July 21st, 2014
Probiotics May Help Reduce Blood Pressure
Larry Husten, PHD
As interest in probiotics has grown in recent years, some evidence has emerged that probiotics may favorably reduce blood pressure, but trials have been small and inconsistent. Now a meta-analysis published in Hypertension suggests that the blood-pressure lowering effects of probiotics may be genuine.
Saman Khalesi and colleagues analyzed data from nine parallel, randomized, controlled trials including 543 participants. Overall, the probiotic arms had a 3.56-mm Hg reduction in systolic blood pressure and a 2.38-mm Hg reduction in diastolic BP, relative to controls. A larger reduction in blood pressure was observed in trials in which baseline blood pressure was at least 130/85 mm Hg, when treatment lasted at least 8 weeks, and when the daily dose of probiotics contained a larger number of colony-forming units.
The authors note that although the treatment effect was “modest … even a small reduction of BP may have important public health benefits and cardiovascular consequences.” They conclude that their findings “suggest that probiotics may be used as a potential supplement for future interventions to prevent hypertension or improve BP control.”
“The small collection of studies we looked at suggest regular consumption of probiotics can be part of a healthy lifestyle to help reduce high blood pressure, as well as maintain healthy blood pressure levels,” said the lead author of the study, Jing Sun, in a press release. “This includes probiotics in yogurt, fermented and sour milk and cheese, and probiotic supplements.”
July 21st, 2014
Study Finds Flaws in Catheter-Directed Thrombolysis for DVT
Larry Husten, PHD
In recent years, catheter-directed thrombolysis (CDT) has been added to the current standard of anticoagulation therapy in some patients with deep vein thrombosis (DVT). The hope was that CDT would help reduce the high rate of post-thrombotic syndrome (PTS), but now an observational study finds no benefits and some important disadvantages associated with CDT.
In a report published in JAMA Internal Medicine, Riyaz Bashir and colleagues analyzed data from more than 90,000 patients hospitalized for DVT, 3649 of whom received CDT plus anticoagulation. In-hospital mortality did not differ significantly between the CDT patients and matched controls who received anticoagulation alone (1.2% and 0.9%, respectively; p=0.15). However, the CDT group had significantly higher rates of pulmonary embolism, intracranial hemorrhage, and vena cava filter placement. The CDT group also had longer and more expensive hospital stays.
The authors acknowledge the limitations of observational studies and call for randomized trials “to evaluate the magnitude of the effect of CDT on outcomes such as mortality, PTS and recurrence of DVT.” They conclude that CDT “should be offered only to patients with a low bleeding risk. … it is imperative that the magnitude of benefit from CDT be substantial to justify the increased initial resource utilization and bleeding risks of this therapy.”
July 17th, 2014
Clinical Events vs. Quality of Life: An Insider’s View of TACT
Gervasio Antonio Lamas, MD
On July 1st, two Trial to Assess Chelation Therapy (TACT) articles were published that appear to show contradictory results regarding the effects of chelation therapy on clinical events and the quality of life.
For those who don’t live and breathe TACT (as I do, being one of the investigators), the 10-year trial tested a disodium ethylene diamine tetra acetic acid (EDTA)-based chelation solution versus placebo chelation, and high doses of oral multivitamins and multiminerals versus oral placebo in post-MI patients age 50 or older on OMT including statins and anti-platelets. For this piece, I will focus on the active-active versus placebo-placebo comparison.
The clinical study appears in the American Heart Journal and reports endpoints in the four factorial groups of TACT. In the overall group, there was a 26% reduction in combined cardiovascular events by active chelation plus active oral vitamins (5-year NNT=12; p=0.016). In patients with diabetes, there was a 51% reduction in combined cardiovascular events by active chelation plus active oral vitamins (5-year NNT=5.5, p<0.001). There is simply nothing else like this in diabetes. Safety data were solid. Edetate disodium chelation, as administered in TACT, was safe.
Over one million Americans survive an MI annually and, of these, about half have experienced a recurrent MI; thus, they are potentially TACT-type patients. A total of 68% of patients with diabetes die with heart disease contributing to their deaths. The public health implications of this trial are obvious. Curiously, medical media — Medscape and theheart.org in particular — chose not to cover this paper, and instead covered the second study and its negative quality of life results. Lay media did not even blink. However, this is a subject for another day.
The second study appears online in Circulation:Cardiovascular Quality and Outcomes, and in it we analyze quality of life (QOL) in a randomly selected 911-patient subgroup of TACT. Patients were mostly asymptomatic at baseline. We prospectively collected a battery of QOL instruments at baseline and at 6, 12, and 24 months after randomization. The primary endpoint was the Duke Activity Status Index (DASI). The analyses were intention-to-treat. We found no treatment-related improvement in QOL.
QOL is a complex endpoint in clinical trials and it always has to be viewed in the context of the study population and the overall benefit of the therapy. If a study population is mostly asymptomatic, it is hard to improve the QOL. TACT patients were mostly asymptomatic. Few had severe angina, so an improvement in the QOL should have been difficult to demonstrate, as it was. There are other effective treatments with similar apparent dissociations between clinical events and QOL. For example, aspirin, ICDs, and statins reduce cardiovascular events, but do not improve QOL, like chelation. Nitrates, on the other hand, improve QOL in angina, but do not reduce events. Therefore, clinical events are key.
Finally, we need to put this emerging literature in context for clinicians. It seems clear that the underlying mechanisms for benefit need exploration. But it is also clear that the treatment, as practiced in TACT, is safe and effective. Future studies will likely be performed, but there is no money on the table yet.
However, there is more to what we do than science. I see patients who want to know how to reduce their risk of another cardiac event. I am finding it increasingly difficult, particularly when I see diabetic post-MI patients (43% mortality reduction, 5-year NNT=12) to tell them that aspirin, statins, ACE inhibitors, and an annual stress test are all they have for options.
Share your thoughts on TACT and chelation therapy.
July 17th, 2014
SIMPLE Can Be Complicated
Joseph G Akar, MD/PhD and Johnny Michel Abboud, MD
The two of us, Joe on the west side of the Atlantic and Johnny across the pond, have always differed in our opinions about routine intraoperative defibrillation testing (DT) of implantable cardioverter-defibrillators (ICDs). Finally, though, we have reached a consensus. In our opinion, results from the SIMPLE trial, reported at the Heart Rhythm Society meeting in May, settle the issue in favor of no DT. However, the SIMPLE findings now expose a 64,000-pound gorilla in the room that may limit the adoption of this strategy in the U.S.
The value of routine DT has been controversial. The vast majority of randomized trials that underpin ICD guidelines have used routine DT, but growing clinical experience suggests that eliminating its routine use is safe and effective. Proponents of each approach have held strong and passionate opinions, prompting a real difference in clinical practice patterns. Many physicians routinely perform DT, but many practitioners, especially outside the U.S., are abandoning the practice.
In the SIMPLE trial, 2500 patients undergoing initial ICD implantation in 18 countries were randomly assigned either to a strategy of intraoperative DT or no DT. A lack of DT was not associated either with greater mortality risk or with worse clinical outcomes. Very notably, the strategy of no DT was associated with fewer perioperative complications (3.0%, vs. 4.5% with testing; P=0.047).
We believe that these results conclusively show that abandoning routine DT is safe for the majority of patients undergoing ICD implantation. But time will tell whether the transatlantic debate is finally over. As with all practice-changing trials, various challenges hinder widespread dissemination and adoption of the results. This is particularly true of SIMPLE because the stakes of a failed shock are high.
With SIMPLE there is also an additional economic challenge that is unique to the U.S.: Intraoperative DT carries a reimbursement code that is separate and independent of the code for the ICD implant procedure itself. This could serve as a financial disincentive for abandoning routine DT.
In effect, the SIMPLE trial has put the spotlight on thorny questions that are not so simple after all:
- To what degree will reimbursement rules impede adoption of SIMPLE’s results?
- Will the Center for Medicare & Medicaid Services bundle ICD implantation with DT, to prevent reimbursement considerations from influencing medical decision making?
Share your thoughts about the SIMPLE dilemma here on CardioExchange.
July 16th, 2014
HPS2-THRIVE: The Final Chapter in the Niacin Story?
Nicholas Downing, MD and Harlan M. Krumholz, MD, SM
Today’s publication of findings from the HPS2-THRIVE trial raises uncomfortable questions for physicians. Even if some subgroups who may benefit from niacin are yet to be studied, did the drug deserve to generate almost a billion dollars in sales? Could we have learned sooner about the significant increases in adverse effects that HPS2-THRIVE found?
Kudos to the marketers. They took a drug that is unpleasant to take and transformed it into one of America’s more lucrative drug franchises, convincing many that the proprietary form of the drug was worth the cost. HPS2-THRIVE revealed that extended-release niacin, even with the laropiprant to blunt the flushing, could not be tolerated by a third of the participants in the run-in period, and adherence across the duration of the trial was less than 80%. (Click here for CardioExchange’s news coverage of the trial.)
From a regulatory standpoint, the FDA hit the nail on the head when it refused to approve Merck’s combination of niacin and laropiprant in 2008, seemingly in an effort to defer a decision until the outcomes data from HPS2-THRIVE became available. In contrast, the European Medicines Agency did approve the drug, but it promptly withdrew its approval in 2013 as the top-line results of HPS2-THRIVE were announced.
Although the rationale behind the FDA’s decision is not publicly available, it appeared to mark a deviation from the agency’s earlier willingness to approve lipid-lowering drugs on the basis of surrogate endpoints. The FDA’s approach to the novel PCSK9 inhibitors, which powerfully lower LDL but have an uncertain effect on real-world outcomes, represents an important opportunity for the agency to reaffirm its commitment to emphasizing meaningful efficacy data.
Lastly, the commercial success of AbbVie’s niacin product, Niaspan, is quite a story. The company booked more than $900 million in sales of the drug in 2012, the first full year after AIM-HIGH was halted, with price increases offsetting declining prescriptions for the drug. It went on to clock $650 million in sales in 2013, after the HPS2-THRIVE results were first announced. Although the generic competition, which finally arrived at the end of 2013, will rapidly deplete AbbVie’s cash cow, physicians who continue to prescribe niacin in great numbers may now be asking themselves why — and at what cost to patients and the health care system?
Share your thoughts with us here.
July 16th, 2014
New Evidence Fuels Concerns About The Safety Of Niacin
Larry Husten, PHD
The string of failures– for HDL therapies in general and for niacin in particular– continues unabated. The publication of the main results of the HPS2-THRIVE trial, along with new information from the AIM-HIGH trial, provide no evidence of a beneficial effect for niacin but do raise concerns that it may cause serious adverse effects.
In HPS2-THRIVE, published in the New England Journal of Medicine, the combination of extended-release niacin and laropiprant (Tredaptive, Merck) was compared to placebo in more than 25,000 high risk patients already receiving statin therapy. Patients in the treatment group had significant reductions in LDL cholesterol (10 mg/dL), significant increases in HDL (6 mg/dL), and significant reductions in triglycerides (33 mg/dL). But there was no difference in the rate of major vascular events (13.2% for niacin-laropiprant versus 13.7% for placebo, RR 0.96, CI 0.90 – 1.03, p=0.29). There was also no significant difference in an exploratory analysis of patients with low HDL and high triglyceride levels who might be expected to benefit the most from niacin therapy.
There were signs of harm associated with niacin-laropiprant. Serious adverse events occurred more often in the combination group (55.6% versus 52.7%, p < 0.001). Diabetes complications were especially concerning. Among patients who had diabetes at the start of the trial, serious complications related to diabetes occurred in 11.1% of patients in the treatment group versus 7.5% of patients in the control group, a 55% increase. Among patients who did not have diabetes at the start of the trial, there was a 32% increase in the diagnosis of diabetes in the treatment group (5.7% versus 4.3%.
Niacin therapy was also associated with significant increases in infections (8% versus 6.6%, p< .001) and bleeding (2.5% versus 1.9%, p < 0.001). These findings came as a surprise to the investigators. There were also significant increases in other, previously known adverse effects of niacin, including gastrointestinal, musculoskeletal, and skin-related adverse events.
The troubling findings of HPS2-THRIVE were not contradicted, and were at least partially confirmed, by a new analysis from the AIM-HIGH trial published in the correspondence section of NEJM. The trial randomized more than 3,400 patients with stable coronary artery disease to extended-release niacin (Niaspan, AbbVie) or placebo in addition to simvastatin and, if needed, ezetimibe. The trial was stopped early for lack of efficacy.
In their new analysis the AIM-HIGH investigators report a significant increase in serious infections (8.1% versus 5.8%, p=0.008) and a nonsignificant increase in serious bleeding events (3.4% versus 2.9%, p=0.36). But there was also a significant increase in all bleeding events in AIM-HIGH (10.1% versus 8.1%%, p=0.04).
The AIM-HIGH authors were reluctant to conclude that the new adverse effects seen in HPS2-THRIVE were also a genuine problem in AIM-HIGH. The findings, they wrote, “should be considered to be provisional and exploratory.” But the HPS2-THRIVE authors were more certain:
In light of the consistency of the results with those from previous trials of niacin alone, we believe that the findings from HPS2-THRIVE are likely to be generalizable to all high-dose niacin formulations. Although niacin might still be relevant for particular patient groups (e.g., patients at high risk for vascular events who have high levels of LDL cholesterol), any potential benefits should be considered in the context of the observed hazards.
Much of the initial discussion about HPS2-THRIVE revolved around the relative importance of the niacin and laropiprant components of the drug. In an accompanying editorial, Donald-Lloyd Jones writes that “the consistency of the overall findings with earlier trials of niacin alone suggest that niacin is the major problem.”
What now should we make of niacin and the HDL cholesterol causation hypothesis? On the basis of the weight of available evidence showing net clinical harm, niacin must be considered to have an unacceptable toxicity profile for the majority of patients, and it should not be used routinely.
The failure of the niacin trials, as well as other HDL-related trials, “lends further credence to the notion that HDL cholesterol is unlikely to be causal.”
Previous posts about niacin:
- HPS2-THRIVE: A ‘Disappointing But Clear’ Result
- Is HDL Fool’s Gold?
- Niacin Therapy in the Crossfire
- Why Has Niacin Therapy Failed to THRIVE?
- HPS2-THRIVE: No Benefit, Signal of Harm for Niacin Therapy
- An Ad That Doesn’t Tell the Entire Story — Part 2: Niaspan
- Experts Clash Over AIM-HIGH
- After AIM HIGH, What Future for Niacin? A CardioExchange Panel
- AIM-HIGH: No Benefit for Niacin on Top of Statins
- AIM-HIGH Halted: A Death Knell for the HDL Hypothesis? Six Experts Weigh In
July 14th, 2014
Can Bivalirudin Stand the HEAT?
Eric Jose Velazquez, MD
CardioExchange’s Harlan Krumholz interviews Peter Berger, coauthor of an editorial accompanying the results of the HEAT-PPCI study comparing bivalirudin and unfractionated heparin during primary PCI. The study is published in the Lancet; details are available in CardioExchange’s news coverage.
Krumholz: Is this study game-changing enough to shift practice and influence guidelines?
Berger: Usually a single study is not sufficient to change practice. However, the bigger and better the study, the less that rule ought strictly to be adhered to. Also, it must be remembered that there aren’t any prior studies that indicate that bivalirudin is superior to heparin alone (at the dose in this study; let alone with other doses, radial access, and potent P2Y12 inhibition). I am not counting the BAT trial from the late 1980s, which compared different doses of both drugs, included prolonged postprocedural infusions, and involved 8-Fr sheaths; that trial’s findings were reported as negative in the New England Journal of Medicine but were reanalyzed years later and reported to be positive in American Heart Journal— and the BAT trial was not in STEMI patients. So the question is not whether prior studies ought be abandoned because of a single, more-recent study. There aren’t any prior studies to help clinicians decide whether to use bivalirudin or heparin alone in STEMI patients.
When study results favored bivalirudin or suggested equivalence of heparin with a more expensive regimen, proponents of the more-expensive drug could not be heard advocating for additional studies.
It should also be noted that due to a great many price increases, bivalirudin is approximately as expensive (average weighted cost of $875 per vial, and in some cases two vials are required) as the glycoprotein (GP) IIb/IIIa inhibitors abciximab and eptifibatide. (Tirofiban is much less expensive than the other GPIIb/IIIa inhibitors, but has <5% of market share in the U.S. It is more commonly used in Europe.)
So, my answer is that clinicians will have to decide for themselves whether one large, well-done trial — the first examining these two drugs in these doses — should lead them to change practice and use a drug that was shown to be more effective and as safe as another, at <1/400th the price.
Krumholz: You have indicated elsewhere that you were already weighing changes in your practice before these findings were published. What evidence prompted you to consider such changes, and why?
Berger: The cath lab where I practice is almost entirely radial (except in patients with contraindications to its use). The most common site of vascular hemorrhage is the arterial access site, which is reduced 70%–90% by use of the radial artery, compared with the femoral. So we were already examining whether the frequency of bivalirudin use ought be reduced in certain patients and clinical situations.
Krumholz: How will this influence the use of decision aids for determining bleeding risk in patients undergoing PCI?
Berger: We don’t use any formal decision aids for determining bleeding risk. We include arterial access site and other clinical and procedural characteristics known to be associated with reduced bleeding. I readily acknowledge that our ability to predict bleeding in an individual patient is poor. But an important question is, if a patient is at increased risk of bleeding, which antithrombin should be used? Bivalirudin, say many proponents of bivalirudin; the HEAT-PPCI results would suggest heparin (at 70U/kg). And of course, the results of any trial should only be applied to patients similar to those enrolled (STEMI patients, etc., in HEAT-PPCI).
Krumholz: You point out the high percentage of radial access in this study, but subgroup analysis found no significant interaction was found between access site and the primary outcome. Doesn’t this imply that the results apply to non-radial cases as well?
Berger: Subgroup analyses lack the power to reliably detect potential differences that may exist. And statistical tests for interactions are notoriously insensitive. We do know for a fact that bleeding is more common with femoral than radial access. We don’t know if the results of HEAT-PPCI would have differed had femoral access been utilized exclusively. My point was that proponents of bivalirudin believe it to be safer than heparin (albeit at higher doses); if such a safety difference exists and were to favor bivalirudin over even 70 U/kg of heparin, it might be less relevant if radial artery access is used.
I will note that NAPLES III did not favor bivalirudin over 70 U/kg of heparin, and only femoral artery access was permitted in that trial of exclusively patients at increased risk of bleeding. And if efficacy and safety outcomes are indeed similar with heparin and bivalirudin, that is obviously a huge win for heparin.
Krumholz: Is this a win overall for low-cost care?
Berger: Yes. I am not sure what role the cost of drugs or procedures ought to play when the more expensive one is associated with a superior outcome. Which readers of this blog want the cheaper but less effective or less safe treatment for themselves? But when different drugs are comparable in safety and efficacy, price should play a major role in selecting which one to administer. And again, in this case, 70 U/kg of heparin was more effective than bivalirudin, and as safe.
July 14th, 2014
Poor Retention of Guideline Recommendations
Harlan M. Krumholz, MD, SM
In an article published in the May 28th edition of JAMA, a group of physicians addressed the question of the retention of clinical practice guideline recommendations over time. The investigators assessed the durability of Class I recommendations to provide a perspective on how often actions that are deemed mandatory become less enthusiastically endorsed as more evidence emerges.
Of 619 Class I recommendations in 11 index guidelines published between 1998 and 2007, 20% of the recommendations did not appear in the subsequent guideline and 9.2% were downgraded or reversed. Even among the recommendations that were supported by multiple trials, 5.7% were not retained in subsequent versions of guidelines and 3.8% were downgraded or reversed. The Class I recommendations at the highest risk for being omitted, downgraded, or reversed were those based on consensus opinion, followed by those based on a single randomized trial or nonrandomized trials.
I would have thought that the strongest recommendations in a guideline would be very unlikely to change over time. In this disturbing study, a substantial proportion of Class I recommendations were not durable over even a 10-year period, showing us that uncertainty surrounds even the strongest guideline recommendations. I wonder whether the writing committees would have been able to predict which of the Class I recommendations were most likely to be omitted, downgraded, or reversed based on future studies. I’d bet they could not have guessed correctly.
JOIN THE DISCUSSION
Why do you think such a high percentage of guideline recommendations are omitted, downgraded or reversed? Does this information affect your opinion of the importance of existing guidelines?
July 14th, 2014
Selections from Richard Lehman’s Literature Review: July 14th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
The BMJ 12 July 2014 Vol 349
Leucocyte Telomere Length and Risk of CVD: This issue of The BMJ makes me wonder if the words “telomere” and “Mendelian randomisation” are just ways of making readers’ eyes glaze over. Telomeres are the things at the end of your chromosomes that show how much longer you have left to live. They do not cause anything. A study here finds that “available observational data show an inverse association between leucocyte telomere length and risk of coronary heart disease independent of conventional vascular risk factors. The association with cerebrovascular disease is less certain.” Is this interesting? Well, maybe, in a spooky kind of way. Short telomeres=earlier death. Man with sickle has many blades. Hah!
Association Between Alcohol and CVD: Someone recently told me that the link between alcohol and reduced coronary disease is purely observational, and that therefore we should not recommend alcohol as part of the “Mediterranean” diet. I didn’t want to argue, but you could say much the same about smoking and cardiovascular disease. The evidence of benefit from alcohol is solid, robust, and repeatedly found wherever you look, but almost impossible to replicate experimentally for the very good reason that people who drink do so as part of their daily pleasure. Yet the several hundred authors of this paper have tried to do something even more impossible: make this evidence disappear by a Mendelian hat trick. I am completely baffled that they should (a) want to do it and (b) think this is good enough: “Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.” No it doesn’t.
July 11th, 2014
Do FFR and IVUS Feed the Elephant?
Richard A. Lange, MD, MBA and L. David Hillis, MD
In an observational study of all patients who underwent PCI in National Health Service hospitals in London between January 1, 2004, and July 31, 2011 (n = 41,688), fractional flow reserve (FFR)-guided and intravascular ultrasonography (IVUS)-guided PCI were not associated with improved long-term survival when compared with standard angiography-guided PCI (performed on the basis of visual lesion assessment).
In an accompanying editorial, Aseem Malhotra remarks: “The elephant in the room is that randomized studies (including patients at low risk and high risk) have not demonstrated outcomes benefit for stenting stable coronary disease in addition to optimal medical therapy despite its widespread use.”
This follows on the heels of a recent Circulation paper by Hopkins cardiologist, Armin Arbab-Zadeh, who notes that “The rationale for the FFR concept…is based on a common misconception of the relationship between provocable myocardial ischemia and risk of adverse cardiac events.”
JOIN THE DISCUSSION
Does FFR/IVUS guided-PCI prevent MI or death?
Are FFR and IVUS overused or underused?
Do you ever discuss FFR or IVUS with your patients?
Does treating provocable ischemia with PCI prevent MI or death?
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