January 14th, 2011
Combination Therapy Beats Single Therapy As Initial Antihypertensive Therapy
Larry Husten, PHD
In the ACCELERATE (Aliskiren and the calcium channel blocker amlopdipine combination as an initial treatment strategy for hypertension control) trial, more than 1200 patients with early essential hypertension were randomized to either aliskiren, amlodipine, or the combination of the two drugs for 4 months. The results, which have been published online in the Lancet, showed that blood pressure reduction was greater by 6.5 mm Hg in the combination group than in the monotherapy groups (p<0.0001). After 4 months, when all patients were switched to combination therapy, the difference between the groups had narrowed to 1.4 mm Hg (p=0.059). The investigators concluded that their results suggest that “a move towards routine initial reduction of blood pressure with combination therapy can now be advocated.”
In an accompanying comment, Ivana Lazich and George Bakris write that “a change in guidelines is clearly necessary after the ACCELERATE report” and the previously reported ACCOMPLISH study. They recommend that “initial combination therapy should be advocated for all those already implementing lifestyle changes who are still above 150/90 mm Hg, as most people in ACCELERATE were.”
January 13th, 2011
Merck’s Thrombin Receptor Antagonist Suffers Major Setback
Larry Husten, PHD
Merck’s thrombin receptor antagonist, vorapaxar, has suffered a major setback in its clinical trial program. In one trial, TRACER, the study drug is being discontinued and the trial will be closed out. The second trial, TRA-2P TIMI 50, is being curtailed but not stopped. The actions were based on recommendations from the combined Data and Safety Monitoring Board for the trials. In a letter to investigators from the study chairs, no explanations were offered about the reasons for the changes. Vorapaxar is a selective protease activated receptor 1 (PAR-1) thrombin receptor antagonist intended to fight clot formation.
In TRACER, 13,000 hospitalized ACS patients were randomized to placebo or vorapaxar in addition to standard care. Merck announced that TRACER had accumulated the predefined number of primary and major secondary endpoints, but not all patients had received the drug for the prespecified one-year followup.
In TRA-2P TIMI 50, more than 25,000 patients with MI, ischemic stroke, or peripheral vascular disease were randomized to either vorapaxar or placebo in addition to standard care for the secondary prevention of MI and stroke. Merck said that vorapaxar would be discontinued in patients who experienced a stroke prior to entry or during the trial. The study drug will be continued in patients with previous MI or peripheral disease, representing approximately three-quarters of the study population.
In the letter to investigators from the study chairmen at the Duke Clinical Research Institute and the TIMI group, no explanations for the actions were presented.
January 12th, 2011
Maybe TAVI Is Not All It’s Cracked Up To Be
Richard A. Lange, MD, MBA and L. David Hillis, MD
The PARTNER trial of transcatheter aortic valve implantation (TAVI) for severe aortic stenosis was among the hottest cardiology stories of 2010. Now that the hype is receding, some are questioning whether TAVI is ready for prime time.
In three letters to the Editor of the New England Journal of Medicine, our colleagues point out that the “conventional treatment” group received a rather unconventional treatment (aortic balloon valvuloplasty) and had a higher average EuroSCORE (i.e., estimated mortality) than those treated with TAVI, which may have exaggerated the benefit of TAVI.
In considering the demonstrated increase in periprocedural strokes and bleeding complications with TAVI and the patient population most likely to undergo the procedure (i.e., the elderly with multiple coexisting conditions, limited life expectancy, and disproportionate health care expenditures), some are calling for an analysis of the cost-effectiveness and quality-of-life benefits of TAVI.
On the basis of the available information, are you ready to recommend TAVI to your patients?
If not, what additional information would you convince you to do so?
January 12th, 2011
Researchers Shed New Light on HDL Cholesterol
Larry Husten, PHD
Two papers published in the New England Journal of Medicine shed new light on the important but often mysterious role of HDL cholesterol in cardiovascular disease.
In the first paper, researchers at the University of Pennsylvania studied 1,000 healthy volunteers and patients with coronary artery disease and observed a strong inverse relationship between cholesterol efflux from macrophages (a key element in reverse cholesterol transport, which is thought to have a protective effect against atherosclerosis) and carotid intima-media thickness.
The investigators also found that cholesterol efflux was independent of HDL level. In an accompanying editorial, Jay Heinecke writes that the study provides evidence to support the view that “HDL efflux capacity is a measure of HDL function that is relevant to the pathogenesis of atherosclerosis.” Further, he writes, the study also supports “the proposal that dysfunctional HDL contributes to the risk of coronary disease.”
In the second paper, researchers in the Netherlands report finding a family with a functional mutation in SR-B1, an HDL receptor that may play a key role in reverse cholesterol transport. The authors report that family members with the mutation had increased HDL levels but reduced cholesterol efflux from macrophages. Although no increase in atherosclerosis was observed in the small group of patients with the mutation, the researchers observed an alteration in platelet function and a decrease in adrenal steroidogenesis.
January 12th, 2011
Clyde Yancy Succeeds Robert Bonow as Chief of Cardiology at Northwestern
Larry Husten, PHD
Clyde Yancy, a former president of the AHA, is leaving Baylor University to succeed Robert Bonow as the chief of the division of cardiology at the Northwestern University Feinberg School of Medicine. Yancy will also serve as the associate director of the Bluhm Cardiovascular Institute at Northwestern Memorial Hospital, according to a heartwire report.
January 12th, 2011
Large Meta-Analysis Explores Cardiovascular Safety of NSAIDs
Larry Husten, PHD
A large network meta-analysis has found “little evidence” to suggest that any of the commonly used NSAIDs or COX 2 inhibitors are safe in terms of cardiovascular risk. In a paper published in BMJ, Sven Trelle and colleagues analyzed data from 31 trials in which patients receiving an NSAID were compared to another NSAID or placebo. Rofecoxib was associated with the highest risk of MI while naproxen appeared to be the safest of the agents studied. The authors concluded that “options for the treatment of chronic musculoskeletal pain are limited and patients and clinicians need to be aware that cardiovascular risk needs to be taken into account when prescribing.”
In an accompanying editorial, Wayne Ray writes that the limitations of the meta-analysis mean the results “should be interpreted with caution.” Although naproxen appears to be the safest agent it may require the concomitant use of a gastroprotective agent. Ray writes that “drugs for symptomatic relief must be evaluated with regard to the target symptoms as well as less frequent yet serious adverse effects. NSAIDs are not an ideal treatment with respect to efficacy or safety.”
January 11th, 2011
Candesartan Beats Losartan in Swedish HF Registry
Larry Husten, PHD
The Swedish Heart Failure Registry followed more than 5,000 patients treated with the angiotensin II receptor blockers (ARBs) candesartan or losartan between 2000 and 2009. According to a paper published in JAMA, survival at one year was 90% in the candesartan group compared to 83% in the losartan group. Five-year survival was 61% and 44%. After adjustment for clinical differences and propensity scores, the hazard ratio for losartan compared to candesartan was 1.43.
Discussing the large difference between the drugs, the authors acknowledge that “the magnitude of our findings may be due to chance, but RCTs may understate ‘real world’ differences, and it is conceivable that candesartan is better than losartan by a magnitude similar to placebo.” They conclude, however, that “clinical decision making should await supportive evidence” and recommend that differences between ARBs should be tested in randomized trials, though they acknowledge it may be more feasible to confirm the finding in other registries.
January 11th, 2011
Absorbable Stent Approved: Now You See It, Now You Don’t
Richard A. Lange, MD, MBA
Have questions about the new stent that just received CE Mark approval in Europe? Here’s a reality checklist.
1. What’s it called? The bioresorbable vascular scaffold (BVS) from Abbott Laboratories is named ABSORB (clever, huh?).
2. What are its advantages over a drug-eluting stent (DES)? Don’t know yet. It may eliminate the need for long-term intensive antiplatelet therapy (speculative). Abbott says that the vessel treated with a BVS may “ultimately move, flex and pulsate similar to an untreated vessel” and calls this potential “vascular restoration therapy.” (In my opinion, this is a stretch…pun intended.)
3. What’s the composition? Everolimus is adhered to a bioabsorbable scaffold of polylactide, which is a biocompatible material commonly used in resorbable sutures.
4. How long does it take to absorb? The device dissolves within 2 years.
5. When will it be available in the U.S? Not in the near future. It’s not been studied in the U.S. Although available for clinical studies in Europe soon, it won’t be fully commercially available even there until late 2012.
6. Lots of data on its efficacy and safety? Surprisingly not. Thus far, the only safety and efficacy data come from a prospective, non-randomized (open label), 2-phase study that enrolled 131 patients from six European countries, Australia, and New Zealand. In the study, major adverse cardiac events (MACE) and treated site thrombosis rates were evaluated at 30 days as well as at 6, 9, 12, and 24 months.
7. What do we know?
- 5% incidence of MACE (composite cardiac death, MI, and ischemia-driven target lesion revascularization) at 9 months
- No stent thrombosis
- Minimal late loss (0.19 mm) at 9 months (comparable to DES)
8. What’s next? The ABSORB EXTEND trial is a single-arm study that will evaluate ~1000 patients with complex CAD in 100 centers in Europe, Asia Pacific, Canada, and Latin America. Later in 2011, a randomized, controlled trial in Europe will enroll ~500 patients at 40 centers to compare ABSORB to Abbott’s XIENCE PRIME everolimus-eluting metal DES.
January 11th, 2011
How Are We Doing?
Harlan M. Krumholz, MD, SM
Dear Colleagues,
We launched CardioExchange in an effort to build a non-partisan venue for the exchange of information and views about the world of cardiology. Our presumption is that there is wisdom in our community and that we can learn from each other. It was a bit of an experiment and we had no idea whether we could reach a point where others would find it useful. Feedback from you is critical to helping us chart the next steps. We need your help to understand what is working, what is not and what would be most useful in making the community most useful to you and encouraging participation.
Please take a moment to complete this survey. Your opinion is important to us and the survey is a way for us to incorporate your perspective in our next steps.
Thank you very much for your participation in CardioExchange.
Best regards,
Harlan
January 10th, 2011
Have the COURAGE to Critique a Substudy
Harlan M. Krumholz, MD, SM
In this journal club, I compare the published data from an original trial with the authors’ conclusions in a substudy from that trial. Often, a substudy provides valuable insights that complement the initial trial findings. Sometimes, however, you need to look closely to identify the additional insight. Case in point: COURAGE.
The Original COURAGE Trial
As reported in 2007 in the NEJM, 2287 patients with objective evidence of myocardial ischemia and significant epicardial coronary artery disease were randomized to receive either optimal medical therapy (OMT) alone or percutaneous coronary intervention (PCI) plus OMT. During a median follow-up of 4.6 years, incidence of the primary endpoint — death or nonfatal MI — was statistically similar in the two groups, but slightly higher with PCI (OMT alone, 18.5%; PCI, 19.0%; P=0.62). PCI also showed no advantage in the individual endpoints of death, nonfatal MI, or hospitalization for acute coronary syndrome — nor (as reported subsequently) in quality of life.
The Nuclear Substudy
In 2008, the COURAGE nuclear substudy (the first substudy from the trial) was published in Circulation. It involved 314 patients who underwent serial rest/stress myocardial perfusion single-photon-emission computed tomography (MPS), both before treatment and then 6 to 18 months after randomization. The primary endpoint was defined as ≥5% reduction in myocardial ischemia at follow-up. The investigators report that the PCI group had a significantly greater mean reduction in ischemic myocardium (–2.7% with PCI vs. –0.5% with OMT alone) and a significantly larger percentage of patients who achieved the ≥5% reduction endpoint (33% vs. 19%). The ≥5% reduction in ischemic burden was not significantly associated with better outcome in a multivariable analysis, and as the authors acknowledge, their study “was not powered to examine differences in clinical outcomes according to change in ischemic burden.” In the conclusion of their abstract, the authors say that “adding PCI to OMT resulted in greater reduction in ischemia compared with OMT alone.” They further state, “Our findings suggest a treatment target of ≥5% ischemia reduction with OMT with or without coronary revascularization.”
The Leap in Logic
The authors’ conclusion is quite provocative. The full trial showed that patients with ischemia did equally well with an initial strategy of PCI or OMT. In the substudy, the authors assert that, given their results, clinicians should seek a target of ≥5% ischemia reduction. The implications are that these patients should undergo MPS, that therapeutic strategies should be guided over time by the MPS results, and that PCI is better than OMT alone in reducing ischemia. How did the authors make this leap? Their reasoning appears to be as follows:
The PCI strategy was better than OMT in reducing ischemia burden by ≥5%. The authors place emphasis on a significant unadjusted association between a reduction in ischemic burden and a reduction in risk (but a critical reader will note that the multivariable analysis was not significant). On the basis of the unadjusted result, the authors conclude that reducing ischemic burden by ≥5% should be a treatment goal and, by implication, that PCI plus OMT would be better than OMT alone for that purpose.
Untangling the Logic
The substudy was not designed to test whether targeting treatment to a certain threshold of ischemia reduction benefits patients; it simply suggested that the PCI strategy was more effective than OMT alone in reducing ischemic burden. [Given that the subjects in this substudy represented a convenience sample of patients and the two treatment groups were not similar it is not clear that they have even demonstrated that PCI reduces ischemic burden more effectively – this is not a comparison of groups that were obtained by randomization – a nuance that is acknowledged but may be easy to miss – and they do not do what is necessary to control for the differences.] Notably, even if PCI reduced ischemic burden, PCI did not significantly reduce the risk for clinical events or substantially affect symptoms in the overall trial. Moreover, in the substudy,the reduction of ischemic burden also did not reduce the risk for events (according to the multivariable analysis in the substudy, which was important since those who had a reduction were likely different at baseline from those who did not – but they do not present this comparison). If ischemic burden reduction had really mattered, the trial should have shown evidence of clinical differences between the two treatment groups.
Another issue is that ischemic burden is a surrogate for the clinical outcomes that affect patients. Surrogate endpoints can be useful when we do not have clinical outcomes to examine. In COURAGE, clinical outcomes were reported. Perhaps the most important finding in this substudy is the failure of ischemic burden as a surrogate endpoint. If COURAGE had just used ischemic-burden reduction as the primary endpoint, the PCI advocates would have declared victory. However, the trial identified no difference between the groups in the major clinical endpoints that were measured, and the surrogate endpoint would have been useless in predicting the outcome of the trial. This finding suggests to me that treating to a target reduction in ischemic burden is not useful.
There are also other issues to consider regarding the study design. In order for the trial participants to have their ischemic burden tracked over time, they had to be around for the follow-up study. They are, then, patients who survived at least 6 months and, in some cases, up to 18 months. We do not have information about who in this substudy was lost to follow-up or did not return for a follow-up MPS study — and whether the time to the follow-up MPS was similar in both intervention groups. That information is essential to evaluating the substudy.
A Better Line of Inquiry
What nuclear substudy might have been most useful to a clinician? I personally would have wanted to know whether PCI was better than OMT alone among patients with a large ischemic burden at baseline. Such an analysis would have investigated an interaction — whether the difference between the PCI and OMT-alone groups varied according to baseline ischemic burden. A reasonable hypothesis would have been that the PCI strategy was superior for patients who initially had the most ischemia according to MPS. Unfortunately, the investigators could not do that analysis, probably due to lack of resources.
Do you think this COURAGE substudy complements the original trial? How do you assess the authors’ suggestion to target a certain reduction in ischemic burden for patients like those in this trial? How would you have written the conclusion to the abstract?
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