Primecuts – This Week In The Journals

April 16, 2012

By Becky Naoulou, MD

Faculty Peer Reviewed

This week in Primecuts, we will get down to the “heart” of business and discuss several recent publications in cardiovascular research. St. Jude, one of the country’s biggest medical device producers has been in the news recently [1]. A report was recently published in the medical journal HeartRhythm that linked 20 deaths to the failures of a component of a St. Jude implanted heart device. The problem involves a particular model, called the Riata, of a lead that connects the debrillator to the myocardium. This lead has been implanted in about 128,000 patients worldwide but it has been noted that the electrical wires within the Riata are breaking through the insulation and causing unintended shocks in some patients. There is additional concern that the wires may fail when a life-saving debrillator shock needs to be delivered. St. Jude stopped selling the Riata in 2010 and a newer model now has an added insulation sheath to prevent the same problem. In the meantime, however, St. Jude shares have dropped more than 11% since March 30. The chief executive of St. Jude contends that the report is biased and accuses its main competitor Medtronic of trying to undercut St. Jude in order to gain business. Many doctors are upset about this fight between the two companies and are concerned that St. Jude has not yet given them enough information about how to deal with patients who have disintegrating defibrillator leads. This back and forth shows us that even the medical field is not immune to media-hype and patients will undoubtedly go to providers with many questions. In less shocking news, we will now move on to explore several recently published trials in acute coronary syndrome and is prevention.

Acute chest pain is the second most common reason for emergency room visits and in the U.S. there are more than 6 million visits each year for chest pain [2]. Although only 10-15% of patients who present with chest pain are ultimately diagnosed with acute coronary syndromes, many are admitted to the hospital, at an estimated cost of over $3 billion annually [3]. A study published this week in NEJM, evaluated whether coronary computed tomographic angiography (CCTA), which has a very high negative predictive value for the detection of coronary disease, would be helpful in facilitating the discharge of low-risk patients from the emergency room [4]. It was a controlled, multicenter trial which randomized patients in a 2:1 ratio to undergo CCTA or to receive traditional care. The study population consisted of patients 30 years or older with signs or symptoms that were consistent with a possible acute coronary syndrome and that would warrant further evaluation or testing. The included patients had TIMI risk scores of 0-2 and their initial EKGs on presentation showed no signs of acute ischemia. The primary outcome was safety, assessed in the subgroup of patients with a negative CCTA. Safety was defined as the absence of myocardial infarction and cardiac death during the first 30 days after presentation. The study enrolled 1370 patients: 908 underwent CCTA and 462 received traditional care. Of 640 patients who had a negative CCTA, which was defined as maximal coronary artery stenosis less than 50%, none died or had a myocardial infarction within 30 days (95% confidence interval (CI): 0-0.57). Compared to the group receiving traditional care, patients who were in the CCTA group had a higher rate of discharge from the emergency department (49.6% vs 22.7%, 95% CI 21.4-32.2), a shorter length of stay (median, 18 hours vs. 24.8 hours, P<0.001), as well as a higher rate of detection of coronary disease (9.0% vs. 3.5%, 95% CI: 0-11.2) . There was one serious adverse event (bradyarrhythmia) in each group, which was thought to be related to the medications given to control heart rate. This study showed that coronary CTA in low risk patients presenting with possible acute coronary syndrome can allow patients who otherwise would be admitted to the hospital to be safely discharged from the emergency department. Some limitations to using coronary CTA include radiation exposure and the need for contrast administration that may preclude its use in some patients with renal failure. In addition, because coronary CTA is an anatomical rather than a functional study, some patients may be found to have coronary artery disease that might not have been related to the presenting symptoms and this may subsequently trigger a series of diagnostic tests that may otherwise not have been indicated.

Also published in this week’s NEJM is the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 P)-Thrombolysis in Myocardial Infarction (TIMI) 50 trial. This trial was a multinational, double-blind, placebo-controlled trial that was designed to evaluate the efficacy and safety of vorapaxar in reducing atherothrombotic events in patients with established atherosclerosis who were receiving standard therapy [5]. Thrombin is a serine protease that is critical in thrombosis. It generates fibrin and is a potent agonist of platelets through interaction with protease-activated receptors (PARs). Vorapaxar is a competitive and selective antagonist of PAR-1 and potently inhibits thrombin-induced platelet aggregation. In the TRA 2P-TIMI 50 trial, the patients who were included had a history of atherosclerosis, which was defined as a spontaneous myocardial infarction or ischemic stroke within the previous 2 weeks to 12 months or peripheral arterial disease. 26,449 patients were randomized in a 1:1 ratio to receive either vorapaxar (2.5 mg daily) or placebo and were followed for a median 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the safety monitoring board reported an excess of intracranial hemorrhage in patients with a history of stroke in the vorapaxar group and recommended discontinuation of the drug in all patients with previous or new stroke. The board did recommend, however, continuation of the trial in patients without a history of stroke. At three years, the primary endpoint occurred in 9.3% of patients in the vorapaxar group and in 10.5% in the placebo group (P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 11.2% in the vorapaxar group and 12.4% in the placebo group (P=0.001). However, moderate or severe bleeding occurred in more patients in the vorapaxar group compared to placebo, 4.2% vs. 2.5% respectively (P<0.001). Intracranial hemorrhage occurred more commonly in the patients receiving vorapaxar compared to placebo, 1.0% vs. 0.5% (P<0.001) and the risk of intracranial bleeding was higher in those patients with a history of stroke. This study showed that the addition of vorapaxar to standard antiplatelet therapy decreased the risk of thrombotic events in patients with a history of atherosclerosis but this reduction came with significant increases in bleeding. Therefore, the use of vorapaxar would require appropriate selection of patients and the risk of bleeding needs to be weighed against that of recurrent thrombotic events on a case-by-case basis.

And now we turn to an article published in this week’s JAMA which evaluates whether the use of losartan increases mortality in patients with heart failure when compared to other angiotensin-receptor blockers (ARBs) [6]. A recent cohort study found that the use of losartan, compared with candesartan, was associated with an increased risk of all-cause mortality [7]. To evaluate this topic further, this week’s article in the JAMA [6], was a nationwide Danish registry-based cohort study which identified patients from the registry that were 45 years or older with first time hospitalization for heart failure in 1998-2008. New users of losartan and candesartan were selected for inclusion in the study cohort and the risk of all-cause mortality was compared in the two groups. The final study cohort consisted of 6479 patients, 2082 users of candesartan and 4397 users of losartan. During 19,491 person-years of follow-up, there were 330 deaths among the candesartan group (incidence rate/100 person-years: 9.0, CI 8.1-10) and 1212 among the losartan group (incidence rate/100 person-years: 10.7, CI 10.1-11.3). Compared with candesartan, losartan was not associated with increased all-cause mortality (adjusted hazard ratio 1.10, CI 0.96-1.25) or cardiovascular mortality (adjusted hazard ratio 1.14, CI 0.96-1.36). However, low-dose (12.5 mg) and medium-dose (50 mg) losartan were associated with increased mortality compared with high doses of candesartan (50 mg), hazard ratio 2.79, CI 2.19-3.55 and hazard ratio 1.39, CI 1.11-1.73, respectively. Use of high dose losartan (100 mg) was similar in risk (hazard ratio 0.71, CI 0.50-1.00). This study showed that one ARB is not superior over another in heart failure and a differential effect on mortality may have been related to the different doses used in previous studies. When compared to high doses of candesartan, high doses of losartan do not impose increased risk of mortality in patients with heart failure.

Finally, we turn to a meta-analysis published in this week’s Archives of Internal Medicine to determine whether omega-3-fatty acid supplements are really effective in the secondary prevention of cardiovascular disease [8]. The literature on the efficacy of omega-3 fatty acids in the prevention of cardiovascular disease is very controversial. There are some studies that contend that these supplements reduce the risk of cardiovascular disease via their anti-inflammatory, antiatherogenic, and antiarrhythmic properties [9]. Other studies demonstrate either no effect or negative effects on the prevention of cardiovascular disease. This week’s meta-analysis included 14 randomized, double-blind, placebo-controlled trials involving 20,485 patients with a history of cardiovascular disease who have used omega-3 fatty acid supplements for at least 1 year. The trial reported outcome measures such as angina, unstable angina, sudden cardiac death, cardiovascular death, all-cause mortality, congestive heart failure, myocardial infarction, transient ischemic attack, or stroke. Subgroup analyses were performed based on a history of cardiovascular disease, geographic area, duration of treatment, dosage of supplement, type of placebo used in the trial, quality of the trial, and concomitant use of statin or antiplatelet therapy. The results of the meta-analysis showed that supplementation with omega-3 fatty acids did not reduce the risk of overall cardiovascular events (relative risk, 0.99, CI 0.89-1.09), all-cause mortality, sudden cardiac death, congestive heart failure, myocardial infarction, or transient ischemic attack or stroke. There was a small reduction in cardiovascular death (relative risk 0.91, CI 0.84-0.99), which disappeared when the authors excluded a study with major methodological problems. In addition, there was no significant preventive effect observed in the subgroup analyses. This meta-analysis disagrees with a previous meta-analysis of 11 trials which recommended dietary supplementation with omega-3 fatty acids for the secondary prevention of cardiovascular events [10]. Notably, the prior study demonstrating a benefit included 2 large open-label trials, making it liable to performance bias. When those two studies were excluded, no preventive effect was seen.

So this concludes this week’s Primecuts. I learned that implantable medical devices are not always perfect, that coronary CTA has the potential to prevent unnecessary hospital admissions in low risk patients presenting to the emergency room with chest pain, vorapaxar is effective in decreasing thrombotic events in patients with atherosclerosis but increases risk of bleeding, high dose losartan does not increase mortality in heart failure, and omega-3-fatty acid supplementation may not be effective in secondary prevention of cardiovascular disease.

Dr. Becky Naoulou a first year resident at NYU Langone Medical Center 

Peer reviewed by Robert J. Gianotti, MD, NYU Chief Medical Resident, NYU Langone Medical

Image courtesy of Wikimedia Commons

References:

1. At St. Jude, Firing Back at Critics. New York Times, April 11, 2012. 

2. Niska R et al. National Hospital Ambulatory Medical Care Survey: 2007 emergency department summary. Natl Health Stat Rep 2010; 26:1-31.

3. Agency for Healthcare Research and Quality. Healthcare Cost and Utilization Project (http://www.hcup-us.ahrq.gov).

4. Litt HI et al. CT Angiography for Safe Discharge of Patients with Possible Acute Coronary Syndromes. NEJM 2012; 366(15): 1393-1403.

5. Morrow DA et al. Vorapaxar in the Secondary Prevention of Atherothrombotic Events. NEJM 2012; 366(15): 1404-1413. http://www.nejm.org/doi/full/10.1056/NEJMoa1200933

6. Svanstrom H et al. Association of Treatment With Losartan vs. Candesartan and Mortality Among Patients With Heart Failure. JAMA 2012; 307(14): 1506-1512.  http://jama.ama-assn.org/content/307/14/1506.abstract

7. Eklind-Cervenka M et al. Association of Candesartan vs Losartan with All-cause Mortality in Patients with Heart Failure. JAMA 2011; 305(2): 175-182.

8. Kwak SM et al. Efficacy of Omega-3 Fatty Acid Supplements (Eicosapentaenoic Acid and Docosahexaenoic Acid) in the Secondary Prevention of Cardiovascular Disease: A Meta-analysis of Randomized, Double-blind, Placebo-Controlled Trials. Archives of Internal Medicine 2012; doi 10.1001/archinternmed.2012.262. http://archinte.ama-assn.org/cgi/content/short/archinternmed.2012.262

9. Wall R et al. Fatty Acids from Fish: the Anti-Inflammatory Potential of Long-Chain Omega-3 Fatty Acids. Nutrition Review 2010; 68(5):280-289.

10. Marik PE et al. Omega-3 Dietary Supplements and the Risk of Cardiovascular Events: a Systematic Review. Clinical Cardiology 2009; 32(7):365-372.

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