ShortCuts- This Week in the Journals

Commentary by Danise Schiliro- Chuang MD

Welcome to this week’s edition of ShortCuts. Hoping as always that this post finds you all doing well. For those of you who have taken or who are about to take the boards, congratulations on the end of a most memorable chapter in your life; you are hereby rewarded with some light reading that you will not be tested on. Enjoy. The studies and events that made headlines this week attempt to answer some of our most common clinical questions, so fasten your seatbelts and prepare to be enlightened.

The first is an age-old question, ‘to cath or not to cath?’ If you’ve pondered this when your clinic patient complains of chest pain on exertion for the last year or when a similar patient with a positive stress test is transferred to your ward service from an outside hospital, then this study might interest you. Familiar to many, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, first published in 2007, compared a strategy of percutaneous coronary intervention (PCI) plus optimal medical therapy with optimal medical therapy alone. The outcome surprised many-it showed no significant difference in the rate death or myocardial infarction during a median follow-up period of 4.6 years. The current study, a part of the COURAGE trial published in this week’s NEJM, sought to determine if PCI provides a benefit in quality of life over that provided by optimal medical therapy among patients with stable coronary artery disease (CAD). About 2300 patients were randomly assigned to receive PCI plus optimal medical therapy or optimal medical therapy alone. Via questionnaires, the authors assessed for differences in symptoms of angina as well as overall quality of life. At baseline, 22% of the patients were free of angina. At 3 months, 53% of the patients in the PCI group and 42% in the medical-therapy group were angina-free, a statistically significant difference. In addition, at 3 months both groups experienced substantial improvements in physical limitations, angina stability, angina frequency, treatment satisfaction, and overall quality of life, with the PCI plus optimal medical therapy having the statistically significant advantage. But while this benefit persisted for up to 24 months, by 36 months there was no significant difference in health status between the treatment groups. Limitations of this study? It should be noted that mostly white men were included, leaving an uncertainty about the health outcomes in women and nonwhites. In addition, there was a significant amount of missing data (i.e. patients who did not respond to the questionnaires) and potential bias that may have resulted from this. Another limitation is that, because patients were aware of their treatment assignments, the potential for placebo effect from PCI exists. It should be noted that those patients with the most severe angina symptoms had the most benefit from PCI. But perhaps the take-home message and the most encouraging finding of this study is that we can do a lot for our patients with stable CAD by optimizing their medical regimen; by doing this, many patients may have a significant and rapid improvement in symptoms and overall quality of life and, in the long-term, may not benefit from PCI.

Okay, moving on to the next common question, “should I add an ARB to the ACE inhibitor?” It’s been shown that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) reduce both proteinuria as well as renal risk (loss of GFR and need for dialysis). What remains unclear, however, is whether a combination of these classes of drugs has an additive effect on renal risk reduction, and whether the effects of ARB and ACE inhibitors are equivalent. Several previous studies have shown that combination therapy reduces proteinuria; however, these trials were limited by their small sample size, short duration of therapy, and did not report on major renal outcomes. The current investigation, the ONTARGET study, published in this week’s Lancet, is a large multi-center, randomized controlled trial that took place over 6 years. Participants were 55 years or older and had established atherosclerotic vascular disease or diabetes with end-organ damage (the baseline mean creatinine was about 1 mg/dl). Over 25,000 patients were assigned to ramipril 10 mg daily, telmisartan 80 mg daily, or to a combination of both drugs. The primary outcome was a composite of dialysis, doubling of serum creatinine and death; the secondary outcome was a composite of dialysis and doubling of serum creatinine. The results of this trial may surprise you. Combination therapy reduced proteinuria to a greater degree than either therapy alone. However, both the primary outcome as well as secondary outcome were similar for telmisartan and ramipril but were increased with combination therapy. The study raises interesting questions regarding the relationship between proteinuria and kidney damage and asks if the reduction in proteinuria by itself can be taken as a definitive marker of improved renal function; these questions will no doubt require further investigation. Study limitations include a population that, at baseline, was well-treated with regards to standard cardiovascular therapy and only included a small subgroup with overt diabetic nephropathy. So this population may not represent the majority of patients we treat in our clinic. Overall, this trial suggests that while monotherapy with either an ARB or ACE inhibitor confers similar beneficial effects on major renal outcomes, combination blockade of the renin-angiotensin system may not be the way to go.

One final common question: what is this drug, Byetta, that everyone’s always talking about? Well, to answer this, you have to start with the Gila monster. This venomous lizard, that can go for prolonged periods without eating, was discovered to produce a protein that helps to slow the emptying of its stomach so it can stay full for prolonged periods. It turns out that humans make a very similar protein called GLP-1. Before long, a synthetic GLP-1 was born and it was named Exenetide, marketed under the name Byetta. This injectable drug slows stomach emptying, increases a feeling of fullness, reduces glucagon release and may help insulin-producing pancreatic beta cells live longer. Its advantages? Well, this drug is less likely than other agents to cause hypoglycemia. In addition, patients taking Byetta typically lose several pounds each year on the medicine. Some disadvantages are that the drug must be injected twice daily and its most common side effect is nausea, limiting its tolerability in some patients. So why bring up the topic of Byetta now? Well, it’s making headlines and you may be hearing more about it in the months to come. A New York Times article this week with the provocative title, “Lilly Diabetes Drug Shows a Life-Extending Promise,” calls to light interesting findings from the Accord trial. In June, findings from this trial were presented at the American Diabetes Association annual conference and suggested that patients who took Byetta had a significant mortality benefit. It’s important to keep in mind that the study wasn’t powered to detect this outcome and, therefore, it is possible that the finding is due to chance. In addition, only about 825 patients of the10,000 studied took Byetta and these patients tended to be healthier that the rest of the study population. But this surprising finding may warrant a large randomized controlled study designed to specifically explore the potential mortality benefit of Byetta. Unfortunately, we may have to wait for such a trial. The Times article points out that Eli Lilly and Amylin, the two companies that jointly market Byetta, are working on a reformulated version of the drug, which could be injected once weekly instead of twice daily, and they may prefer to run the trial on the new medicine, which has not yet been approved by the FDA.

Image courtesy of Wikimedia Commons

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