Author: Dr. Hassan Gargoum

 The role of routine supplemental oxygen for patients with uncomplicated acute myocardial infarction (AMI) has recently been questioned. There is conflicting data on the possible effects of hyperoxia on ischemic myocardium. The few clinical trials examining the role of oxygen in AMI were performed prior to the modern approach of emergent reperfusion and advanced medical management.                                                                                       

METHODS: Air Verses Oxygen In myocarDial infarction study (AVOID Study) is a prospective, multi-center, randomized, controlled trial conducted by Ambulance Victoria and participating metropolitan Melbourne hospitals with primary percutaneous coronary intervention capabilities. The purpose of the study is to determine whether withholding routine supplemental oxygen therapy in patients with acute ST-elevation myocardial infarction but without hypoxia prior to reperfusion decreases myocardial infarct size. AVOID will enroll 490 patients,>18 years of age with acute ST-elevation myocardial infarction of less than 12 hours duration.                                                                                             

CONCLUSIONS: There is an urgent need for clinical trials examining the role of oxygen in AMI. AVOID will seek to clarify this important issue. Results from this study may have widespread implications on the treatment of AMI and the use of oxygen in both the pre-hospital and hospital settings.

**Source: DocGuide.com

The US Food and Drug Administration (FDA) is warning of possible risks when using blood pressure medicines containing Aliskiren (Rasilez) with angiotensin converting enzyme(ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with diabetes or renal impairment.

These drug combinations should not be used in patients with diabetes. In addition, a new warning is being added to avoid use of these drug combinations in patients with renal impairment.

In ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) study, the risks of renal impairment, hypotension, and hyperkalemia in a group of patients taking Aliskiren plus an ARB or ACE inhibitor increased relative to a group of patients taking an ARB or ACE plus placebo.

The preliminary data from ALTITUDE also demonstrated a slight excess of cardiovascular events (death or stroke) in the Aliskiren group. However, the FDA has reached no definite conclusion regarding an actual link between these drugs and death or stroke.

The FDA will evaluate the final trial results as well as results from other Aliskiren trials and will communicate any new information when it becomes available.

The following recommendations are being added to the drug labels:
• A new contraindication against the use of Aliskiren with ARBs or ACE inhibitors in patients with diabetes because of the risk of renal impairment, hypotension, and hyperkalemia.
• A warning to avoid use of Aliskiren with ARBs or ACE inhibitors in patients with moderate to severe renal impairment (i.e., glomerular filtration rate <60 mL/min).

The purpose of ALTITUDE study was to determine whether Aliskiren plus conventional treatment reduces death and disease caused by the heart, the circulatory system, and the kidney. Patients with type 2 diabetes with renal disease were randomized to Aliskiren 300 mg daily (n = 4,283) or placebo (n = 4,296). All patients were receiving concomitant therapy with an ARB or an ACE inhibitor.

The primary efficacy outcome was the time to the first event of the primary composite endpoint, which consisted of cardiovascular death, resuscitated sudden death, non-fatal myocardial infarction, non-fatal stroke, unplanned hospitalization for heart failure, onset of end-stage renal disease, renal death, and doubling of serum creatinine concentration from baseline sustained for at least 1 month.

After a median patient follow up of about 27 months, the trial was terminated early for lack of efficacy. Greater risks of renal impairment, hypotension and hyperkalemia were observed in the Aliskiren group compared with the placebo group.

**Source: DocGuide.com

Physicians “are one step closer to a simple test that could predict whether a patient is about to have a heart attack – by using a blood sample to detect cells that have sloughed off of damaged blood vessel walls.” This finding,  published on March 21, 2012  in the journal Science Translational Medicine, could potentially address ‘the greatest unmet need’ facing cardiologists, said lead author Dr. Eric Topol, a cardiologist at the Scripps Translational Science Institute in San Diego.”  The findings are based on a study of 50 people who reported to four San Diego County hospitals while they were having a heart attack. Researchers compared blood samples of these “patients with 44 healthy volunteers, and found a much higher level of abnormal circulating endothelial cells, or CECs, according to the study.   The study suggests those cells are harmed not just in the minutes prior to a heart attack, but probably hours, maybe even days’ earlier.  The relationship of elevated CEC amounts to acute MI has been known for over a decade, but the CellSearch technology makes it possible to capture CEC data more quickly, efficiently, and robustly than ever before.

A commercially available point-of-care blood test based on this CEC signature will be available within about two years. The test will take about 20 to 30 minutes and could be performed on every patient presenting to the emergency department with chest pain. This assay will be used on a peripheral whole-blood sample before coronary angiography, which is important in the STEMI population because a coronary catheter disrupts plaques, leading to false elevations in circulating endothelial-cell count.

Source: The Heart.org

Statins are a class of prescription drugs intended to lower blood levels of low-density lipoprotein cholesterol, when used together with diet and exercise. Single-ingredient statins include atorvastatin, fluvastatin, lovastatin, lovastatin extended-release, pitavastatin, pravastatin, rosuvastatin, and simvastatin. Also available are combination statins, including lovastatin/niacin extended-release, simvastatin/niacin extended-release, and simvastatin/ezetimibe.

The FDA’s announcement on the label changes does not question the benefit of statins to lowering cholesterol, but it does provide patients and healthcare providers the most current information about the safe use of statins.

The US Food and Drug Administration (FDA) has approved class safety labeling changes for statins, including removal of the recommendation for routine monitoring of liver enzymes and the addition of new information about reversible cognitive adverse effects and reports of increased blood glucose and glycosylated hemoglobin (HbA1c) levels (statin use has also been linked to increases in levels of HbA1c and fasting serum glucose).

In the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, there was a 27% increase in investigator-reported diabetes mellitus in rosuvastatin-treated patients vs placebo-treated patients. High-dose atorvastatin was also associated with worsening glycemic control in the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE-IT TIMI 22) substudy.

Meta-analyses also showed that statin therapy was associated with a 9% to 13% increased risk for incident diabetes.

In addition, the updated safety label for the statin lovastatin now includes new contraindications and dose limitations when the drug is administered concurrently with certain medications that can increase the risk for myopathy and/or rhabdomyolysis.

Instead of routine monitoring of liver enzymes, the FDA now recommends that clinicians test liver enzymes in their patients before prescribing statin treatment and as clinically indicated thereafter. Statin treatment should be interrupted in patients who develop serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice, and the statin should not be restarted unless an alternate cause is found.

More caution has to be taken in people with prior history of liver disease, people who drink or who are taking multiple drugs metabolized by the liver. Also, the contraindications of use of in particular anti-HIV drugs with Mevacor (lovastatin) are important to reemphasize as is the known but infrequent increase in blood sugar in patients taking statins.

Rare post marketing reports have documented mild, generally reversible symptoms of cognitive impairment associated with statin use. These symptoms may include memory loss, forgetfulness, amnesia, memory impairment, and/or confusion. Times to symptom onset vary from 1 day to years, and resolution of symptoms on statin discontinuation also varies, with a median of 3 weeks.

The updated lovastatin label indicates that the following drugs are contraindicated with lovastatin: itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, and nefazodone.  Cyclosporine and gemfibrozil should be avoided in patients taking lovastatin, as should grapefruit juice exceeding 1 quart daily. A daily dose of 20 mg of lovastatin should not be exceeded with danazol, diltiazem, or verapamil and 40 mg of lovastatin daily should not be exceeded with amiodarone.

The National Lipid Association’s Liver Expert Panel and Statin Safety Task Force stated that the available scientific evidence does not support routine liver function test monitoring in asymptomatic patients receiving statins. Irreversible liver damage resulting from statins is exceptionally rare and is likely idiosyncratic, and no data exist showing that routine periodic monitoring of liver biochemistries will identify the very rare individual who may develop significant liver injury. Routine periodic monitoring could actually identify patients with isolated increased aminotransferase levels, resulting in changes in or discontinuation of statin treatment that could increase the risk for cardiovascular events.

Clinical Implications

• The FDA now recommends that clinicians test liver enzymes in their patients before prescribing statin treatment and as clinically indicated thereafter, rather than routinely monitoring liver enzymes as was recommended previously. Statin treatment should be interrupted in patients who develop serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice, and drug therapy should not resume unless an alternate cause is found for the hepatic dysfunction.
• Statin use may rarely be associated with mild, generally reversible symptoms of cognitive impairment, with variable time to symptom onset and resolution of symptoms on statin discontinuation. Statin use has also been associated with increases in levels of fasting serum glucose and HbA1c.
• The updated safety label for lovastatin now includes new contraindications and dose limitations when the drug is given concurrently with certain medications that can increase the risk for myopathy and/or rhabdomyolysis.

The antihypertensive drug aliskiren ( Rasilez) should no longer be co-administered with angiotensin-converting–enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), the manufacturer announced following the early termination of the ALTITUDE trial. Patients taking these combinations should be switched to another antihypertensive regimen.

In the study, patients with type 2 diabetes and impaired renal function were given aliskiren or placebo in addition to an ACE inhibitor or ARB. A data monitoring group opted to stop the trial after the aliskiren group had a higher-than-expected incidence of nonfatal stroke, renal complications, hyperkalemia, and hypotension after 18 to 24 months.

A Prospective, Randomized Trial of Transapical Transcatheter Aortic Valve Implantation (TAVI) vs. Surgical Aortic Valve Replacement (AVR) in Operable Elderly Patients With Aortic Stenosis (The STACCATO trial). This study was sponsored by the Danish Heart Foundation and was presented this year (2011).

This trial sought to compare outcomes after trans-apical trans-catheter Aortic Valve Implantation (TAVI) as compared with surgical aortic valve replacement (AVR) in elderly patients with severe aortic stenosis who were otherwise not at an elevated risk for undergoing surgical AVR.                                                                                                                                                                            The investigators planned to enroll 200 patients, but the Data Safety and Monitoring Board terminated the trial early after enrollment of 70 patients. Of these 70 patients, 34 underwent transapical TAVI and 36 underwent surgical AVR. Baseline characteristics were fairly similar between the two arms.  About one half of the patients (52%) were significantly symptomatic (New York Heart Association [NYHA] class III/IV). The mean aortic valve area was 0.7 cm².
The primary endpoint of all-cause mortality, stroke, or renal failure requiring dialysis was significantly higher  in the transapical TAVI arm as compared with the surgical AVR arm (14.7% vs. 2.8%).                                                                                                                                                                                                                                                                                                                                                                There was a higher incidence of death (8.8% vs. 0%) and stroke (5.9% vs. 2.8%).   Other significant events at 3 months were also higher in the transapical TAVI arm (23.5% vs. 5.6%).          Both aortic valve area and peak aortic valve gradient were significantly improved in both arms at follow-up, with no difference between the two arms.
The incidence of paravalvular aortic regurgitation was significantly higher in the transapical TAVI arm (moderate/severe: 13% vs. 0%; minimal: 43% vs. 6%; p < 0.001).   The incidence of permanent pacemaker implantation was 5.8% vs. 2.7%, p = 0.52, and mean hospital stay was 8.8 vs. 7.6 days, p = 0.32.

The results of this small trial indicate that transapical TAVI is not superior to surgical AVR in elderly patients with severe aortic stenosis who are otherwise candidates for surgical AVR; outcomes including mortality and strokes were all elevated in the transapical arm at 30 days and at 3 months.
These results suggest that transapical TAVI (in its current stage of development) use should be restricted to patients who are at high risk for surgical AVR.

Reference: A Prospective, Randomized Trial of Transapical Transcatheter Aortic Valve Implantation vs. Surgical Aortic Valve Replacement in Operable Elderly Patients With Aortic Stenosis: Presented by Dr. Leif Thuesen at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2011), San Francisco, CA, November 10, 2011.

The US FDA has issued a safety communication and updated the prescribing information for the cholesterol-lowering agent fenofibric acid (Trilipix, Abbott), stating that the drug may not lower the risk of major cardiovascular events. This is based on data from the ACCORD Lipid trial, in which the combination of fenofibrate plus simvastatin was compared with simvastatin alone in patients with type 2 diabetes mellitus.

Fenofibrate was approved in 2008 to be used with a statin to reduce triglycerides and increase HDL cholesterol in diabetic patients with mixed dyslipidemia and coronary disease or at risk of coronary disease who are already on optimal statin therapy to achieve their LDL-cholesterol goal.

Over nearly five years of follow-up in ACCORD trial, the composite of fatal cardiovascular events, nonfatal myocardial infarction (MI), and nonfatal stroke was around 11% in both patients randomized to simvastatin plus fenofibrate and patients randomized to simvastatin plus placebo. However, there was a strong trend toward fewer cardiac events in patients with high triglycerides and low HDL cholesterol treated with fenofibrate. In the current safety communication, the FDA refers to this result as “hypothesis raising” and needing confirmation by another trial.

The FDA has reviewed this trial as part of its ongoing investigation of the safety and efficacy of fenofibric acid. The agency notes that its review found that there was no significant difference in the risk of experiencing a major adverse cardiac event between the fenofibrate/simvastatin group and the simvastatin-alone group in the trial. In addition, a subgroup analysis showed that relative to treatment in men, there was an increase in the risk for major adverse cardiac events in women receiving the combination therapy vs simvastatin alone. But it adds that the clinical significance of this subgroup finding is unclear.

Based on these results and other clinical trials of similar drugs, the FDA says it has requested Abbott to conduct a clinical trial to evaluate the cardiovascular effects of fenofibric acid in patients at high risk for cardiovascular disease who are already taking statins.

These results from the trial have been added to the product label and to the patient medication guide. The agency says: “Healthcare professionals should consider the benefits and risks of Trilipix when deciding to prescribe the drug.”

Source: heart.org

According to a new study by Hermida, R.C. et al (from University of Vigo, Spain), published on October 24, 2011 in the Journal of the American Society of Nephrology,  among patients with chronic kidney disease (CKD) and hypertension, taking at least one antihypertensive medication at bedtime significantly improves blood-pressure (BP) control, with an associated decrease in risk for cardiovascular events.

The study included 661 patients with CKD who were randomly assigned either to take all prescribed hypertension medications on awakening or to take at least one of them at bedtime. Ambulatory BP at 48 hours was measured at least once a year and/or at three months after any adjustment in treatment.

The composite measure of cardiovascular events used included death, MI, angina pectoris, revascularization, heart failure, arterial occlusion of lower extremities, occlusion of the retinal artery, and stroke.

Patients were followed for a median of 5.4 years; during that time, patients who took at least one BP-lowering medication at bedtime had approximately one-third the CVD risk as those who took all medications on awakening .

A similar significant reduction in risk with bedtime dosing was noted when the composite CVD outcome included only cardiovascular death, MI, and stroke.

Patients taking their medications at bedtime also had a significantly lower mean BP while sleeping, and a greater proportion of these patients had ambulatory BP control.

The researchers estimate that for each 5-mm-Hg decrease in mean sleep-time systolic BP, there was a 14% reduction in the risk for cardiovascular events during follow-up.

According the authors of this study: Treatment at bedtime is the most cost-effective and simplest strategy of successfully achieving the therapeutic goals of adequate asleep BP reduction and preserving or reestablishing the normal 24-hour BP-dipping pattern.

Reference:      Hermida RC, Ayala DE, Mojón A, Fernández JR. Bedtime dosing of antihypertensive medications reduces cardiovascular risk in CKD. J Am Soc Nephrol 2011; DOI:10.1681/ASN.2011040361.

In a population based case-control study using data from medical databases , Schmidt M, et al., from Denmark, examined the risk of atrial fibrillation or flutter associated with use of non-selective non-steroidal anti-inflammatory drugs (NSAID) or selective cyclo-oxygenase (COX)2 inhibitors. This study has been published in the British Medical Journal (BMJ) this year.

They studied 32602 patients with a first inpatient or outpatient hospital diagnosis of atrial fibrillation or flutter between 1999 and 2008; 325 918 age-matched and sex matched controls based on risk-set sampling.

They concluded that the  use of non-aspirin NSAIDs was associated with an increased risk of atrial fibrillation or flutter. Compared with non-users, the association was strongest for new users (first ever prescription redemption within 60 days before diagnosis date), with a 40-70% increase in relative risk (lowest for nonselective NSAIDs and highest for COX2 inhibitors).  Results for individual NSAIDs were similar.

This study adds evidence that atrial fibrillation or flutter needs to be added to the cardiovascular risks to be considered when prescribing NSAIDs.

Reference: Schmidt M; Christiansen CF; Mehnert F; Rothman KJ; Sørensen HT, BMJ.  2011; 343:d3450