July 27, 2015
FDA Approves New LDL-Lowering Agent Alirocumab As widely expected, the US Food and Drug Administration (FDA) today approved alirocumab for lowering LDL-cholesterol (LDL-C). The indication is for patients with heterozygous familial hypercholesterolemia or those at high CV risk who cannot lower their LDL-C with statins. This is the first proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor to be approved in the US. Alirocumab received an approval recommendation from the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) of the FDA in June. The drug, which is delivered via subcutaneous injection, was also recommended for approval by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency. That recommendation is now on its way to the European Commission (EC), who will make the final decision on whether to grant marketing authorization throughout the European Union. The EC approved the drug's PCSK-9 competitor evolocumab earlier this week. Alirocumab was approved before the completion of its CV-outcomes trial. The primary outcome measures for ODYSSEY-Outcomes, which is scheduled to finish by December 2017, include possible first occurrence of CHD death, any non-fatal MI, fatal and nonfatal ischemic stroke, and unstable angina requiring hospitalization. Secondary measures included time to first occurrence of any CHD event, major CHD event, any CV event, and all-cause mortality.
EMA Committee Backs Approval of PCSK9 Inhibitor Alirocumab The European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP) has recommended approval of the proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor alirocumab for individuals who cannot lower their high LDL-cholesterol levels with statins or who cannot tolerate statins. The indications earmark the drug as an adjunct to diet in patients with both heterozygous familial and non-familial hypercholesterolemia or with mixed dyslipidemia. After examining data on more than 3300 patients with alirocumab, the committee also noted that the drug's safety profile is acceptable, with few serious treatment-related adverse events or discontinuations, according to its press release. However, the effect...on cardiovascular morbidity and mortality has not yet been determined. Alirocumab is a monoclonal antibody given through biweekly subcutaneous injections. Today's thumbs-up from the CHMP will now be sent to the European Commission, who will make the final decision on whether this drug should be approved and made available within the European Union (EU).
Prasugrel loading dose does not increase bleeding in patients with STEMI undergoing PCI Patients with STEMI undergoing primary PCI who were pretreated with a loading dose of clopidogrel and then administered a loading dose of prasugrel did not have increased major bleeding events, according to results of the nonrandomized, observational studies COMFORTABLE and SPUM-ACS which published in JACC Interventional Journal. Researchers analyzed data on 2,023 patients with STEMI who were enrolled in the COMFORTABLE or SPUM-ACS studies between September 2009 and October 2012. Of those, 21% received concurrent administration of a clopidogrel and prasugrel loading dose, 22% received a prasugrel loading dose only and the rest received a clopidogrel loading dose only. The primary safety endpoint of the study was Bleeding Academic Research Consortium (BARC) types 3 to 5 bleeding at 30 days. This endpoint occurred in 1.9% of patients who received clopidogrel and a loading dose of prasugrel vs. 3.4% of those who received prasugrel only (adjusted HR = 0.57; 95% CI, 0.25-1.3). The concurrent loading dose and clopidogrel-only loading dose groups also had similar rates of TIMI major bleeding (1.2% vs. 1.8%, respectively), TIMI minor bleeding (0.7% vs. 1.6%), GUSTO severe bleeding (0.5% vs. 1.3%) and GUSTO moderate bleeding (0.5% vs. 0.5%) at 30 days. The researchers also assessed the HAS-BLED bleeding score and found a trend toward a lower bleeding risk among patients who received prasugrel only (P = .076). An analysis adjusted for the primary safety endpoint using the HAS-BLED score yielded consistent results for BARC types 3 to 5 bleeding at 30 days with clopidogrel and prasugrel (adjusted HR = 0.54; 95% CI, 0.23-1.27). At 1 year, the primary safety endpoint occurred in 3.9% of patients who received clopidogrel and a loading dose of prasugrel vs. 4.3% of patients who received prasugrel only (adjusted HR = 0.91; 95% CI, 0.46-1.79). The researchers observed no difference in the composite rate of cardiac mortality, MI or stroke at 30 days between the groups (HR = 0.66; 95% CI, 0.27-1.62).
Ischemic stroke occurs more frequently than hemorrhagic stroke in PCI
Patients undergoing primary PCI are three times more likely to experience ischemic stroke than hemorrhagic stroke, according to recent findings from a study published in European Heart Journal.
The researchers noted that the prevalence of incident ischemic stroke complications among patients undergoing primary PCI increased between 2007 and 2012, while hemorrhagic stroke became less common during this period.
The study included data collected from the British Cardiovascular Intervention Society database on 426,297 patients who underwent primary PCI between 2007 and 2012. Rates of stroke complications were evaluated by the year PCI was performed. Thirty-day mortality and in-hospital MACE (defined as a composite of in-hospital mortality, MI, re-infarction and revascularization) with stroke complications served as outcome measures.
Ischemic stroke or transient ischemic attack occurred in 436 patients, or 0.1% of the cohort. Hemorrhagic stroke complications were reported in 0.03%.
In 2007, ischemic stroke or TIA complications occurred in 0.67 (95% CI, 0.47-0.87) per 1,000 patients vs. 1.14 (95% CI, 0.94-1.34) per 1,000 patients in 2012 (P = .006). Conversely, a nonlinear decrease was reported for hemorrhagic stroke rates, from 0.29 (95% CI, 0.19-0.39) in 2007 to 0.15 (95% CI, 0.05-0.25) per 1,000 patients in 2012 (P = .009).
Results of an analysis adjusting for baseline clinical and procedural demographics indicated an independent association between ischemic stroke and both key outcomes (30-day mortality, OR = 4.92; 95% CI, 3.06-7.92; in-hospital MACE, OR = 3.11; 95% CI, 1.83-5.27).
Hemorrhagic complications yielded a larger increase in risk for 30-day mortality (OR = 13.87; 95% CI, 6.37-30.21) and in-hospital MACE (OR = 13.5; 95% CI, 6.3-28.92).
No increase in transient ischemic attack rates was reported from 2007 to 2012. However, ischemic stroke rates increased from 0.33 (0.23-0.43) in 2007 to 0.75 (0.55-0.95) in 2012.
QTc Interval Prolongations on Two ECGs Aid in SCD Risk Stratification: Rotterdam Study A new analysis of participants in a population-based cohort study suggests at least two ECGs might be useful to stratify individuals at risk for sudden cardiac death (SCD) because of a prolongation in the heart-rate–corrected QT (QTc) interval. While the risk of sudden death was significantly increased among individuals with a prolonged QTc interval, the risk of SCD was not significantly increased among those participants with an inconsistently prolonged QTc interval—defined as a prolongation on one ECG measurement but not in a second follow-up ECG—in a multivariable adjusted model. The conclusions are based on findings from 3484 participants in the Rotterdam Study. Overall, the time between the first and second ECG ranged from 0.7 to 4.4 years, with a median time of 1.8 years between ECGs. Approximately 97% of individuals with a normal QTc interval on the first ECG had a second normal ECG. For the individuals with an abnormal QTc interval on the first assessment, approximately two-thirds had a normal ECG on the second assessment. For those with a prolonged QTc interval at baseline, the risk of sudden cardiac death was significantly increased by more than twofold (hazard ratio [HR] 2.36; 95% CI 1.55–3.60].
Personalized 3D Printing of Heart Model Aids in LAA-Closure Procedure Australian physicians are taking advantage of 3D printing to create an exact replica of the patient's cardiac anatomy when planning left atrial appendage (LAA) closure procedures. The researchers say that 3D printing is useful when closing the LAA with the device, particularly in patients where the anatomy is complex and the interaction between the device and the appendage is difficult to quantify, even using advanced imaging methods. In a letter to the editor in Journal of the American College of Cardiology: Cardiovascular Interventions, the researchers published data on their experience with 3D printing of the LAA in a 74-year-old man with a history of paroxysmal atrial fibrillation who was intolerant to oral anticoagulation. Using data from the CT scan, they printed a 3D model, which is made up of a rubberlike material to simulate atrial mechanical properties of the left atrium and LAA. The 21-mm, 24-mm, and 27-mm Watchman devices were placed into the 3D model, which was then reimaged with CT. With the three devices in the 3D model, they were able to analyze the anatomic deformation for each device. This helped identify the areas and extent of engagement of the device on the flexible atrial model,according to the investigators. Interestingly, based on the TEE, the group reports the 21-mm device would have been selected but the data from CT scan of the 3D model suggested it would have been too small. Data from the 3D model/CT scan showed the 27-mm Watchman device was too large to be selected for the patient.
July 13, 2015
Chronically elevated BP in young adulthood linked to cardiac dysfunction in middle age Cumulative exposure to high BP from young adulthood through middle age was associated with left ventricular systolic and diastolic dysfunction later in life, according to new data from the CARDIA study which published in JACC. Using data from the CARDIA study, researchers evaluated 5,115 healthy black and white individuals. The participants were followed for 25 years, starting in early adulthood, and were evaluated with repeat measures of BP and CV risk factors. In total, 3,498 participants received 25-year evaluations in 2010 to 2011, and 3,474 had LV function measured by 2-D echocardiography and cardiac deformation by speckle-tracking echocardiography. After excluding 995 participants with incomplete BP measurements during follow-up, 2,479 participants were included in the analysis. The mean age at 25-year follow-up was 50 years. In the overall cohort, systolic BP gradually increased after age 35 years; diastolic BP and mean arterial pressure increased from baseline to about age 40 years, then plateaued; and pulse pressure decreased until age 40 years, then increased with age. Compared with white participants, black participants aged older than 25 years had higher levels of systolic BP, diastolic BP and mean arterial pressure. Elevated pulse pressure was more common in men compared with women. Overall, 135 participants had systolic or diastolic dysfunction: 70 had LV systolic dysfunction (LV ejection fraction < 50%) and 69 had diastolic dysfunction (E/e’ ratio > 15). The researchers assessed long-term exposure to BP using cumulative exposure of BP over 25 years, from early adulthood (18 to 30 years) to middle age (43 to 55 years), to represent long-term exposure to BP levels. The results indicated that cumulative exposure to high systolic and diastolic BP levels was associated with a lower longitudinal strain rate (P < .001 for both). The researchers found no correlation between cumulative BP measures and LV ejection fraction.
FDA strengthens warning of link between NSAIDs and MI, stroke The FDA is strengthening a label warning of increased risk for MI or stroke associated with the use of nonsteroidal anti-inflammatory drugs, according to a safety announcement. The labeling for all non-aspirin NSAIDs must be updated to reflect this change, the agency stated. The new warning follows an FDA review of safety data from observational studies, a combined analysis of clinical trials and other information on both prescription and over-the-counter NSAIDs. The new labeling for prescription NSAIDs must reflect the following information, and the FDA will request similar updates to labeling for over-the-counter, non-aspirin NSAIDs, according to the announcement: - MI and stroke risk can occur within weeks of beginning NSAID use, and may increase at higher doses and with longer duration of use. - The risk for MI or stroke appears to be similar for all NSAIDs, but there is not sufficient information to definitively indicate a higher or lower risk with one NSAID over another. - NSAID use can increase MI or stroke risk in patients regardless of whether they already have heart disease or risk factors for heart disease. However, the likelihood of MI or stroke is greatest among those with pre-existing disease or risk factors due to a higher baseline risk. Patients who received initial treatment with NSAIDs post-MI were more likely to die within 1 year than those who were not.
FDA Approves Valsartan/Sacubitril Combination for Heart Failure The US Food and Drug Administration (FDA) has now approved the combination tablet valsartan/sacubitril for the treatment of patients with heart failure. The combination drug, formerly known as LCZ696, is the first approved agent in the angiotensin receptor-neprilysin inhibitor (ARNI) class and exerts its effect within and beyond the renin-angiotensin system. Chemically, the agent consists of the angiotensin-receptor blocker valsartan affixed to the neprilysin inhibitor sacubitril. The US approval is based on results of the Prospective Comparison of ARNI with ACE-I to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. In this study that included more than 8000 chronic-heart-failure patients, treatment with the valsartan/sacubitril combination significantly reduced cardiovascular death or heart-failure hospitalizations — the study's primary end point — by 20% compared with treatment with the ACE inhibitor enalapril alone. All-cause mortality, a secondary end point, was also significantly reduced with the ARNI when compared with enalapril.
July 6, 2015
New AHA/ASA Guideline Recommends Endovascular Stroke Therapy
The American Heart Association/American Stroke Association (AHA/ASA) has updated its guidelines on endovascular treatment for acute ischemic stroke — strongly recommending its use in certain patients — based on the influx of new clinical trial data that have recently become available. The "2015 AHA/ASA Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment" was published online in Stroke Journal.
The guidelines are based on five new clinical trials reported in the past few months: MR CLEAN, ESCAPE, EXTEND-IA, SWIFT-PRIME, and REVASCAT.
According the authors the main bottom-line messages about thrombolysis are:
- None of these new results changes the fact that patients suspected of having had a stroke need to get to a primary stroke center fast so they can be given tissue plasminogen activator (tPA). This is still the first-line therapy for acute ischemic stroke.
- All patients who fit the criteria for endovascular therapy should be considered for this treatment in addition to receiving tPA. If patients are in the eligible group they should be taken to a comprehensive stroke center, where endovascular treatment can be performed.
- Systems of care, such as a hub-and-spoke model, for acute ischemic stroke need to be put in place so that eligible patients can be quickly transported to the comprehensive centers for endovascular treatment.
New Mutation Associated With Severe Obesity
A single-gene mutation that shuts down production of the carboxypeptidase-E (CPE) enzyme, and causes severe obesity and type 2 diabetes, has been identified.
The mutation affects insulin processing and appetite suppression and leads to intellectual disability and reproductive problems, according to the new research published in PLoS One.
The CPE gene encodes CPE, which is involved in the processing of a number of hormones including insulin and a range of neuropeptides, including those that regulate appetite and the reproductive system. CPE deficiency is a recessive condition, so an individual would need to inherit the altered genetic sequence from both parents to be affected. The frequency of the CPE gene defect is currently unknown, but according the authors is currently screening 1500 obese adults to see if there are other cases. Referring to the wider issue of genetic causes of obesity, she pointed out that the number of genetic forms of obesity is unknown because obese people are "simply not usually tested."
Tight glucose control benefits cardiac surgery patients without diabetes
Postoperative morbidity in patients without diabetes undergoing cardiac surgery was reduced with perioperative initiation of intensive insulin therapy, according to recent study findings published in The Journal of Clinical Endocrinology & Metabolism. However, this effect was minimal in patients with diabetes, according to the researchers.
The researchers evaluated 2,383 patients aged 18 to 90 years undergoing cardiac surgery at an academic tertiary hospital between January 2007 and June 2012 to compare the effects of perioperative and postoperative initiation of tight glucose control on adverse events. Participants were randomly assigned to intensive insulin therapy perioperatively (n = 1,134) or postoperatively (n = 1,249). All participants were expected to receive postoperative ICU treatment for at least 2 consecutive days after the surgery. The target glucose range was 4.4 mmol/L to 6.1 mmol/L. Compared with the postoperative group, the perioperative group was significantly less likely to develop organ complications (RR = 0.68; 95% CI, 0.6-0.78).
Patients without diabetes had even more favorable effects of intraoperatively initiated tight glucose control and achieved a risk reduction of 37% for developing any postoperative complication (RR = 0.63; 95% CI, 0.54-0.74).
No difference was found for postoperative complication incidence for all complications except cardiovascular ones among patients with diabetes in both groups.
June 29, 2015
Nebivolol, Hydrochlorothiazide Combo Improves Blood Pressure Better Than Irbesartan in the Elderly The antihypertensive combination of nebivolol and hydrochlorothiazide shows greater reductions in 24-hour systolic blood pressure in elderly patients, compared with irbesartan plus hydrochlorothiazide, researchers reported at the 25th Scientific Meeting of the European Society of Hypertension (ESH) on Hypertension and Cardiovascular Protection. Combined drug therapies are recommended in for the treatment of isolated systolic hypertension (ISH) in helping to control blood pressure in older adults. In an effort to compare the efficacy of two anti-hypertensive combinations, the investigators randomised 124 patients with isolated systolic hypertension to treatment with nebivolol 5 mg plus hydrochlorothiazide 12.5 mg (NH, n = 62) or irbesartan 150 mg and hydrochlorothiazide 12.5 mg (IH, n = 62) once daily for 12 weeks. Patients had a median age of 69 years. Results showed a significantly greater reduction in sitting systolic blood pressure in the NH group compared with the IH group after 12 weeks (25.8 ± 1.6 vs 20.6 ± 1.7mm Hg; P < .03) as well as in heart rate (HR, 7.0 ± 1.0 vs 2.5 ± 1 b/min; P < .01). The NH group meanwhile showed a non-significantly greater decrease in diastolic and pulse blood pressure than the IH group (7.4 ± 1.0 and 18.3 ± 1.5 vs 5.0 ± 0.09 and 15.7 ± 1.7 mm Hg). The degree of reduction in 24-hour, daytime and night-time systolic blood pressure was nearly the same in both groups, but the NH group had a greater heart rate reduction at all time-points compared with the IH group (P < .001). The NH group also showed significantly greater reductions in 24-hour systolic blood pressure variability compared with the IH group when expressed as standard deviation (4.4 ± 2.7 vs 2.2 ± 5.1 mm Hg; P < .02) as well as a coefficient of variation (2.0 ± 2.6 vs 0.3 ± 3.4; P < .01)
Edoxaban approved in the EU for Stroke Prevention in Nonvalvular Atrial Fibrillation and for the Treatment and Prevention of Recurrent DVT and PE The European Commission (EC) has granted Marketing Authorisation for edoxaban, an oral, once-daily selective factor Xa-inhibitor, for the prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (NVAF) with one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack (TIA) as well as for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. The EC approval is based on two phase 3 clinical trials, ENGAGE AF-TIMI 48 and Hokusai-VTE, which compared treatment with once-daily edoxaban to warfarin, a current standard of care for stroke prevention in patients with AF or for the treatment and prevention of VTE. These studies represent the largest single comparative trials of a novel oral anticoagulant in these patient populations, involving 21,105 and 8,292 patients, respectively. In the ENGAGE AF-TIMI 48 study, once-daily edoxaban showed comparable efficacy (stroke or SEs) in comparison to warfarin (1.18% vs. 1.50% per year, edoxaban 60 mg vs. warfarin respectively; hazard ratio [HR], 0.79; 97.5% confidence interval [CI], 0.63 to 0.99, p<0.001) and superior safety, significantly reducing major bleeding (2.75% vs. 3.43% per year, edoxaban 60 mg vs. warfarin respectively; HR, 0.80; 95% CI, 0.71 to 0.91, p<0.001), in a broad range of patients with NVAF. The Hokusai-VTE study demonstrated that edoxaban effectively reduces symptomatic recurrent VTE, including DVT and fatal and non-fatal PE risk across a broad range of patients (3.2% vs. 3.5% of patients, edoxaban 60 mg vs. warfarin respectively; HR, 0.89; 95% CI, 0.70 to 1.13, p<0.001). Edoxaban also showed a significant 19% risk reduction of clinically relevant bleeding in patients with VTE compared to warfarin (8.5% vs. 10.3% of patients, respectively; HR, 0.81; 95% CI, 0.71 to 0.94, p=0.004).
Depression, anxiety increase mortality risk in patients undergoing oral anticoagulation Among outpatients receiving long-term oral anticoagulation, elevated symptoms of depression and anxiety are associated with all-cause mortality, according to research published in the International Journal of Cardiology. Findings from a study that used a four-item Patient Health Questionnaire (PHQ-4) to assess depression and anxiety underscore the need to implement routine screening procedures and to develop and evaluate psychosocial treatment approaches, according to researchers. The patients were part of the observational thrombEVAL study in the German federal state of Rhineland-Palatinate and receiving long-term oral anticoagulation with vitamin K antagonists. At baseline, depression and anxiety symptoms were assessed with the PHQ-4, and the medical history obtained. The researchers looked for all-cause mortality during 24 months; the median follow-up period was 13.3 months. The death rate was 13.8%, with 191 patients dying. Every PHQ-4 point increase was associated with a 10% increase in mortality (HR = 1.1; 95% CI, 1.05-1.16) after adjusting for age, sex, high school graduation, partnership, smoking, obesity, frailty (Barthel index, Charlson comorbidity index) and CHA2DS2-VASc score. Mortality increased by 22% based on the depression component of the questionnaire and by 11% based on the anxiety component. Medical history of mental disorders did not predict excess mortality, nor did the intake of antidepressants, anxiolytics or hypnotics.
June 22, 2015
Dabigatran Reversal Agent Looks Good in Real-World Clinical Testing In the International Society for Thrombosis and Haemostasis (ISTH) 2015 Congress, investigators presented data from their preplanned interim analysis of the first 90 patients enrolled in the RE-VERSE AD trial and published online in NEJM simultaneously. This is a real-world clinical test of idarucizumab which shows that the agent safely and effectively reverses the anticoagulant effect of the direct oral thrombin inhibitor dabigatran in a group of high-risk patients undergoing emergency surgery or suffering from life-threatening bleeding. RE-VERSE AD study is an ongoing, international open-label trial with an expected enrollment of 250 to 300 patients. Study investigators are enrolling two types of dabigatran-treated patients in the clinical trial: patients who experience life-threatening or uncontrolled bleeding (group A) and patients who require an emergency surgery or procedure (group B). So far, 90% of patients have atrial fibrillation and were prescribed dabigatran for stroke/systemic embolism prophylaxis. Investigators have signed up approximately 400 sites worldwide to enroll the planned 300 patients, recognizing how uncommon it is for emergency centers to need to stop dabigatran and treat such patients. In 51 group A patients, the median maximum percentage reversal in anticoagulation measured at 4 hours was 100%. In the 39 group B patients, median maximum percentage reversal in anticoagulation was also 100%. For the group B patients, 36 underwent emergency surgery while one patient avoided surgery after the administration of idarucizumab. Two other patients had complete reversal of anticoagulation but were too unstable for surgery. In the 36 patients who underwent surgery, 33 had normal intraoperative hemostasis as reported by the surgeon onsite, two had mildly abnormal hemostasis, and one patient had moderately abnormal hemostasis.
FDA Approves Third-Generation Sapien Transcatheter Heart Valve
The US Food and Drug Administration has approved the third-generation Sapien transcatheter heart valve for the treatment of patients with aortic stenosis. The Sapien 3, which is approved for patients who are unable to undergo aortic-valve-replacement surgery or are considered high risk for surgery, includes a design change over previous iterations in that it includes a polyethylene terephthalate outer skirt designed to minimize paravalvular leak. In the FDA announcement, the agency notes the rate of moderate or greater aortic insufficiency at 30 days is significantly reduced in patients treated with the Sapien 3 valve compared with those who received the older Sapien device.
The approval of the Sapien 3 valve was based on data from the PARTNER II S3 study, a clinical trial involving 583 patients with aortic-valve stenosis who were at high risk for aortic-valve-replacement surgery or who could not undergo the surgery due to excess risk.
LAA closure confers CV mortality benefit vs. warfarin in AF Findings from a meta-analysis of the PROTECT AF and PREVAIL trials which published in JACC indicated that left atrial appendage closure yielded a survival benefit compared with warfarin in patients with nonvalvular AF. The meta-analysis included 2,406 patients with 5,931 patient-years of follow-up. The mean follow-up duration was 2.69 years. Closure with the Watchman device yielded 0.15 hemorrhagic strokes per 100 patient-years vs. 0.96 per 100 patient-years with warfarin (HR = 0.22; P = .004). CV or unexplained mortality also was significantly lower in the LAA closure group (1.1 vs. 2.3 events per 100 person-years; HR = 0.48; P = .006), as was nonprocedural bleeding (6% vs. 11.3%; HR = 0.51; P = .006). Rates of all-cause mortality or systemic embolism were 1.75 per 100 person-years in the LAA closure group vs. 1.87 per 100 person-years in the warfarin group, which the researchers noted were statistically similar (HR = 1.02; 95% CI, 0.62-1.7). The researchers suggested that the improved mortality rates in the device group may be multifactorial. They noted that novel anticoagulant drugs generally confer a mortality benefit of approximately 10% to 15% compared with warfarin. Patients treated with the device experienced 1.6 ischemic strokes per 100 person-years, whereas warfarin was associated with 0.9 ischemic strokes per 100 person-years (HR = 1.95; P = .05). Analysis for the composite efficacy endpoint indicated that event rates were nonsignificantly lower in the LAA closure group (HR = 0.79; P = .22).
Recurrent major CV events increased in patients with type 2 diabetes
The risk for major cardiovascular events in patients with coronary artery disease was increased when the patients also had type 2 diabetes, according to recent findings of a study published in Diabetes Care Journal. However, type 2 diabetes does not appear to be a major risk factor for subsequent major CV events in all patients with symptomatic vascular disease. In the study were participated 6,841 patients with clinically manifest vascular disease with type 2 diabetes (n = 1,155) and without (n = 5,686) to determine the effect of diabetes on recurrent major CV events. Participants were from the SMART cohort study.
The overall prevalence of type 2 diabetes was 22% in participants with polyvascular disease, 15% in those with peripheral arterial disease (PAD), 13% in participants with cerebrovascular disease and 11% in those with abdominal aortic aneurysm (AAA). The poorest glycemic control was found among participants with type 2 diabetes and PAD, with the highest fasting plasma glucose and HbA1c levels. Researchers found a 21% risk for 5-year recurrent vascular events in participants with polyvascular disease, followed by 20% in AAA, 9% in cerebrovascular disease and PAD, and 7% in CAD. Compared with patients with CAD without diabetes, those with CAD and diabetes had a higher risk for the combined vascular endpoint (HR = 1.67; 95% CI, 1.21-2.21). A higher risk for vascular endpoint also was found in those with cerebrovascular disease and diabetes (HR = 1.36; 95% CI, 0.9-2.07) but not for those with PAD and diabetes (HR = 1.42; 95% CI, 0.79-2.56) or polyvascular disease and diabetes (HR = 1.12; 95% CI, 0.83-1.5; P = 0.28 for interaction type 2 diabetes and location of vascular disease). Participants with diabetes and CAD had increased risk for vascular mortality (HR = 1.55; 95% CI, 1-2.41) as did those with cerebrovascular disease (HR = 1.57; 95% CI, 0.91-2.7). All-cause mortality was increased in participants with PAD and diabetes (HR = 1.64; 95% CI, 1.01-2.68), cerebrovascular disease and diabetes (HR = 1.34; 95% CI, 0.9-1.98), and CAD and diabetes (HR = 1.29; 95% CI, 0.95-1.75).
June 16, 2015
FDA panel recommends approval of evolocumab The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted to recommend approval of evolocumab for reduction of LDL. The committee voted 15-0 that the benefits of evolocumab, a fully human monoclonal antibody PCSK9 inhibitor, outweigh the risks in patients with homozygous familial hypercholesterolemia (HoFH), and 11-4 that its benefits outweigh its risks in at least one patient population other than HoFH. The manufacturer company is seeking indications for the reduction of LDL and changes to other lipid parameters in adults with primary hyperlipidemia or mixed dyslipidemia, including statin-intolerant patients, either alone or in combination with other lipid-lowering therapies; and for the reduction of LDL and other lipid parameters in adults and adolescents aged 12 years or older with homozygous familial hypercholesterolemia, in combination with other lipid-lowering therapies. In the vote regarding patient populations aside from HoFH, most of those who voted yes cited patients with heterozygous familial hypercholesterolemia and those at high or very high risk for CV events who cannot achieve LDL targets despite maximally tolerated statin therapy as populations for whom the drug should be approved.
Chronic Use of Proton Pump Inhibitors Increases Heart Risk
Proton pump inhibitors (PPIs) appear to have a negative effect on vascular function, thereby increasing the risk for myocardial infarction (MI) in the general population, according to a data-mining study published online in PLOS ONE. This association has not yet been demonstrated in a randomized controlled trial.
The investigators reviewed more than 16 million clinical documents on 2.9 million individuals for pharmacovigilance data. They describe their approach as a "novel analytical pipeline" and report that PPIs, but not H2 blockers, appear to be associated with an elevated risk for MI. Specifically, patients with gastroesophageal reflux disease who were exposed to PPIs had a 16% increased risk of MI (95% confidence interval, 1.09 - 1.24). The investigators also documented a twofold (hazard ratio, 2.00; 95% confidence interval, 1.07-fold to 3.78-fold; P = .031) increase in risk for cardiovascular mortality. Although the researchers acknowledge that PPI usage may be serving as a marker for a sicker population, they believe this is unlikely, given the lack of increased risk seen in patients taking H2 blockers.
VTE rates following colorectal surgery remain stable despite increased prophylaxis
Venous thromboembolism incidence has remained low and largely unchanged following colorectal surgery despite an increase in pre- and post-surgical prevention strategies, according to a study published in JAMA Surg. The analysis included data from 16,120 consecutive patients (mean age, 61.4 years; 54.5% women) who underwent colorectal cancer surgery at 52 hospitals in Washington State between 2006 and 2011.
The use of perioperative (31.6% to 86.4%) and in-hospital (59.6% to 91.4%) VTE chemoprophylaxis significantly increased from 2006 to 2011 (P < .001 for both). Overall, 10.6% of patients were discharged following surgery on a chemoprophylaxis regimen. VTE occurred in 2.2% of patients. A higher rate of 90-day VTE occurred among patients undergoing abdominal operations compared with patients undergoing pelvic operations (2.5% vs. 1.8%; P = .001). A similar 90-day VTE rate occurred among patients undergoing surgery for cancer compared with those undergoing surgery for non-malignancies (2.1% vs. 2.3%). Results of adjusted analyses demonstrated an increased risk for 90-day VTE among older patients, patients undergoing nonelective surgery, patients with a history of VTE and patients receiving surgery for inflammatory disease (P ˂ .05 for all). Researchers observed no significant decrease in VTE incidence over time, and VTE rates remained between 1% and 3% annually.
June 08, 2015
Silent AF after acute MI led to worse outcomes at 1 year Patients with silent atrial fibrillation after acute MI experienced a nearly threefold increase in 1-year mortality compared with patients without atrial fibrillation, according to recent findings from a study published in Heart. The aim of the study was to evaluate 1-year prognosis and CV outcomes in a cohort of 737 patients with acute MI who were evaluated for silent AF using continuous ECG monitoring. Clinicians prospectively assessed patients with monitoring during the first 48 hours after hospital admission. They defined silent AF as asymptomatic episodes lasting a minimum of 30 seconds. The silent AF rate was 14.3%, with 4.3% developing symptomatic AF. The median age of patients with silent AF was 79 years vs. 62 years for those without AF (P < .001). Patients with silent AF also had increased rates of hypertension (71% vs. 49%; P < .001), lower smoking rates (23% vs. 37%; P < .001) and higher rates of impaired left ventricular ejection fraction (50% vs. 55%; P < .001). Patients with silent AF and symptomatic AF had similar risk factors, according to the results. However, 10% of patients with silent AF had a history of stroke compared with 25% for those with symptomatic AF. Also, a history of AF was less frequent in the silent group compared with the symptomatic group (10% vs. 38%). One-year outcomes indicated that hospitalization for HF occurred more frequently in the silent AF arm than in the arm without AF, 6.6% vs. 1.3% (P < .001), as did CV-related mortality (5.7% vs. 2%; P < .001). The overall CV mortality rate was 3.2%. Mortality risks were 5.7% for silent AF, 18.8% for symptomatic AF and 2% for no AF (P < .001).
IMPROVE-IT published: Adding ezetimibe to simvastatin lowers LDL, improves CV outcomes Confirming findings previously presented, adding ezetimibe to statin therapy lowered LDL levels and improved CV outcomes in patients with ACS, according to the results of the IMPROVE-IT study published in The New England Journal of Medicine. The researchers conducted a randomized, double blind trial of 18,144 patients hospitalized for ACS in the past 10 days who had LDL 50 mg/dL to 100 mg/dL if receiving lipid-lowering therapy or 50 mg/dL to 125 mg/dL if not receiving lipid-lowering therapy. Results were initially presented at the American Heart Association Scientific Sessions in November 2014. Patients were assigned 40 mg simvastatin plus 10 mg ezetimibe or 40 mg simvastatin plus placebo. The primary endpoint was a composite of CV death, nonfatal MI, unstable angina requiring rehospitalization, coronary revascularization 30 days or more after randomization and nonfatal stroke. Median follow-up was 6 years. According to the results, the median time-weighted average LDL level was 53.7 mg/dL in the simvastatin-ezetimibe group compared with 69.5 mg/dL in the simvastatin monotherapy group (P <l; .001). The event rate for the primary endpoint at 7 years was 32.7% in the simvastatin-ezetimibe group vs. 34.7% in the simvastatin monotherapy group (absolute risk difference, 2 percentage points; HR = 0.936; 95% CI, 0.89-0.99).
Statins underused in patients with diabetes, noncoronary atherosclerosis Statin use is lower and less aggressive among patients with diabetes and noncoronary atherosclerotic vascular disease compared with those with diabetes and CAD, according to recent findings. Researchers conducted a retrospective, observational study of electronic medical records of 3,336 adult patients with diabetes at University of Kansas Hospital and Medical Center. Patients had diabetes and CAD (n = 3,102) or diabetes without CAD but with one or more of the following noncoronary atherosclerotic vascular diseases: peripheral arterial disease, abdominal aortic aneurysm or carotid stenosis (n = 234). Patients with diabetes and noncoronary atherosclerotic vascular disease had higher mean total cholesterol than patients with diabetes and CAD (152 mg/dL vs. 146 mg/dL; P = .019). Patients with diabetes and noncoronary atherosclerotic vascular disease also had higher mean levels of LDL (86 mg/dL vs. 80 mg/dL; P = .04). Although LDL was well controlled overall, the researchers observed a significant difference between the percentage of patients who achieved an LDL of less than 100 mg/dL (70% of patients with diabetes and noncoronary atherosclerotic vascular disease vs. 80% of patients with diabetes and CAD; P < .001). In addition, fewer patients with diabetes and noncoronary atherosclerotic vascular disease attained an LDL of less than 70 mg/dL (34% vs. 44%; P = .002). All patients with diabetes and CAD were using statins compared with 75% of patients with diabetes and noncoronary atherosclerotic vascular disease (P < .001). Powerful statins were less commonly used in the diabetes and noncoronary atherosclerotic vascular disease group, and mean statin doses were lower overall in these patients.
June 01, 2015
Fasting Triglycerides Predict CVD Risk in Statin-Treated Patients n patients with ACS treated with statin therapy, elevated fasting triglyceride levels were significantly associated with an increased risk of cardiovascular events in the short- and long-term follow-up of two major clinical trials, according to the results of a new post hoc analysis of MIRACL and dal-OUTCOMES studies which published in JACC. The present analysis included 15.817 patients with ACS in dal-OUTCOMES randomly assigned to dalcetrapib on top of statin therapy and followed for 31 months. Dalcetrapib had no effect on cardiovascular outcomes, and there was no significant interaction of triglyceride levels and treatment assignment on those outcomes. In MIRACL, 1501 patients were treated with high-dose atorvastatin following an acute coronary event and followed for 16 weeks. Like the long-term dal-OUTCOMES results, the researchers also observed a significantly increased risk of clinical events—defined as all-cause mortality, nonfatal MI, unstable angina, or cardiac arrest requiring resuscitation—among the MIRACL participants with elevated baseline triglyceride levels. In both studies, each 10-mg/dL increment in triglycerides was associated with a similar increase in adjusted relative cardiovascular risk: 1.4% in MIRACL and 1.8% in dal-OUTCOMES. In MIRACL, individuals with the highest baseline levels, those in the highest tertile with triglycerides >195 mg/dL, had a 50% increased risk of the composite primary end point compared with those in the lowest tertile (<135 mg/dL).
Current but not past smoking increases the risk of cardiac events. Smoking is a major risk factor for coronary artery disease (CAD) and adverse cardiac events. Several previous studies have shown that risk of adverse cardiac events in individuals who have quit smoking is similar with those who have never smoked. Why event rates do not remain elevated in individuals who have quit smoking is not clear. In a new study published in European Heart Journal, the authors evaluated the presence, extent, severity of CAD and major adverse cardiac events in patients who never smoked, past, and current smokers. The study included 9456 patients without known CAD from patients enrolled in the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) registry whose smoking status was known. The patients were classified as never smokers (n=5685), past smokers who quit smoking ≥3 months ago (n=2183), and current smokers who currently smoking or quit <3 months ago (n=1588). Compared with never smokers, current and past smokers had greater prevalence of obstructive CAD. The extent of atherosclerotic plaques was also higher in current and past smokers. In a mean follow-up of 2.8+1.9 years, 297 major adverse cardiac events occurred. Compared with never smokers, risk of major adverse cardiac events was higher in current smokers (HR 1.9, 95% CI: 1.4-2.6, p<0.001) whereas it was slightly but not significantly higher in past smokers (HR 1.2, 95% CI: 0.8–1.6, p=0.35). Current smokers had higher rates of all-cause death whereas past smokers did not. The same results were obtained in groups formed by propensity score matching.
Beta-Blockade Risky for Noncardiac Surgery in Low-Risk Patients Perioperative β-blockade was associated with lower 30-day mortality in patients with three to four cardiac risk factors undergoing noncardiac surgery (NCS), but with increased mortality in patients with no cardiac risk factors, according to a retrospective cohort study published online in JAMA Surgery. The goal of this retrospective observational analysis was to examine the effect of perioperative β-blockade on patients undergoing NCS, particularly among those with no cardiovascular risk factors. The study cohort consisted of 326,489 patients undergoing NCS surgery (n = 314,114) or cardiac surgery (n = 12,375) from October 1, 2008, through September 31, 2013, at Veterans Affairs hospitals. The investigators calculated a 4-point cardiac risk score by assigning 1 point each for renal failure, coronary artery disease, diabetes mellitus, and surgery in a major body cavity. Among patients with three or four cardiac risk factors who had NCS, β-blockade at any time between 8 hours before surgery and 24 hours postoperatively significantly lowered the odds ratio for unadjusted 30-day surgical mortality (odds ratio, 0.63; 95% confidence interval, 0.43 - 0.93). However, β-blockade had no effect on patients with one or two cardiac risk factors, and it was associated with significantly increased mortality in patients with no risk factors (odds ratio, 1.19; 95% confidence interval, 1.06 - 1.35). Unadjusted 30-day mortality rates for NCS among patients not receiving β-blockers were 0.5% for patients with no cardiac risk factors, 1.4% for those with one or two risk factors, and 6.7% for those with three or four risk factors. Among patients treated with β-blockers, these rates were 1.0%, 1.7%, and 3.5%, respectively.
May 25, 2015
EMA Committee Recommends Approval of Evolocumab Evolocumab, an investigational human monoclonal antibody for proprotein convertase subtilisin-kexin type 9 (PCSK9), is one step closer to being available in Europe. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approving evolocumab as an adjunct to diet in patients with elevated cholesterol levels who are unable to reach their recommended LDL-cholesterol goal despite taking an optimal dose of statin. Patients deemed statin intolerant or those in whom a statin is contraindicated would also be eligible for treatment with evolocumab. The committee also recommended that the PCSK9 inhibitor, the first in its class to receive a positive opinion from CHMP, be available to treat patients with homozygous familial hypercholesterolemia (FH). The drug, which requires a subcutaneous injection every 2 or 4 weeks depending on the dose, works by blocking the PCSK9 protein. PSCK9 limits the number of LDL receptors available in the liver and reduces the body's ability to remove LDL cholesterol from the bloodstream. EMA stated that the positive review from CHMP is based on the efficacy of evolocumab for lowering LDL-cholesterol levels in nine studies of patients with hypercholesterolemia/mixed dyslipidemia and in two studies of patients with homozygous FH. The PCSK9 inhibitor was considered safe based on data from more than 6000 patients followed for at least 6 months and more than 1100 patients followed for at least 2 years.
Sitagliptin may prevent heart disease in HIV patients The antidiabetic drug sitagliptin demonstrated beneficial systemic and adipose anti-inflammatory effects in HIV-infected adults with impaired glucose tolerance, according to research published in the Journal of Clinical Endocrinology and Metabolism. It is a randomized, placebo-controlled, double blind study of 36 men and women with HIV, aged 18 to 65 years, who had received combination ART (cART) for the past 6 months and whose immune and virologic statuses were stable. None of the patients had type 2 diabetes or were taking antidiabetes medications, nor did they have an AIDS-defining diagnosis, history of heart failure, chronic kidney or liver dysfunction, pancreatitis, or active malignancy, according to the researchers. Participants were given either 100 mg sitagliptin daily or placebo for 8 weeks. Both glucose area under the curve (P = .002) and oral glucose insulin sensitivity index (P = .04) improved more in patients assigned sitagliptin compared with controls. At 8 weeks, those who received sitagliptin experienced a decrease in plasma high-sensitivity C-reactive protein (hsCRP) and CXCL10 (P ≤ .008) — both discriminative markers for inflammation, particularly in cART-treated HIV patients. This was in sharp contrast to the placebo group, which saw an increase in hsCRP. In addition, in terms of immune regulation, adipose tissue monocyte chemoattractant protein-1 mRNA abundance declined more in patients receiving sitagliptin (P = .01), and epidermal growth factor-like module containing mucin-like hormone receptor 1 mRNA abundance tended to decline more in the treatment arm as well, although this was not statistically significant.
Perioperative Dabigatran Protocol Seems Safe, Doable, Effective In a multicenter Canadian study of more than 500 patients who had to have dabigatran therapy interrupted when they underwent major or minor surgery, adherence to a new specific protocol for stopping and resuming dabigatran was high and the incidence of major bleeding was low. The protocol was largely based on the recommendations that were implemented partway through the phase 3 RE-LY study of the novel oral anticoagulant (NOAC) in patients with atrial fibrillation. However, the current protocol specified exactly when to stop dabigatran, "4 hours, 48 hours, or 96 hours [prior to surgery], depending on the patient's kidney function and [the procedure-related] risk of bleeding. A total of 217 patients (40%) underwent surgery that entailed a high bleeding risk, notably implantable cardioverter defibrillator (ICD) or pacemaker insertion, endoscopy/bronchoscopy with combined polyp removal, abdominal surgery, orthopedic surgery, and brain surgery. The other 324 patients (60%) underwent surgeries classed as having a standard bleeding risk, notably endoscopy (without polyp removal), ablation therapy, and cardiac catheterization. For surgeries with a standard risk of bleeding, the study protocol specified that dabigatran should be stopped 24 hours earlier, 2 days earlier, or 4 days earlier, if a patient's calculated creatinine clearance was >50 mL/min, >30 to 50 mL/min, or <30 mL/min, respectively. For procedures with a high risk of bleeding, the protocol specified that dabigatran should be stopped 2 days earlier, 4 days earlier, or 6 days earlier, respectively, for these levels of creatinine clearance. Dabigatran was stopped according to protocol in 89% of cases and resumed according to protocol in 77% of the cases. Preoperative bridging with heparin was not used, but nine patients received postoperative heparin mainly after bowel surgery when they could not take any oral medication. During the 30-day follow-up, 10 patients (1.8%) each had a major bleeding event, which was managed with a transfusion in six of 10 cases. Another 28 patients (5.2%) had 35 minor bleeding events. One patient had a TIA, which was the only thromboembolic complication in this cohort. There were four deaths unrelated to bleeding or thrombosis.
May 18, 2015
Use of Digoxin Raises Mortality in a new Meta-analysis Digoxin use was linked with a 29% increased risk of mortality in more than 235,000 patients with atrial fibrillation (AF) and with a 14% increased risk of death in more than 91,000 patients with congestive heart failure (CHF) during an average follow-up of 2.5 years, according a new metanalysis published online in the European Heart Journal. The metanalysis includes studies of digoxin published since 1993, comprising 326,426 patients: nine studies in patients with AF, seven in patients with CHF, and three in patients with both conditions. In follow-up ranging from 0.83 to 4.7 years, digoxin use was associated with an increased risk of all-cause mortality. Among all patients, digoxin was associated with an increased relative risk for all-cause mortality (HR = 1.21; 95% CI, 1.07-1.38). In the subgroup of 235,047 patients with AF, those assigned digoxin had a 29% increased mortality risk compared with those not receiving glycosides (HR = 1.29; 95% CI, 1.21-1.39), and in the subgroup of 91,379 patients with congestive HF, digoxin was associated with a 14% increased mortality risk (HR = 1.14; 95% CI, 1.06-1.22). The results are consistent with a post hoc analysis of the DIG trial of digoxin in patients with HF, which found that higher serum digoxin levels (≥ 1.2 ng/mL) were significantly associated with mortality.
Long-term depression may increase stroke risk Long-term depressive symptoms are associated with increased risk for stroke, and this association persists even if the depressive symptoms remit, according to new findings of a study published online in J. Am. Heart Assoc. Researchers evaluated 16,178 participants in the Health and Retirement Study (mean age, 65.7 years; 41.5% men; 78.2% white) who were aged at least 50 years, stroke-free and not institutionalized at baseline. Participants were interviewed biennially from 1998 to 2010.It was observed 1,192 strokes during the study period (mean follow-up, 8.88 years). The authors found that, compared with those who had stable low/no depressive systems, participants with stable high depressive symptoms had elevated risk for stroke (adjusted HR = 2.14; 95% CI, 1.69-2.71), as did those with remitted depressive symptoms (adjusted HR = 1.66; 95% CI, 1.22-2.26). The risk for stroke was not significantly different between those with stable high or remitted symptoms. Stable high depressive symptoms were associated with higher stroke risk across all age, sex and race/ethnicity subgroups. Remitted depressive symptoms were associated with higher stroke risk in women (adjusted HR = 1.86; 95% CI, 1.3-2.66) and non-Hispanic whites (adjusted HR = 1.66; 95% CI, 1.18-2.33), and marginally so in Hispanics (adjusted HR = 2.36; 95% CI, 0.98-5.67).
Physical Activity Linked to Survival in ICD Patients ( ALTITUDE Study) Physical activity may improve survival rates in patients with implantable cardioverter-defibrillators (ICDs), suggests a new analysis from the ALTITUDE registry. The findings, which were published in the Journal of the American Heart Association and included almost 100,000 ICD patients, showed 4-year postprocedure survival rates of 91% in the subgroup that was most active at baseline (mean 33 min/day) vs 50% in the least active group (mean 208 min/day; P&ly;0.001). There was also an adjusted hazard ratio of 1.44 for death (95% CI 1.4–1.5) in participants who had lower mean baseline activity, defined as incremental difference of 30 min/day. The current analysis examined data on 98,437 participants at baseline (defined as 30 to 60 days postimplantation) and at a mean follow-up of 2.2 years. Baseline physical activity was 107.5 min/day. Not surprisingly, the least active group was older than the other five subgroups, in which activity levels ranged from 68 to 208 min/day. A larger percentage of the least active group also had a CRT vs the most active group (53.2% vs 30.4%, P<0.0001). One-year follow-up for the most and least active groups showed survival rates of 98.7% and 86.5%, respectively (P<0.001). The between-group difference in survival became more pronounced over time, with rates of 96.5% vs 71.3%, respectively, at 2 years; 93.9% vs 59.3% at 3 years; and 90.5% vs 50.0% at 4 years.
May 11, 2015
Neprilysin inhibition may accelerate the progression of Alzheimer’s disease. According a new study published online in Eur. Heart Journal , the authors draw attention the potential deleterious effect of neprilysin inhibition on Alzheimer disease. Neprilysin which is also known as the neutral endopeptidase is a protease with a broad range of substrates including natriuretic peptides, vasoactive peptides (endothelin-1, bradykinins), neuropeptides (substance P, enkephalins), and the b-amyloid peptide. Due to its central role in the metabolism of cardiovascular peptides and the b-amyloid peptide, neprilysin has become a research subject for both cardiovascular diseases and Alzheimer’s disease. Neprilysin is responsible for the degradation of natriuretic peptides and other cardiovascular peptides. Neprilysin inhibitors prolong and potentiate the beneficial effects of vasoactive/natriuretic peptides. However, neprilysin degrades both vasoconstrictor and vasodilator peptides. In order to eliminate this limitation, neprilysin inhibitors are combined with an ACEI (omapatrilat) or an ARB (LCZ696). The PARADIGM-HF trial showed that LCZ696 is superior to enalapril for the treatment of chronic heart failure with reduced EF. In Alzheimer’s disease and cerebral amyloid angiopathy, b-amyloid peptide accumulates in the brain. Several proteases degrade b-amyloid peptide, of which the most effective is neprilysin. There are multiple lines of evidence showing the crucial role of neprilysin in Alzheimer’s disease. Therefore, numerous researches are being conducted to modulate neprilysin activity in the brain. When neprilysin inhibitors are used for the treatment of cardiovascular diseases, there is a risk of b-amyloid accumulation in the brain and thus accelerating the progression of Alzheimer’s disease and cerebral amyloid angiopathy. Indeed, since intracerebral infusion of the NEPi provokes Alzheimer disease lesions in animal models. The ongoing PARAGON-HF trial assessing the effect of LCZ696 in heart failure with preserved EF will evaluate cognitive function. However, the duration of follow-up of this trial may not be sufficient to show any deleterious effect of LCZ696 on cognitive function. Therefore, it is important to continue follow-up of the patients after the end of the trials in order to confirm the safety of LCZ696. In summary, the authors draw attention to a potential serious side effect of neprilysin inhibition. Indeed, inhibition of an enzyme responsible from the degradation of a broad range of peptides has a potential for serious side effects. As known from other drugs, some side effects are noticeable after a long time.
Spontaneous bleeding after PCI is as dangerous as MI Percutaneous coronary intervention related bleeding is associated with increased mortality according a new study published in JACC. The effect of spontaneous bleeding occurring after hospital discharge on prognosis is unclear. The study enrolled 32,906 patients (14% with acute coronary syndrome) who had PCI between January, 1996 and December, 2008 in Kaiser Permanente Northern California healthcare delivery system. During 7 and 365 days post-discharge, 530 patients (2.14 per 100 person-years) had spontaneous bleeding. Patients who had a bleeding were older, more likely to be women, had a greater comorbidity burden and more likely to receive warfarin compared to patients without bleeding. The use of antiplatelet therapy was similar between the groups. In the same period, 991 patients (4.26 per 100 person-years) had myocardial infarction. Patients who experienced an MI were older, more likely to be women, had a greater comorbidity burden and lower levels of GFR and Hb compared to patients who did not experience an MI. During mean follow-up of 4.4 years, 4048 deaths occurred. At follow-up, 31% of the patients with spontaneous bleeding died, 32% of the patients with spontaneous MI died, 53.8 of the patients with both spontaneous bleeding and MI died, and 11.4% of the patients without spontaneous bleeding and MI died. The crude annual death rate after spontaneous bleeding (9.4%) and after spontaneous MI (7.6%) was higher compared with patients who experienced neither event (2.6%). The multivariate analysis revealed that bleeding was associated with an increased mortality and risk of death increased by 61% in patients who had bleeding compared to the reference group who had neither bleeding nor MI (adjusted HR: 1.61, 95% CI: 1.30-2.00). Risk of death increased by 91% in patients who had MI compared to the reference group who had neither bleeding nor MI (adjusted HR after MI: 1.91, 95% CI: 1.62 to 2.25). The results were similar in subgroups of elective or urgent PCI.
Outpatient treatment safe for select patients with acute PE Favorable short-term outcomes of patients with pulmonary embolisms after hospital discharge suggest these patients can safely receive outpatient treatment, according to a study published in JAMA Int. Med. The analysis included data from the Cardiovascular Research Network Venous Thromboembolism study, a collaboration of four geographically diverse health care delivery systems. Researchers identified 494 patients (median age, 61 years; range, 48-73) who were diagnosed with PE between 2004 and 2010 and who were discharged from hospital EDs with an anticoagulant prescription within 7 days. The cohort was 73.9% white and 49.2% (n = 243) female. Hospital readmission within 30 days and death within 90 days served as the primary endpoints. Researchers observed that 18.6% (n = 92) of patients with PE returned to the hospital within 30 days, and 7.9% (n = 39) of those patients were readmitted. Eleven patients (2.2%) had a primary diagnosis of hemorrhage during a subsequent hospital visit within 30 days. Researchers noted mortality rates were low. No deaths were reported within the first 7 days after discharge, and only two deaths occurred after 90 days. Patient discharge rates significantly increased during the study period. Approximately 11% of patients with PE were discharged in 2010 vs. 5.6% of patients with PE discharged in 2004 (P ˂ .001 for trend). The investigators acknowledged limitations to their study, including the reliance on ICD-9 codes and pharmacy data to identify patients, as well as the lack of appropriate data to calculate a complete PE severity risk classification. The investigators also were unable to identify the specific reasons for patient disposition plans. Still, mortality rates from this analysis are similar to those from previous clinical trials and suggest outpatient care can be implemented safety for select patients with acute PE, according to the researchers.
May 04, 2015
The 61% of TAVR Patients Alive at 3 Years: UK Registry Analysis Three years after transcatheter aortic-valve replacement (TAVR), 61% of individuals with severe symptomatic aortic stenosis who receive the new valve remain alive, according to data from the UK Transcatheter Aortic Valve Implantation (TAVI) Registry which published in the last issue of JACC: Cardiovascular Interventions . At 5 years, 45.5% of the UK patients who underwent TAVR were still alive. Survival to 3 years was largely predicated on patient characteristics, with baseline renal dysfunction, atrial fibrillation, respiratory disease, impaired left ventricular function, and a higher EuroSCORE (>18.5) associated with an increased risk of mortality, report investigators. The data is based on 870 patients who underwent TAVR in the UK between 2007 and 2009. The mean age of patients at the time of implantation was 82 years, and the minimum time from TAVR to data census was 4.1 years (maximum 7.0 years). Patients in the registry received either the Sapien balloon-expandable valve or the self-expanding CoreValve.
AF is associated with increased risk for non-STEMI After a median follow-up of more than 20 years, researchers found an increased risk of non-ST elevation myocardial infarction (non-STEMI) in patients with atrial fibrillation even when adjusting for cardiovascular and other risk factors. However, there was no association between atrial fibrillation and STEMI. These are the results of Atherosclerosis Risk in Communities study which published online in Circulation. Approximately two-thirds of MI’s in the U.S. each year are non-STEMI, according to the researchers. In addition, an estimated 2.7 million to 6.1 million people in the U.S. have atrial fibrillation, which is a risk factor for stroke. However, researchers said it was unclear if the disease was a risk factor for MI. In this community-based population study, researchers examined 15,792 adults who were interviewed and visited a clinic between 1987 and 1989. They followed up with them on several occasions from 1990 to 2013 and excluded patients who did not have quality echocardiograms at baseline and those with coronary heart disease. The final analysis included 14,462 patients. The mean age was 54 years, 56% of patients were women. Of the patients, 31 had atrial fibrillation at baseline and 1,514 had atrial fibrillation during the follow-up period before having MI. During a median follow-up period of 21.6 years, researchers identified 1,374 incident MI events by contacting patients and examining hospital medical records. There were 829 non-STEMI events and 249 STEMI events. The mean time from atrial fibrillation diagnosis to MI was 4.82 years. Researchers found atrial fibrillation was associated with a 63% increased risk of MI. There was a significantly higher rate of MI in women with atrial fibrillation compared with men.
ISAR-TRIPLE: Net clinical outcomes similar for 6-week vs. 6-month triple therapy Six weeks of triple therapy with oral anticoagulation, aspirin and clopidogrel was not superior to a 6-month regimen for the primary outcome of death, MI, definite stent thrombosis, stroke or TIMI major bleeding at 9 months, according to data from the ISAR-TRIPLE trial. published in the Journal of the American College of Cardiology. The randomized, open-label trial included 614 patients who were receiving concomitant oral anticoagulation and aspirin therapy and underwent drug-eluting stent implantation for stable angina or ACS at centers in Denmark and Germany from September 2008 to December 2013. Patients were randomly assigned to a 6-week (n = 307) or 6-month (n = 307) regimen of clopidogrel therapy 75 mg on top of oral anticoagulation and aspirin. Patients were followed up by phone or at the physician’s office after 6 weeks, 6 months and 9 months. The primary endpoint occurred in 9.8% of the 6-week therapy group vs. 8.8% of the 6-month therapy group (HR = 1.14; 95% CI, 0.68-1.91). Researchers reported no significant difference in the secondary combined ischemic endpoint of cardiac death, MI, definite stent thrombosis and ischemic stroke between the two groups (6 weeks, 4%; 6 months, 4.3%; HR = 0.93; 95% CI, 0.43-2.05). Both durations also were associated with similar rates of TIMI major bleeding (6 weeks, 5.3%; 6 months, 4%; HR = 1.35; 95% CI, 0.64-2.84). In a post-hoc landmark analysis, the 6-month therapy group experienced significantly more bleeding events, as defined by Bleeding Academic Research Consortium (BARC) classifications.
April 27, 2015
Bococizumab reduces LDL in patients with hypercholesterolemia Use of the PCSK9 monoclonal antibody bococizumab in patients with hypercholesterolemia was associated with significant reductions in LDL across all doses according the results of a phase 2b, multicenter, double blind, placebo-controlled, dose-ranging trial which published in Am. J. Cardiol. The study population were 351 adults with hypercholesterolemia (baseline fasting LDL, ≥ 80 mg/dL; triglycerides, ≤ 400 mg/dL; no incidence of CV events within past 6 months). Patients were randomly assigned subcutaneous placebo or bococizumab 50 mg, 100 mg or 10 mg every 2 weeks or bococizumab 200 mg or 300 mg every 4 weeks. The dose was reduced if LDL persistently deceased to 25 mg/dL or lower. The primary endpoint was mean difference in LDL from baseline to week 12. Randomized treatment continued for another 12 weeks to assess the safety of bococizumab. 16% of patients assigned bococizumab 100 mg or 150 mg every 2 weeks had their dose reduced during the study. At 12 weeks, mean change in LDL was –35.4 mg/dL in the 50-mg group, –52.3 mg/dL in the 100-mg group and –54.2 mg/dL in the 150-mg group compared with –2.8 mg/dL in the placebo group. A pharmacokinetic/pharmacodynamics (PK/PD) model-predicted and placebo-adjusted mean change in LDL from baseline to 12 weeks ranged from –36.4 mg/dL for the 50-mg every 2 weeks dose to –72.2 mg/dL for the 150-mg every 2 weeks dose. 44% of patients assigned bococizumab 200 mg and 39% assigned 300 mg every 4 weeks had their dose reduced during the study. At 12 weeks, mean change in LDL was –21.3 mg/dL in the 200-mg group and –38.3 mg/dL in the 300-mg group compared with –1.3 mg/dL in the placebo group. Approximately 70% of patients in the 300 mg-group showed LDL reductions after 2 weeks.
EU Approval Recommended for Edoxaban for Stroke, Systemic Embolism in AF Patients The new oral anticoagulant edoxaban (factor Xa inhibitor) has received approval recommendation from the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) for use in the prevention of stroke and systemic embolism in patients with nonvalvular AF, as well as for prevention and treatment of recurrent venous thromboembolism. CHMP is recommending marketing authorization for the medication, which will be available as film-coated tablets in doses of 15, 30, and 60 mg. CHMP reports that soft tissue hemorrhage is the most common treatment-related adverse event, followed by epistaxis and vaginal hemorrhage. The agency also adding that anemia, rash, and abnormal liver-function tests are other common side effects. The full indication notes that it should be used for stroke and systemic embolism in nonvalvular AF patients with congestive heart failure, diabetes, or hypertension who are older than 74 years or who had a transient ischemic attack or stroke previously; and for treatment and prevention in patients with pulmonary embolism (PE) and deep vein thrombosis (DVT). In January of this year, FDA also approved edoxaban to reduce risk of stroke and systemic embolism in patients with nonvalvular AF and to treat DVT and PE. Its approval was based on results from the ENGAGE AF-TIMI 48 trial, which showed that the medication was noninferior to warfarin.
Heart Risk From Amiodarone Plus Hepatitis C Antivirals (EMA) The European Medicines Agancy (EMA) has confirmed a risk of severe bradycardia or heart block when the hepatitis C medicines (sofosbuvir with ledipasvir) or a combination of sofosbuvir and daclatasvir which are used in patients who are also taking the medicine amiodarone. To manage this risk the Agency recommends that amiodarone should only be used in patients taking these hepatitis C medicines if other antiarrhythmics cannot be given. If concomitant use with amiodarone cannot be avoided, patients should be closely monitored. Because amiodarone persists for a long time in the body, monitoring is also needed if patients start such hepatitis C treatments within a few months of stopping amiodarone. The recommendations follow a review of cases of severe bradycardia or heart block in patients taking amiodarone who started treatment with the hepatitis C combinations. It was considered that there was a likely relationship of these events to the medicines. The possible mechanism behind these effects is unknown and further investigation of other cases with sofosbuvir and other hepatitis C medicines is ongoing.
April 20, 2015
FDA approves ivabradine for treatment of HF A drug already available in Europe has been approved by the US Food and Drug Administration for reducing the risk for hospitalization from worsening heart failure. The agent, ivabradine, is indicated for stable patients with heart failure and a heart rate of >70 per minute on maximally tolerated beta-blockers. The approval is based on the international, placebo-controlled SHIFT trial, published in 2010, which randomized >6500 patients in New York Heart Association class II-IV heart failure and left ventricular ejection fraction ≤35%. The trial saw a highly significant 18% drop in risk for cardiovascular death or hospitalization for worsening heart failure over an average of 23 months in patients treated with ivabradine.
FDA Advisory Panel Gives the green light for Cangrelor in PCI The Cardiovascular and Renal Drugs Advisory Committee of the US Food and Drug Administration (FDA) voted 9 to 2, with one member abstaining, that the injectable antiplatelet agent cangrelor should be approved for reducing thrombotic events in PCI. Last year, the committee voted 7 to 2 against recommending cangrelor for PCI because of data problems and they felt that the risk/benefit profile was not sufficiently strong enough. The Medicines Company then underwent further sensitivity analyses and supplied a more simplified application. Earlier this week, FDA reviewers gave a favorable review that the agent now be approved "in patients in whom treatment with an oral P2Y12 platelet inhibitor prior to PCI is not feasible and when glycoprotein IIb/IIIa receptor antagonists are not anticipated to be used." They also noted that PHOENIX was sufficient enough as a stand-alone trial to warrant approval of cangrelor.
Micra Miniature Leadless Pacemaker Gains CE Mark Approval European physicians will now have access to a second leadless pacemaker, as Medtronic announced today the Micra transcatheter pacing system (TPS) has gained CE Mark approval in Europe. The Micra, which is not much larger than a one Euro coin (or nickel) at one-tenth the size of a traditional pacemaker, was approved in Europe as part of the Micra TPS Global Clinical Trial, a larger ongoing study. For the CE Mark approval, European regulators approved the device on safety and efficacy outcomes of 60 patients who had the tiny pacemaker implanted and were followed for 3 months. The device, which is delivered via catheter and eliminates the traditional surgical "pocket," is not approved in the US, but researchers plan to enroll as many as 780 patients from 50 clinical centers as part of the ongoing global trial.
LDL variability predicts CV events in patients with CAD Visit-to-visit LDL variability was independently predictive of CV events in patients with CAD, according to new data from the TNT trial which published in JACC. Researchers evaluated 9,572 patients with CAD and LDL level less than 130 mg/dL who were randomly assigned atorvastatin at doses of 80 mg/day or 10 mg/day. They evaluated visit-to-visit LDL variability from 3 months after randomization to determine its potential impact on CV outcomes. LDL variability measurements included standard deviation, average successive variability, coefficient of variation and variation independent of mean. The primary outcome was incidence of any coronary event. Secondary outcomes were any CV event, death, MI and stroke. in the population studied, standard deviation and average successive variability were lower among those assigned atorvastatin 80 mg/day than in those assigned atorvastatin 10 mg/day (standard deviation, 12.03 ± 9.7 vs. 12.52 ± 7.43; P = .005; average successive variability, 12.84 ± 10.48 vs. 13.76 ± 8.69; P < .0001). The authors also found that each 1-unit standard deviation increase in LDL variability by average successive variability increased the risk of any coronary event by 16% on adjusted analysis (HR = 1.16; 95% CI, 1.1-1.23). They also observed increases in the risk for any CV event (HR = 1.11; 95% CI, 1.07-1.15), death (HR = 1.23; 95% CI, 1.14-1.34), MI (HR = 1.1; 95% CI, 1.02-1.19) and stroke (HR = 1.17; 95% CI, 1.04-1.31). These results were independent of treatment effect and achieved LDL levels, and were consistent after adjustment for medication adherence, according to the researchers.
April 14, 2015
Lead-free cardiac pacemaker shows good safety, performance at 1 year (LEADLESS published)
Confirming a previous report, a leadless cardiac pacemaker system demonstrated stable performance and good safety results at 1 year, according to data from the LEADLESS trial which published online in JACC. The researchers assessed 6-month and 1-year follow-up data for 31 of the 33 patients implanted with the leadless pacemaker between December 2012 and April 2013 (mean age, 76 years; 65% men). At implantation, one patient had cardiac tamponade and died due to massive cerebral artery ischemic infarct, and another required an implantable cardioverter defibrillator and underwent successful retrieval of the leadless pacemaker 7 days after implantation.
There were no pacemaker-related adverse events reported between 3 months and 1 year, the researchers wrote.
Mean pacing threshold at a 0.4-ms pulse width was 0.4 V at 6 months and 0.43 V at 1 year, R-wave amplitude was 10.6 mV at 6 months and 10.3 mV at 1 year, and impedance was 625 ohms at 6 months and 627 ohms at 1 year, according to the researchers.
At 1 year, the rate response sector was activated in 61% of patients, all of whom had an adequate rate response, the researchers found.
EMA Committee Warns of Cardiovascular Risk With High-Dose Ibuprofen
The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) is warning of an increased risk of cardiovascular events in patients who take high doses of the anti-inflammatory ibuprofen. The committee, states there is a small increase in the risk of MI and stroke with ibuprofen when taken at doses of 2400 mg/day or higher. The risk, according to the committee, is similar to the risk observed with other nonsteroidal anti-inflammatory drugs (NSAIDs), such as COX-2 inhibitors and diclofenac.
The committee is recommending physicians assess patients' risk factors for cardiovascular conditions before starting them on long-term high-dose ibuprofen. Overall, PRAC says the benefits of high-dose ibuprofen outweigh the small increased risk of cardiovascular events, but physicians should use caution when prescribing and avoid high-dose ibuprofen in select patients. High doses of ibuprofen (2400 mg per day or higher) should be avoided in patients with serious underlying heart or circulatory conditions, such as heart failure, heart disease, and circulatory problems or in those who have previously had a heart attack or stroke," according to PRAC. With 1200 mg of ibuprofen, the most commonly used over-the-counter dose of ibuprofen in the European Union, there is no signal of harm, according to PRAC. The recommendations of the committee also extend to dexibuprofen, which is similar to ibuprofen. A high-dose of dexibuprofen is 1200 mg/day or more.
The recommendations of PRAC will now be sent to the Coordination Group for Mutual Recognition for Decentralized Procedures—Human (CMDh). The CMDh reviews the recommendations of PRAC and will adopt a final position.
Bivalirudin Bests Heparin for Fewer Bleeding Events During PCI (BRIGHT study)
Publication of the multicenter Chinese BRIGHT study has reopened the bivalirudin-heparin debate on treatment for patients undergoing PCI. The randomized trial showed that patients who received bivalirudin after an acute MI had significantly fewer net adverse clinical events (NACE) and bleeding events at 30 days and 1 year than those receiving heparin plus the GP IIb/IIIa inhibitor tirofiban and those receiving heparin alone.
There were no between-group differences in major cardiac events or stroke, in rates of stent thrombosis or acute stent thrombosis, or acquired thrombocytopenia.
The results, are published in the Journal of the American Medical Association.
A total of 2194 adult patients with acute MI were enrolled between August 2012 and June 2013 at 82 centers in China. All were randomly assigned to one of three treatment arms upon arrival in the cath lab for emergency PCI: bivalirudin (n=735; 82.7% men; mean age 57.3 years), heparin (n=729; 81.6% men; mean age 58.1 years), or heparin/tirofiban (n=730; 82.1% men; mean age 58.2 years).
Bivalirudin was given as a bolus of 0.75 mg/kg followed by infusion of 1.75 mg/kg/h during the PCI procedure and for at least 30 minutes but no more than 4 hours afterward. The heparin-only group received a dose of 100 U/kg; the combination group received heparin 60 U/kg and tirofiban 10 µg/kg followed by postprocedure infusions of tirofiban at 0.15 µg/kg/min for 18 to 36 hours.
NACE at 30 days' postprocedure, the primary end point, were reported for 8.8% of the bivalirudin group vs 17% of the heparin/tirofiban group (relative risk [RR] 0.52; 95% CI 0.39–0.69; P<\0.001).NACE also occurred in 13.2% of the heparin-only group (RR 0.67; 95% CI 0.50–0.90; P=0.008).
The 30-day bleeding rate occurred in 4.1% of the patients receiving bivalirudin vs 12.3% of those receiving heparin/tirofiban vs 7.5% of those receiving heparin alone.
One-year follow-up results were similar. At that time, NACE occurred in 12.8% of the bivalirudin group vs 20.5% of the heparin/tirofiban group (P <\0.001) vs 16.5% of the heparin-only group (P=0.05). Bleeding rates at 1 year were 6.3% vs 14.2% and 9.9%, respectively.
April 6, 2015
Dronedarone in Middle Age Linked to More Admissions
Treatment with dronedarone was associated with a higher risk for hospitalization than treatment with amiodarone or other antiarrhythmic drugs, in an observational study involving nongeriatric atrial fibrillation (AF) patients without cardiovascular disease, which published in the last issue of Circulation: Cardiovascular Quality and Outcomes.. In patients age 61 and younger (median age 56) , the risk of AF-related hospitalization was greater with dronedarone than Class Ic (propafenone and flecainide) drugs (hazard ratio 1.59, 95% CI 1.13-2.24), amiodarone (HR 2.63, 95% CI 1.77-3.89) and sotalol (HR 1.72, 95% CI 1.17-2.54). Cardiovascular hospitalization risk also was lower with amiodarone (HR 0.80, 95% CI 0.70-0.92) and sotalol (HR 0.63, 95% CI 0.53-0.75) compared with class Ic drugs.
The study included 8,562 AFpatients between the ages of 49 and 61 without known heart disease identified using health plan claims data. All were prescribed antiarrhythmic drugs (AADs) from the beginning of 2006 to the end of 2010.
The primary outcome was time from first prescription to AF hospitalization, and secondary outcomes were time to cardiovascular and all-cause hospitalization. Just 608 of the 8,562 study participants were treated with dronedarone, compared with 2,984 patients treated with class Ic drugs, 2,065 patients treated with Sotalol, and 2,905 patients treated with amiodarone.
Smoking linked to poor outcomes after revascularization in patients with complex CAD
Cigarette smoking was associated with adverse clinical outcomes, including recurrent MI, stroke and death, in patients with complex CAD undergoing revascularization with CABG or PCI, according to 5-year follow-up data from the SYNTAX trial in a study published online in the Journal of the American College of Cardiology. Researchers analyzed data on smoking status and history collected at baseline, 6 months, 1 year, 3 years and 5 years among participants of the SYNTAX trial (n = 1,793) who underwent CABG or PCI.
At baseline, 1 in 5 patients with complex CAD reported smoking. Of those, 60% stopped smoking after revascularization. Overall, 17.9% of patients had changes in smoking status during the 5-year follow-up.
According to the results, smoking at baseline did not influence death/MI/stroke or major adverse CV and cerebrovascular events at 5-year follow-up. However, when smoking was considered a time-dependent variable, smoking increased the risk for death/MI/stroke (HR = 1.38; 95% CI, 1.02-1.86) and major adverse cardiovascular/cerebrovascular events (HR = 1.28; 95% CI, 1.01-1.61) at follow-up. Baseline smoking status was associated with increased risk for MI, specifically. During follow-up, the effect of smoking as a time-dependent covariate was predominantly on subsequent MI (adjusted HR = 2.08; 95% CI, 1.3-3.32).
During follow-up, 98 patients reported always smoking and 1,374 reported never smoking. Risk for MI and stent thrombosis/graft occlusion was significantly higher among always smokers, but this group did not have increased risk for all-cause revascularization, compared with never smokers.
Additionally, smoking was identified as an independent predictor of death/MI/stroke (HR = 1.8; 95% CI, 1.3-2.5) and major adverse cardiovascular/cerebrovascular events (HR = 1.4; 95% CI, 1.1-1.7). In subgroup analyses, smoking independent predicted poor outcomes in patients who underwent CABG (HR = 1.52; 95% CI, 1.02-2.25) and PCI (HR = 1.26; 95% CI, 0.9-1.75).
SPYRAL HTN program to evaluate renal denervation for uncontrolled hypertension
Medtronic announced with a press release the launch of a clinical trial program that will assess the use of renal denervation in patients with uncontrolled hypertension. The SPYRAL HTN global clinical trial program comprises two prospective, randomized, sham-controlled trials: SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED. The trials will be conducted simultaneously. In both, participants will undergo renal denervation by experienced operators with the Symplicity Spyral catheter and Symplicity G3 radiofrequency generator. SPYRAL HTN-OFF MED will evaluate the impact of renal denervation on BP reduction without the use of antihypertensive medications. SPYRAL HTN-ON MED will assess renal denervation in patients with uncontrolled hypertension despite treatment with three antihypertensive medications; these drugs are not required to be prescribed at maximum tolerated medication dosages, a factor which may have contributed to variability in patient adherence and the large number of medication changes during the SYMPLICITY HTN-3 trial, according to the release.
The trials will include approximately 100 patients with moderate- to high-risk hypertension, enrolled at 20 centers worldwide.
March 23, 2015
CoreValve Bests Surgery at Two-Year Mark Data from a U.S. pivotal trial showed patients who underwent transcatheter aortic valve replacement using CoreValve had a higher two-year survival rate than those who had their valves surgically replaced. The difference in all-cause mortality between the two groups jumped from 4.8 percent at one year to 6.5 percent at the end of the second year. Patients in the TAVR arm also had a lower stroke rate than those in the control group — 10.9 percent versus 16.6 percent. The multicenter clinical trial randomized 747 patients with advanced forms of aortic stenosis to with TAVR or open-heart surgery. The patients had an estimated mortality risk of 15 percent or greater at 30 days and preexisting surgical risk factors such as frailty and disability. The FDA approved the CoreValve system last year for patients in need of aortic valve replacement who are at high or severe risk for surgery. The device is also available in countries that recognize the CE mark
Next-generation subcutaneous ICD system receives FDA approval, CE Mark Boston Scientific Corporation has received FDA and CE Mark approval of the EMBLEM™ Subcutaneous Implantable Defibrillator (S-ICD) System. The EMBLEM S-ICD System is a treatment option that provides protection for patients at risk of sudden cardiac arrest (SCA), yet leaves the heart and vasculature untouched, minimizing the risk of complications associated with conventional transvenous implantable cardioverter-defibrillators (TV-ICDs). A controlled and limited market release has begun in a small number of European centers with a broad European launch scheduled for May 2015 and subsequent U.S. launch planned for the third quarter of 2015. Unlike traditional ICDs that require placement of at least one lead in or on the heart, the S-ICD System is implanted just under the skin and provides the patient the same protection from cardiac arrest without invading the heart and blood vessels. Leads in the heart may be associated with infrequent but serious complications, including lead displacement, fracture and systemic blood infections, or the need for lead extraction, which may lead to hospital readmission, increased mortality and associated costs. The new generation EMBLEM S-ICD System is 19% thinner and is projected to last 40% longer than the previous S-ICD System. These improvements will further improve patient comfort and cosmetic outcomes while reducing the number of times the device will require replacement. The EMBLEM S-ICD System is also enabled for remote patient management through the LATITUDE™ NXT Patient Management System for increased patient convenience.
Anacetrapib lowers LDL in patients with familial hypercholesterolemia (REALIZE trial) One-year treatment with anacetrapib in patients with heterozygous familial hypercholesterolemia was well tolerated and yielded significant decreases in LDL cholesterol. For the phase 3, multicenter, double-blind, randomized, placebo-controlled REALIZE study, researchers evaluated 306 patients with a genotype-confirmed heterozygous familial hypercholesterolemia. Patients were included if they were on a therapeutic dose of statin, such as simvastatin (Zocor, Merck) 40 mg, atorvastatin 20 mg, rosuvastatin (Crestor, AstraZeneca) 5 mg, pitavastatin (Livalo, Kowa Pharmaceuticals) 4 mg, lovastatin 80 mg, or pravastatin 80 mg or higher, or one or more additional lipid-modifying drugs for 6 or more weeks prior to screening. Patients also were required to have LDL levels ≥ 2.59 mmol/L with no history of CVD, or LDL levels ≥ 1.81 mmol/L with a history of CVD. After a 2-week placebo run-in period, patients were randomly assigned 2:1 to daily anacetrapib (Merck) 100 mg (n=204) or matching placebo (n=102) for 1 year. The patients were seen for a 12-week follow-up after the conclusion of anacetrapib treatment to evaluate patient safety when off treatment. The primary efficacy endpoint was s percentage change from baseline in LDL to 1 year. At 1 year, anacetrapib decreased mean LDL levels from 3.3 mmol/L to 2.1 mmol/L (percentage change, 36%; 95% CI, – 39.5 to – 32.5) compared with an increase in LDL with placebo from 3.4 mmol/L to 3.5 mmol/L (percentage change, 3.7%; 95% CI, – 1.2 to 8.6). The difference in percentage change between anacetrapib and placebo was – 39.7% (95% CI, – 45.7 to – 33.7; P < .0001). Patients in the anacetrapib group experienced a higher number of CV events vs. those in the placebo group (4 [2%] of 203 patients vs. 0 of 102 patients; P = .1544), but the percentage of those with adverse events that prompted discontinuation was comparable (12 (6%) of 203 patients vs. 5 [5%] of 102 patients).
Smoking Worsens Outcomes for Patients Following PCI/CABG Smoking is associated with worse clinical outcomes, especially MI, following coronary revascularization, indicating that there is no "smoker's paradox" when smoking status is accounted for across time, the SYNTAX trial shows. The study was published in the last issue of the Journal of the American College of Cardiology. The SYNTAX trial was a prospective, multicenter, randomized trial that compared PCI with CABG surgery in patients with complex CAD. Complex CAD included left main stem disease, triple-vessel disease, or both. A total of 1793 patients were included in the analysis. Smoking status was ascertained for all patients at baseline and at 6 months and 1, 3, and 5 years. The study end point was the impact of smoking on a composite end point of death, MI or stroke after 5 years of follow-up. Some 20% of the cohort was smoking at baseline, but this dropped to 8.6% at 6 months and was still 8.7% at 1 year. At 5 years, smoking was associated with a 38% increased risk of the composite end point of death, MI, or stroke (hazard ratio [HR] 1.38, 95% CI 1.02–1.86; P=0.035). Smoking was also associated with a 28% increased risk of major adverse cardiac and cerebrovascular (MACCE) events (HR 1.28, 95% CI 1.01–1.61; P =0.041). Patients who always smoked had significantly higher rates of MI and stent thrombosis or graft occlusion as well, although not all-cause revascularization, compared with those who had never smoked.Subgroup analysis also showed that smoking independently increased the risk of poor outcomes by 52% in CABG patients (HR 1.52; 95% CI 1.02–2.25; P =0.038) and by 26% for PCI patients (HR 1.26, 95% CI 0.90–1.75; P=0.177). Baseline smoking status was also associated with poor outcomes.
March 16, 2015
FDA approves left atrial appendage closure device The U.S. Food and Drug Administration (FDA) approved the WATCHMAN Left Atrial Appendage (LAA) Closure Device, a first-of-its kind treatment that gives patients with non-valvular atrial fibrillation (AF) an alternative option to long-term warfarin therapy. Watchman is indicated to reduce the risk of thromboembolism from the left atrial appendage in patients with non-valvular atrial fibrillation who are at increased risk for stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc scores, are deemed by their physicians to be suitable for warfarin; and have an appropriate rationale to seek a non-pharmacologic alternative to warfarin, taking into account the safety and effectiveness of the device compared to warfarin. The PROTECT AF trial concluded that use of the watchman device for LAA ligation is feasible among patients with nonvalvular AF. The trial demonstrated a noninferior rate of cardiovascular death, stroke or systemic embolism, compared with warfarin alone, which was sustained to five years of follow-up. The PREVAIL trial found that percutaneous closure of the LAA is feasible in patients with AF. Compared with the PROTECT AF trial, there was improved procedural implant success with reduced device-related complications.
Apixaban does not increase bleeding in patients with renal insufficiencies Compared with conventional anticoagulants, use of apixaban resulted in a lower bleeding risk in patients with mild or moderate-to-severe renal impairment, according to results of a meta-analysis published online in Am. J. Cardiol. The researchers performed a meta-analysis and systematic review to assess this risk. They included six randomized controlled trials involving 40.145 patients in their meta-analysis. The results showed that apixaban had a statistically significant lower bleeding risk in patients with mild renal impairment compared with conventional anticoagulants (vitamin K antagonist, warfarin, aspirin, placebo) (RR = 0.80; 95% CI, 0.66-0.96, I2 = 13%). The bleeding risk was similar in patients with moderate-to-severe renal insufficiency (RR = 1.01; 95% CI, 0.49-2.10, I2 = 72%). The study did not examine severe renal impairment, which may have led to underestimation of bleeding risk in the moderate-to-severe renal impairment subgroup.
One-Year, Real-World TAVR Data Help Identify Risks, Benefits In a study published in the Journal of the American Medical Association, with 12.182 patients who underwent transcatheter aortic-valve replacement (TAVR) in clinical practice in the US from November 2011 through June 30, 2013, 1 year after the procedure, 23.7% had died, 4.1% had a stroke, and 26% had either died or had a stroke. Furthermore, following TAVR, 59.8% of the patients, who had a median age of 84, went home rather than to a nursing home or extended-care facility. At 1 year, 46.8% of patients who were alive had not been hospitalized again. Being very elderly, on dialysis, with severe lung disease, or a high STS Predicted Risk of Operative Mortality (STS PROM) score was linked with a higher risk of 1-year mortality, and women who underwent TAVR had a higher risk of stroke than men. Most patients (57.4%) had STS PROM scores below 8%; 30.8% had scores between 8% and 15%; and 11.9% had scores above 15%—which indicates low risk of death from surgery, high risk of death from surgery, and inoperable, respectively. The median STS PROM score was 7.1%, which was lower than in PARTNER A and PARTNER B (11.8% and 11.2%, respectively), but similar to that in the CoreValve study (7.3%), the researchers note. Most patients were either 75 to 84 years old (38.2%) or 85 to 94 years old (47%). Only 12.7% were younger than 75 and 2.1% were 95 or older. About half were women. At 30 days after TAVR, 7% of patients had died and 2.5% had had a stroke.
Low Prevalence of Diabetes Found Among Patients With Familial Hypercholesterolemia The prevalence of type 2 diabetes among patients with familial hypercholesterolemia is significantly lower than unaffected relatives, with the prevalence varying by the type of gene mutation, according to a study published in the last issue of JAMA. Statins have been associated with increased risk for diabetes, but the cause for this is not clear. One theory is that statins increase expression of low-density lipoprotein (LDL) receptors and increase cholesterol uptake into cells including the pancreas, which could cause pancreatic dysfunction. Familial hypercholesterolemia causes decreased LDL transport into cells. Researchers have hypothesised, in patients with familial hypercholesterolemia, decreased pancreatic LDL transport would lessen cell death and ultimately lead to lower rates of diabetes. In the study was assessed the prevalence of type 2 diabetes between patients with familial hypercholesterolemia and their unaffected relatives. The study included all individuals (n = 63,320) who underwent DNA testing for familial hypercholesterolemia in the national Dutch screening program between 1994 and 2014. The prevalence of type 2 diabetes was 1.75% in patients with familial hypercholesterolemia (n = 440/25,137) versus 2.93% in unaffected relatives (n = 1,119/38,183), with adjusted figures indicating that patients with familial hypercholesterolemia had a 51% lower odds of having type 2 diabetes. Prevalence varied by the type of gene mutation. The researchers observed an inverse dose-response relationship between the severity of the familial hypercholesterolemia causing mutation and prevalence of type 2 diabetes.
March 09, 2015
Idarucizumab filed with EMA and Health Canada as Antidote for Dabigatran Boehringer has submitted BI 655075 (idarucizumab) for approval of marketing authorization to the European Medicines Agency (EMA) and Health Canada, for use in patients who require rapid reversal of the anticoagulant effect of dabigatran, the active ingredient in Pradaxa. This follows filing with the FDA. The submissions are based on the results from clinical trials of idarucizumab in volunteers, including elderly and renally impaired individuals. Phase I data showed an immediate, complete and sustained reversal of the anticoagulant effect of dabigatran following the administration of idarucizumab and no pro-thrombotic effect. The submissions also include first interim data from the ongoing RE-VERSE ADTM study. RE-VERSE ADTM is an ongoing global Phase III patient study in which Boehringer Ingelheim continues to evaluate idarucizumab in patients treated with Pradaxa who are in need of emergency intervention, or experience an uncontrolled or life-threatening bleeding event.
TAVR improves quality of life in patients at extreme surgical risk Transcatheter aortic valve replacement yielded substantial improvements in disease-specific and health-related quality of life among patients with severe aortic stenosis at extreme surgical risk, according to new data from the CoreValve U.S. Extreme Risk Pivotal Trial which published online in JACC Intrev. Journal. The new analysis characterized health status outcomes after TAVR with a self-expanding prosthesis. Researchers assessed the health status of patients at baseline and at 1, 6 and 12 months after the procedure using the Kansas City Cardiomyopathy Questionnaire (KCCQ), the Short Form-12 and the EuroQol-5D surveys. Death, KCCQ overall summary score less than 45 or decline in KCCQ overall summary score of 10 points at 6 months indicated poor outcome after TAVR. The transfemoral approach was used in 471 patients. Of those, 93% completed the baseline health status survey, the results of which indicated considerable impairment in all health status measures at baseline. The KCCQ overall summary scores increased by 23.9 points at 1 month, 27.4 points at 6 months and 27.4 points at 12 months (P < .001 for all comparisons). Individual KCCQ subscales that measured total symptoms, physical limitations, social limitations and quality of life showed similar results. Short Form-12 physical and mental scores improved by approximately 5 points from baseline to follow-up at 6 and 12 months (P < .001 for all comparisons). Substantial increases in EuroQOL-5D utilities from baseline to follow-up at 6 and 12 months were also reported (P < .003). The proportion of patients with large KCCQ overall summary score improvement was 58% at 1 month and 59% at 12 months. The proportion of patients with an excellent outcome, defined as survival with a large improvement in KCCQ overall summary score, was 52% at 1 month and 41% at 12 months. In contrast, the proportion of patients with a poor outcome was 39% at 6 months; 22% had died and 16% had very poor quality of life. Preprocedural factors independently associated with poor outcome included wheelchair dependency, lower aortic valve gradient, previous CABG, need for home oxygen and Society of Thoracic Surgeons mortality risk greater than 15%.
Anacetrapib on Top of Optimal Therapy Provides Large LDL-Lowering Benefit in FH (REALIZE study) For patients with heterozygous familial hypercholesterolemia (FH) well treated with existing medical therapy, including high-intensity statins and ezetimibe , the addition of anacetrapib for 1 year further reduced LDL-cholesterol levels and other atherogenic lipoproteins, according to the results of REALIZE study which published in Lancet. Among 204 patients who received anacetrapib, LDL-cholesterol levels were reduced from 127 mg/dL at baseline to 81 mg/dL at 1 year. For the 102 patients who received a placebo, LDL-cholesterol levels increased slightly over the 52 weeks. Treatment with anacetrapib also resulted in a significant increase in HDL-cholesterol levels, with baseline levels doubling after 1 year of treatment (up from 54 mg/dL to 108 mg/dL). The investigators say anacetrapib was well tolerated, with no reported differences in serious adverse events, drug-related adverse events, or adverse events leading to drug discontinuation between the anacetrapib- and placebo-treated patients. The researchers did not observe any changes in blood pressure among the anacetrapib-treated patients, an off-target effect that was observed with torcetrapib. This study was not powered for changes in clinical outcomes, but they did observe a numerically higher, although statistically nonsignificant, number of cardiovascular events among the anacetrapib-treated patients. In total, four patients who received anacetrapib had an adjudicated cardiovascular event (stroke, MI, or unstable angina) vs none in the placebo arm, a finding that warrants watching, say the researchers.
Recent AF Guidelines Would Significantly Expand OAC Use An update of the guidelines for the management of patients with atrial fibrillation (AF)—one that saw a shift from the CHADS2 score to the CHA2DS2-VASc score for stroke risk assessment—significantly increases the number of patients eligible for oral anticoagulant therapy, according to the results of a new analysis published in JAMA: Internal Medicine. Using data from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF), the researchers found that the overall proportion of patients recommended for oral anticoagulation increased from 71.8% under the 2011 American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) guidelines to 90.8% with the 2014 AHA/ACC/HRS clinical recommendations. Using the new CHA2DS2-VASc score, researchers say that nearly every AF patient older than 65 years of age and nearly every woman with AF would be eligible for oral anticoagulation. In fact, with the 2014 recommendations guiding the management of AF, 98.5% of patients 65 years of age and older and 97.7% of women would receive a definitive recommendation for oral anticoagulant therapy.
March 02, 2015
Heart failure patients who struggle with daily tasks are hospitalised more often and die earlier Heart failure patients who struggle doing daily tasks are more likely to be hospitalised and die early, according to new research published online in the American Heart Association journal Circulation: Heart Failure. The risk is higher for older women, unmarried people and those with chronic conditions that affect mobility and ability, including obesity, dementia, anemia and diabetes, researchers said. Researchers reviewed questionnaires from 1,128 heart failure patients. Half were female, the average age was about 75, and half were married. Eighteen per cent were obese and most had other medical conditions including high blood pressure (87.4%), anemia (57%), diabetes (36.5%), peripheral vascular disease (26.5%) and cerebrovascular disease (almost 30%). Patients were grouped as having minimal, moderate or severe difficulty with daily activities that included getting dressed, using the bathroom, cleaning the house, climbing stairs and taking medications. Most patients had a hard time with at least one daily activity, but there was a corresponding relationship between how easily one could go about their day and overall mortality.
Subcutaneous-ICD patients may be able to undergo MRI scans at 1.5T safely Subcutaneous implantable cardioverter-defibrillator patients may be safe to be exposed to magnetic resonance imaging (MRI) procedures at 1.5T with a pre-specified scanning and monitoring protocol. The results of a first-of-its-kind study exploring the potential for safely imaging patients with the subcutaneous implantable cardioverter system was reported—ahead-of-print in Europace. According the authors, it is estimated that as many as 75% of active cardiac device recipients will become indicated for MRI. However, the majority of such devices are contraindicated for MRI due to potential hazards such as heating of the electrode that resides in the heart, damage to myocardium, elevation of pacing thresholds, unintended induction of ventricular tachycardia or ventricular fibrillation, pacing inhibition, permanent device malfunction, and distortion of the MRI scan. The authors note that none of the components of the S-ICD system are on or in the heart, hence heating near or around the electrode cannot harm the myocardium. However, they say, heating near the S-ICD’s electrode and can may still cause serious patient discomfort. In this single-centre prospective non-controlled study, 15 patients (12 males, mean age 53 years) were enrolled for MRI testing over a period of 18 months. They underwent a total of 22 randomised examinations, which included cardiac, brain, cervical, lumbar and knee scans. Keller et al comment that there was not a specific requirement for an MRI. The S-ICD is currently not certified for use with an MRI. For the scanning protocol, the S-ICD was programmed off to minimise the risk of inappropriate therapy and patients were monitored throughout the procedure with pulse oximetry and standard ECG to detect any arrhythmia. An external defibrillator was available. The S-ICD was evaluated prior and immediately after the scan to verify proper functioning. Patients were also asked to report immediately any pain, torqueing movement, or heating sensation in the area of pocket or electrode. They were also questioned immediately following the MRI to assess any discomfort around the can or electrode.
Tandem Troponin-BNP Readings Predict CRT Outcomes in Heart Failure Tandem measurements of cardiac troponin T (TnT) and brain-type natriuretic peptide (BNP) provide insight into how well patients scheduled for cardiac resynchronization therapy (CRT) will do at 12 months, suggests a multicenter, prospective study published online in Pacing and Clinical Electrophysiology Journal. Classification of patients into high-, intermediate-, and low-risk categories based on the initial biomarkers significantly predicted mortality and risk of heart-failure hospitalization. The study stratified 267 patients at 32 centers, prior to implantation of biventricular pacemakers with defibrillators (CRT-D), into three risk groups based on whether TnT was detectable and BNP elevated. A detectable TnT meant >0.01 ng/mL, whereas an elevated BNP was defined as >440 pg/mL. Patients were defined as high risk when they had both a detectable TnT and a high BNP; intermediate risk if they had either a detectable TnT or a high BNP and low-risk if they had an undetectable TnT and a low BNP. Most of the cohort consisted of men, their mean LVEF was 25%, and just over half had ischemic cardiomyopathy; their mean QRS interval was 155 ms. Within the first year of follow-up, there were 13 deaths and 25 first hospitalizations for heart-failure events among 19 patients. Patients in both the high and the intermediate categories of biomarker risk had significantly worse survival at 1 year than those categorized in the low-risk group (P <0.001). In the multivariate model containing risk group, age, NYHA class, ejection fraction, and QRS duration, the risk group into which patients had been initially categorized retained its independent predictive power for death or HF hospitalization, with a hazard ratio (HR) of 7.34 (95% CI 2.48–021.69) for the high-risk group compared with the low-risk group and 2.50 (95% CI 1.04–6.04) for the intermediate-risk group compared with the low-risk group (P =0.001 for both comparisons). Risk group at baseline was not associated with response to CRT or with likelihood of defibrillator shocks, the authors point out.
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- Sheikh N, Papadakis M, Schnell F et al. Clinical Profile of Athletes With Hypertrophic Cardiomyopathy. Circ Cardiovasc Imaging. 2015;8:e003454 … more
- Badar AA, Perez-Moreno AC, Hawkins NM et al. Clinical Characteristics and Outcomes of Patients With Coronary Artery Disease and Angina: Analysis of the Irbesartan in Patients With Heart Failure and Preserved Systolic Function Trial. Circ Heart Fail. 2015;8:717-724. … more
- Patel PA, Zhao X, Fonarow GC et al. Novel Oral Anticoagulant Use Among Patients With Atrial Fibrillation Hospitalized With Ischemic Stroke or Transient Ischemic Attack Circ Cardiovasc Qual Outcomes. 2015;8:383-392. … more
- Philippart R, Brunet-Bernard A, Clementy N et al. Prognostic value of CHA2DS2-VASc score in patients with ‘non-valvular atrial fibrillation’ and valvular heart disease: the Loire Valley Atrial Fibrillation Project. Eur Heart J 2015;36: 1822-1830 … more
- Schulman S, Carrier M, Lee AYY et al. Perioperative Management of Dabigatran: A Prospective Cohort Study. Circulation. 2015;132:167-173. … more
- Kusunose K, Yamada H, Hotchi J et al. Prediction of Future Overt Pulmonary Hypertension by 6-Min Walk Stress Echocardiography in Patients With Connective Tissue Disease. J Am Coll Cardiol. 2015;66:376-384 … more
- Cho JR, Rollini F, Franchi F et al. Pharmacodynamic Effects of Ticagrelor Dosing Regimens in Patients on Maintenance Ticagrelor Therapy: Results From a Prospective, Randomized, Double-Blind Investigation. J Am Coll Cardiol Intv. 2015;8:1075-1083 … more