Further information: Percutaneous Coronary Intervention for Acute Myocardial Infarction (see p1021) from Cardiovascular Medicine, 3rd Edn*

The same group of investigators conducted two large, phase 3, randomized clinical trials that compared cangrelor, a rapid-acting, reversible adenosine diphosphate (ADP) receptor antagonist with clopidogrel, both P2Y12 antagonists. In one trial, “Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PCI),” [1] the drugs were administered to patients before percutaneous coronary intervention (PCI), and in a second trial, CHAMPION PLATFORM [2], the drugs were administered at the beginning and before the end of the procedure.

Trials conducted to find the most efficacious P2Y12 antagonist are important to patients with acute coronary syndromes (ACS) who need PCI. Current guidelines recommend an oral loading dose of 300–600 mg clopidogrel, preferably administered prior to PCI, and followed by 75 mg daily. Clopidogrel requires approximately an hour to achieve platelet inhibition, is irreversible, and platelets are slow to normalize after cessation of the drug, creating difficulty for patients who must undergo CABG instead of PCI. In addition, the effect of clopidogrel may be adversely influenced by genetic polymorphisms that create clopidogrel nonresponders. Conversely, cangrelor is administered intravenously, is rapid, predictable, and reversible.

CHAMPION PCI was a randomized, double-blind, double-dummy, active-control trial that enrolled 8877 patients and compared cangrelor with 600 mg clopidogrel in patients undergoing PCI. The drugs were administered at least 30 min before PCI and continued for at least 2 h or until the conclusion of the procedure. Patients were randomly assigned to either cangrelor or clopidogrel in a 1:1 double-blind, double-dummy design. The primary efficacy end-point of the study was composite of death from any cause, myocardial infarction (MI), or ischemia-driven revascularization at 48 h. The secondary end-points included death or MI at 48 h and at 30 days, or ischemia-driven revascularization.

Results showed that at 48 h, the primary end-point occurred in 7.5% of the cangrelor patients and 7.1% of patients in the clopidogrel group, and thus, cangrelor was not superior to clopidogrel. Results also showed that cangrelor was not significant at 30 days. Assessment of bleeding was based on three criteria: GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries), TIMI (Thrombolysis in Myocardial Infarction) and ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy). Statistics for the rate of major bleeding differed with each tests, and results are reported in the article. For secondary end points, a trend toward cangrelor was shown, but it was not statistically significant (0.6% vs. 0.9%; odds ratio [OR], 0.67; 95% confidence interval [CI], 0.39–1.14; P=0.14). Investigators concluded that cangrelor, administered 30 min before PCI and continued for 2 h, was not superior to an oral loading dose of 600 mg clopidogrel that was administered 30 min before PCI in reducing the composite end-points of death, MI, or ischemia-driven revascularization in 48 h.

The major difference between the two trials was the timing of the administration of the study drugs, cangrelor vs. clopidogrel. In the first trial, both drugs were administered within 30 min prior to the start of PCI. In the second trial, cangrelor was administered at the beginning of PCI, and clopidogrel was administered at the end of the procedure. CHAMPION PLATFORM was a double-blind, placebo-controlled study in which a total of 5362 patients from 18 countries were enrolled from October 2006 to May 2009. Patients were assigned to receive either cangrelor (2654 patients) or placebo (2641 patients) at the time of PCI, followed later by 600 mg clopidogrel. The primary end-point was a composite of death, MI, or ischemia-driven revascularization 48 h post PCI, while the secondary end-points included individual rates of death, MI, new Q-wave MI, ischemia-driven revascularization, abrupt vessel closure, or stroke at 48 h.

Of the 2654 patients who received cangrelor, the primary end point occurred in 185 (7.0%) and of the 2641 patients who received placebo, it occurred in 210 (8.0%). An interim analysis was conducted that concluded the trial would be unlikely to show significant superiority for the primary end point. However, in the cangrelor group, two secondary end points were significantly reduced at 48 h. The rate of stent thrombosis was reduced from 0.6% to 0.2% (OR, 0.31; 95% CI, 0.11–0.85; P=0.02). The rate of death from any cause was reduced from 0.7% to 0.2% (OR 0.33; 95% CI, 0.13–0.83; P=0.02). There was no significant difference in the rate of blood transfusion. The rates of major bleeding did not differ significantly between the two groups according to the TIMI or GUSTO criteria, but according to the criteria for minor bleeding, ACUITY and GUSTO, the rates of minor bleeding were significantly higher in the cangrelor group because of the number of groin hematomas. The investigators concluded that additional study of cangrelor should be considered.

The writers of an accompanying editorial [3] recognized that cangrelor had negative results on the basis of the findings in both CHAMPION PCI and CHAMPION PLATFORM. The question raised in the editorial is whether or not the study design of the CHAMPION trials gave the drug an optimal chance to show better results that might be possible with cangrelor considering its advantages of intravenous administration and rapid onset and offset of action. The authors of the editorial believe that a drug with such assets warrants further study.

[1] Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI (CHAMPION PCI). N Engl J Med 2009;361:2318-2329

[2] Bhatt DL, Lincoff MA, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI (CHAMPION PLATFORM ). N Engl J Med 2009;361:2330-2341

[3] Kastrati AK, Ndrepepa G. Cangrelor—a champion lost in translation? N Engl J Med 2009;361:2382-2384

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Further information: Venous Disease (see p1705) from Cardiovascular Medicine, 3rd Edn*

After myocardial infarction (MI) and stroke, venous thromboembolism (VT) is the third most common cause of vascular death. The anticoagulant warfarin is the current standard treatment for VT, but it requires constant monitoring and is subject to interactions with foods and other drugs. In this study, the investigators for the RE-COVER study [1] conducted a double-blind, double-dummy, randomized trial to compare the use of dabigatran, as an alternate therapy, with warfarin for patients with AVT. From April 2006 through November 2008, 2539 patients were enrolled from 228 clinical centers in 29 countries. The patients were 18 years of age or older and had acute, symptomatic, proximal deep-vein thrombosis of the legs or pulmonary embolism and were patients for whom 6 months of anticoagulant therapy was appropriate. A total of 1274 patients received a dose of 150 mg of dabigatran twice daily, and 1265 patients received warfarin that was dose-adjusted to achieve an international normalized ratio (INR) of 2.0–3.0. The primary outcomes were a recurrent incidence of VT and related deaths at 6-months. The safety end points were bleeding events, acute coronary syndromes (ACS), other adverse events, and results of liver-function tests.

Results showed that the effectiveness and the safety of each drug were similar. For patients given dabigatran, 30 had recurrent thromboembolism, as compared to 27 patients who were in the warfarin arm. The difference in risk was 0.4% (95% confidence interval [CI], -0.8 to 1.5; P<0.001 for the prespecified noninferiority margin). Hazard ratio (HR) for dabigatran patients was 1.10 (95% CI, 0.65–1.84). Twenty dabigatran patients had major bleeding episodes, as compared to 24 warfarin patients (HR with dabigatran, 0.82; 95% CI, 0.45–1.48). For episodes of any bleeding, 205 occurred in dabigatran patients and 277 in warfarin patients (HR with dabigatran, 71; 95% CI, 0.59–0.85). For both groups of patients, the number of deaths, ACS, and abnormal liver-function tests were similar. The data from this study support the use of dabigatran because it has no known interactions with foods, minimal interactions with other drugs, and thus, does not require routine monitoring.

On the Cardiovascular-Medicine.com website, a summary of an article from The New England Journal of Medicine (N Engl J Med 2009;361:1139-1151) was posted on October 27, 2009 on the use of the dabigatran as compared to warfarin for patients with atrial fibrillation (AF) [2], and it may be of interest to the readers of this summary.

[1] Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism (RE-COVER). N Engl J Med 2009;361:2342-52

[2] Dabigatran Versus Warfarin in Patients with Atrial Fibrillation (RE-LY). http://cardiovascular-medicine.com/?p=193

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Further information: Surgical Treatment of Advanced Heart Failure (see p1461) from Cardiovascular Medicine, 3rd Edn*

In this study for advanced heart failure patients who were ineligible for heart transplantation [1], patients were randomized to receive either a pulsatile-flow left ventricular assist device (LVAD) or a continuous-flow LVAD in an effort to determine which device showed more improvement in rate of survival, quality of life, and functional capacity of patients. Conducted at 38 cities in the US, a total of 200 patients were enrolled and randomly assigned to implantation of the continuous-flow LVAD (n=134) or the pulsatile-flow LVAD (n=66) between March 2005 and May 2007. The primary end point was a composite of survival at 2 years, absence of disabling stroke (Rankin score >3), or reoperation to replace the device. Secondary endpoints were actuarial survival, frequency of adverse events, functional status, and the quality of life. In both treatment groups, the baseline characteristics were similar and included a median age of 64 years, a mean LV ejection fraction (EF) of 17%, and approximately 80% of patients received intravenous inotropic agents.

In comparison of the two devices, more patients who received the continuous-flow LVAD achieved the primary composite end point than those with pulsatile-flow LVADs (62 of 134 [46%] vs. 7 of 66 [11%]; P<0.001 hazard ratio, 0.38; 95% confidence interval, 0.27–0.54; P<0.001). Patients who received continuous-flow LVADs had superior actuarial survival rates at 2 years (58% vs. 24%, P=0.008). Quality of life and functional capacity were improved significantly in both groups, while adverse events and device replacements were less frequent in patients with continuous-flow LVADs. Therefore, the investigators in this study believe that the continuous-flow LVAD provides greater long-term benefits to the heart failure patient.

[1] Slaughter MS, Rogers JG, Milano CA, et al. Advanced heart failure treated with continuous-flow left ventricular assist device (HeartMate II). N Engl J Med 2009;361:2241-2251

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Further information: Coronary Risk Factors: An Overview (see p2609) and Management of Cholesterol Disorders (see p2667) from Cardiovascular Medicine, 3rd Edn*

In a presentation of results from a controversial late-breaking clinical trial at the November 2009 American Heart Association Scientific Sessions in Orlando, Florida, Dr. Allen Taylor reported that the ARBITER6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) trial had been terminated early. The full results are summarized in the first paper [1]. The study, which enrolled 363 patients, involved using either ezetimibe or extended-release niacin. The patients had at a high risk for atherosclerotic vascular disease and were already receiving statin therapy. They also had a serum LDL cholesterol level (<100 mg/dL), as well as a low serum HDL level (mean, 42 mg/dL). The patients in this open-label randomized trial of two adjunctive medications were randomly assigned to receive either extended-release niacin (target dose was 2000 mg/day) or ezetimibe (10 mg/day). A surrogate marker for the progression of atherosclerosis (identified as a change in the common-carotid intima-media thickness) was the primary endpoint.

Because the trial was terminated early on the basis of efficacy, data from only 208 patients were available for analysis. However, on the basis of the small sample size and the with the use of a surrogate marker, both of which created controversy, the authors reported the following conclusions. In the niacin group, the mean HDL cholesterol level increased by 18.4%, and the mean LDL cholesterol and triglyceride level were significantly reduced. In the ezetimibe group, LDL cholesterol was reduced by 19.2%. A paradoxical finding regarding ezetimibe indicated that an association between reduction in the patient’s LDL level was accompanied by an increased carotid intima-media thickness. Based on these results the authors concluded that niacin therapy was superior to ezetimibe.

Two editorials were published with the article. Blumenthal and Michos [2] raised four major concerns regarding the trial and expressed the opinion that premature termination of the trial, a small number of patients, and limited follow-up precluded a statement of decisive conclusions. Kastelein and Bots [3] expressed that although the trial had several limitations, the results were likely to be correct. Both editorials pointed to additional studies currently underway that, when concluded, will produce results likely to aid in the evaluation of the use of niacin and statin therapies.

[1] Taylor AJ, Villines TC, Stanek EJ, et al. Extended release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med 2009;361:2113-22

[2] Blumenthal RS, Michos ED. The HALTS trial—halting atherosclerosis or halting too early? N Engl J Med 2009;361:2178-80

[3] Kastelein JJP, Bots ML. Statin therapy with ezetimibe or niacin in high-risk patients. N Engl J Med 2009;361:2180-83

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Further information: Hypertrophic Cardiomyopathy (see p1261) and Muscular Dystrophies Affecting the Heart (see p2567) from Cardiovascular Medicine, 3rd Edn*

Over the past 25 years, infertility has become an increasing problem in the US as couples have delayed marriage and childbearing years. Among other efforts to solve infertility issues, sperm banks have been created to provide a woman a means to achieve pregnancy when her partner is infertile. The Food and Drug Administration (FDA) has in place an inspection process for the purpose of preventing the spread of infectious diseases, but at this time, there is no screening process to identify genetic diseases.

The authors of this paper [1] have provided a brief report of a case report that involved sperm donation and inherited heart diseases, in this case, hypertrophic cardiomyopathy (HCM). Because the donor’s contract with a sperm bank was for a 2-year period, and there were no restrictions as to the number of pregnancies permitted for the donor, 22 children were produced (13 families, including his own) and nine were positive for the HCM mutation. The donor in this report was healthy and had no prior knowledge of his underlying heart disease. The currently used standard testing procedure prior to sperm donation revealed no negative results, and the donor’s disease was not identified until after the disease was identified in his offspring. An important conclusion reached from this study stressed the significant value of a genetic screening requirement for sperm donors.

[1] Maron BJ, Lesser JR, Schiller NB. Implications of hypertrophic cardiomyopathy transmitted by sperm donation. JAMA 2009;302:1681-4

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