procedure for endovascular interventionalists in treating patients whose iliac arteries are difficult to navigate when they are small and tortuous." The iliac arteries connect the femoral arteries, the entry point for stent grafts, to the aorta, the site of aortic aneurysms.

The Xcelerant Hydro Delivery System represents the seventh generation of innovation for the Talent Abdominal Stent Graft, which was introduced in Europe in April 1998. In bench testing, the Xcelerant Hydro Delivery System was shown to generate a 99 percent reduction in friction compared to the previous delivery system, which does not have the hydrophilic coating. Hydrophilic means "affinity for water"; because water is a major component of blood, the hydrophilic coating is designed to ease the delivery system's passage through the artery.

The Xcelerant Hydro Delivery System features a uniquely integrated sheath that contributes to the system's low profile characteristics, which are intended to enable excellent tracking and access through small vessels.

"Experience remains the foundation of our innovations in endovascular therapy, and the Xcelerant Hydro Delivery System represents our latest innovative contribution to this exciting field," said Katie Szyman, vice president and general manager of the Endovascular Innovations business at Medtronic. "Combined with the Talent Stent Graft, Medtronic now offers endovascular physicians in Europe an even stronger option for their EVAR procedures."

Medtronic has been an innovator and leader in the endovascular stent graft industry for more than a decade, as evidenced by more implants than any other company. Its long history includes more than 130,000 patients treated with aortic stent grafts dating back to 1995. Medtronic currently offers the broadest portfolio of endovascular stent grafts in the industry. These include the AneuRx AAAdvantage Abdominal Stent Graft System in the United States, and the Talent Abdominal, Talent Thoracic and Valiant Thoracic Stent Graft Systems outside the United States.

Present in an estimated one million people in Europe, an abdominal aortic aneurysm (AAA) is a dangerous bulge or weakening of the body's main artery that can rupture with fatal consequences if left untreated. If detected before rupturing, AAAs with diameters of more than twice the size of the normal infrarenal aorta are typically treated with either open surgical repair or endovascular repair. In contrast to open surgical repair, EVAR involves a minimally invasive procedure in which a tube-like sleeve called a stent graft is threaded through the femoral artery in a compressed state on a delivery system and expanded inside the aorta at the site of the aneurysm. Once in place, the sleeve creates a new path for blood flow, reducing pressure on the aneurysm. The delivery system is then removed.

EVAR has been shown to be an effective therapy for AAA, with fewer postoperative complications and shorter recovery times than open surgical repair. In a landmark study conducted in the United Kingdom and published in The Lancet (Sept. 4, 2004), the 30-day mortality rate for EVAR patients was 1.7 percent compared to 4.7 percent for patients who underwent open repair - a nearly threefold difference. Similarly, results from a U.S. study published recently in The New England Journal of Medicine (Jan. 31, 2008) indicate that perioperative mortality was significantly lower after EVAR than after open repair (1.2 percent vs. 4.8 percent - a fourfold difference).

Clinical Trial Shows Ubiquinol Has Significant Effect On Patients With Congestive Heart Failure

2008-03-13T04:03:00.000-07:00

Patients suffering from advanced congestive heart failure exhibited significantly improved heart function after supplementing with ubiquinol, according to a recent clinical trial. Ubiquinol, only available in supplement form since late 2006, is the active antioxidant form of Coenzyme Q10 (CoQ10). CoQ10, a vitamin-like substance found in every cell in the body, plays a vital role in cellular energy production and protects cells from free radical damage.

In the first clinical trial evaluating ubiquinol effects on late-stage congestive heart failure, cardiologist Peter Langsjoen found that critically ill patients who supplemented with ubiquinol for just three months experienced a 24 to 50 percent increase in their hearts' ability to pump blood. In some cases, patients' plasma levels of CoQ10, which are key to overall heart health, more than tripled. At the start of the study, each of the patients evaluated had a life expectancy of less than six months. However, all demonstrated significantly improved heart function by the trial's end, and survived past initial expectations.

"The effects of ubiquinol on late-stage heart failure patients resulted in striking improvements beyond anything I've seen in 25 years of cardiology practice," said Dr. Langsjoen, who conducted the research in Tyler, Texas. "It is my strong feeling that this ubiquinol product is a major breakthrough."

Scientists at Kaneka Corporation, the world's largest manufacturer of CoQ10, developed the method to produce ubiquinol, commercially available as KanekaQH™, for supplemental use. Because the reduced ubiquinol reverts back to CoQ10 when exposed to air and light, the process of stabilizing the nutrient outside of the body took more than a decade to test and perfect before it was launched a little more than a year ago.

"Over the last several years, our team of scientists have documented that KanekaQH can be several times more absorbable than CoQ10, but to see that higher bioavailability translate into such staggering improvements in these patients' lives is particularly gratifying," said Dr. Robert Barry of Kaneka Nutrients, L.P., who recently released a book entitled The Power of KanekaQH™ (Ubiquinol): The Key to Energy, Vitality and a Healthy Heart in which he documents some of the most intriguing research to date on CoQ10 and ubiquinol in regards to aging and heart health.

The oxidized form of CoQ10, ubiquinone, was first used as a dietary supplement for cardiac patients in Japan 40 years ago. It has since gained popularity worldwide for the many health and condition-specific benefits identified in the thousands of studies conducted since its discovery in 1957.

Two forms of CoQ10: Ubiquinone and Ubiquinol

Both ubiquinone and ubiquinol are essential to generating cellular energy and sustaining life; however, the reduced form, ubiquinol, is responsible for the powerful antioxidant benefits associated with CoQ10. More than 90 percent of the CoQ10 found in a healthy person's plasma is in its reduced ubiquinol form.

For the past 40 years, only ubiquinone was available as a supplement. KanekaQH™, the world's only supplemental ubiquinol, has only been available for the past year. The ingredient, manufactured exclusively by Kaneka, is currently available in more than 30 consumer supplements and is the subject of a number of new trials expected to begin in 2008.

"Cardiovascular patients, those fighting age-related diseases and even healthy people over the age of 40 have a critical need to optimize plasma CoQ10 levels within their bodies," explained Dr. Barry. "Because it's so much better absorbed by the body, KanekaQH™ can raise CoQ10 levels more effectively and, as we're seeing from Dr. Langsjoen's study, can have tremendous health impact on those suffering from debilitating diseases."

An abstract of Dr. Langsjoen's supplemental ubiquinol study is available at http://www.kanekaqh.com/clinicaltrials. Full results of the study are expected to be published in a major scientific journal in 2008.

More information on supplemental ubiquinol is available at http://www.kanekaqh.com.

For more information on the numerous clinical research conducted on CoQ10 over the past 50 years, visit http://www.kanekaq10.com/clinicaltrials

FDA Approval For SIMCOR(R) (Niaspan(R) / Simvastatin), A Novel Combination Medicine For Comprehensive Cholesterol Management

2008-02-16T08:08:00.000-08:00

Abbott received U.S. Food and Drug Administration (FDA) approval for SIMCOR(R), the first fixed-dose combination of two widely prescribed cholesterol therapies, Niaspan(R) (Abbott's proprietary niacin extended-release) and simvastatin. SIMCOR is approved for use along with diet to lower levels of elevated total cholesterol, LDL "bad" cholesterol and triglycerides, and to raise HDL "good" cholesterol in patients with complex lipid disease when treatment with simvastatin or Niaspan monotherapies are not considered adequate.

"Managing cholesterol encompasses many factors, not just lowering LDL. There is a clear need for medicines that both raise good and comprehensively lower the bad components of cholesterol," said Christie Ballantyne, M.D., the Methodist DeBakey Heart and Vascular Center, Houston, and lead SIMCOR investigator. "SIMCOR represents an important new option to help patients reach healthy lipid levels."

An estimated 80 million Americans have high levels of the bad LDL cholesterol, and more than 44 million have low levels of the good HDL cholesterol, which the body uses to remove bad cholesterol from the bloodstream. Studies have shown that along with diet, SIMCOR can help patients with lipid disorders reach their treatment goals by addressing more than just bad cholesterol, targeting multiple lipids with one pill.

The FDA's approval was based on SIMCOR safety and efficacy trial data from more than 640 patients with mixed dyslipidemia and type II hyperlipidemia. In the SEACOAST clinical trial, patients receiving SIMCOR 1000/20mg achieved significant cholesterol improvements over and above what simvastatin 20mg alone provided. Patients treated with SIMCOR 1000/20mg had additional lipid improvements beyond simvastatin 20-mg treated baseline, with additional LDL reductions of 12 percent and an additional 21 percent HDL increase compared to a 7 percent decrease in LDL and an 8 percent increase in HDL with simvastatin 20mg alone. Furthermore, SIMCOR reduced triglycerides by an additional 27 percent compared to 15 percent with simvastatin 20mg alone.

SIMCOR was generally well tolerated by patients in clinical studies. Six percent of patients discontinued therapy due to flushing, the most commonly reported side effect of SIMCOR and niacin-based therapies. Flushing can be minimized by taking aspirin or an NSAID 30 minutes prior to taking the medication at bedtime. Flushing may subside over several weeks of consistent SIMCOR use.

"With SIMCOR, doctors now have a new option for helping patients reach their LDL and HDL cholesterol treatment goals with a combination of two proven therapies," said Eugene Sun, M.D., vice president of Global Clinical Development for Abbott. "Abbott is committed to bringing forward new cholesterol therapies, and SIMCOR represents a new treatment option for patients in Abbott's rapidly expanding portfolio of cholesterol treatments for lipid disorders."

The American Heart Association, National Cholesterol Education Program (NCEP) and American College of Cardiology recommend more aggressive treatment of HDL to reduce cardiovascular risk. Cholesterol and other lipids can build up in the bloodstream forming plaque and restricting blood flow, which can lead to heart disease. According to NCEP guidelines, a reduction in LDL of 1 percent is associated with a 1 percent reduction in heart disease risk. Additionally, raising HDL by 1 point is associated with a 2 percent heart disease risk reduction.

Abbott is committed to the continued research of its products and has sponsored the National Heart Lung and Blood Institute's AIM-HIGH outcomes study. The study is designed to evaluate the effects of niacin extended- release and simvastatin in reducing cardiovascular events in patients with existing heart disease. AIM-HIGH began enrolling patients in 2005 with final results expected to be reported in 2011.

SIMCOR Indications

SIMCOR is the combination of two cholesterol-lowering medications: niacin extended-release (Niaspan(R)) and simvastatin. SIMCOR is used along with diet to lower levels of total cholesterol, LDL "bad" cholesterol and triglycerides, and to increase HDL "good" cholesterol. SIMCOR is used when treatment with simvastatin monotherapy or niacin extended-release monotherapy is considered inadequate, and when diet and other non-drug measures alone have not been successful. Patients should stay on a diet low in saturated fat and cholesterol while taking this medicine. No additional benefit of SIMCOR on heart disease over and above that shown for niacin alone and simvastatin alone has been demonstrated.

Important Safety Information About SIMCOR

SIMCOR should not be used by people with liver problems, stomach ulcers, or serious bleeding problems; in women who are pregnant, may become pregnant, or nursing; and in people allergic to any product ingredient. Patients should contact their health care provider if symptoms of unexplained muscle pain, tenderness, or weakness occur, as this may be a sign of a serious but rare muscle disorder, from which rare cases of death have occurred. Health care provider should be informed about any other medications, vitamins, or nutritional supplements people are taking to avoid possible serious drug interactions. SIMCOR should not be substituted for equivalent doses of immediate-release niacin. Liver damage has been reported when substituting sustained-release niacin products with immediate-release niacin at equivalent doses. Always check with a health care provider before changing medication. SIMCOR should be used with caution by patients who consume large amounts of alcohol. Health care providers may do simple blood tests before and during treatment with SIMCOR to check for liver problems.

SIMCOR may cause an increase in blood sugar levels. Patients with diabetes should report any changes in blood sugar levels to their health care provider. Women of childbearing age should use an effective method of birth control to prevent pregnancy while using SIMCOR. Flushing (warmth, redness, itching, and/or tingling of the skin) is the most common side effect and may become less frequent over time. Additional symptoms may include rapid or pronounced heartbeat, shortness of breath, sweating, chills, dizziness, fainting, and/or swelling. Flushing may vary in severity and is more likely to occur when starting therapy or during dose increases. By taking SIMCOR at bedtime, flushing will most likely occur during sleep. If awakened by flushing, patients should take their time getting up, especially if feeling dizzy, faint, or taking blood pressure medications. Other common side effects may include headache, itching, nausea, back pain, and diarrhea.

About Niaspan

Available since 1997, Niaspan is the only FDA-approved, once-daily extended-release prescription formulation of niacin for treating abnormal cholesterol levels.

Niaspan Indications

Niaspan is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate, to reduce elevated total cholesterol, LDL- C, Apo B, and triglyceride levels, and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia. In patients with a history of myocardial infarction and hypercholesterolemia, niacin is indicated to reduce the risk of recurrent non-fatal myocardial infarction. In patients with coronary artery disease and hypercholesterolemia, niacin, in combination with a bile acid binding resin, is indicated to slow progression or promote regression of atherosclerotic disease.

Important Safety Information About Niaspan

Niaspan is contraindicated in patients with allergies to any of its ingredients, active peptic ulcer disease, significant or unexplained persistent liver dysfunction, or arterial bleeding. Niaspan should not be substituted for equivalent doses of immediate-release niacin. Niaspan should be prescribed with caution in patients who consume substantial amounts of alcohol and/or have a past history of liver disease. Liver function tests should be performed on all patients during therapy with Niaspan. Use of Niaspan with other lipid-altering medications called statins may increase the risk of rhabdomyolysis, a rare condition that causes muscles to breakdown. The most common side effect with Niaspan is flushing of the skin. Patients with diabetes should carefully monitor their blood sugar and report changes to their doctor. Other commonly reported side effects include indigestion, headache, pain, abdominal pain, nausea, itching, diarrhea, runny nose, vomiting and rash.

Important Safety Information About Simvastatin

Simvastatin is a prescription tablet and isn't right for everyone, including women who are nursing or pregnant or who may become pregnant, and anyone with liver problems. Unexplained muscle pain or weakness could be a sign of rhabdomyolysis, a rare but serious side effect and should be reported to a doctor right away. Simvastatin may interact with certain foods or other medicines including lipid-lowering medications called fibrates or niacin, increasing the risk of getting this serious side effect. Patients should tell their doctor about any other medications they are taking. The most common side effects are headache, abdominal pain, and constipation.