January 19th, 2012
Are We Ready to Stop Treating Cholesterol Levels and Start Treating Risk?
Harlan M. Krumholz, MD, SM
We are on the cusp of the Fourth Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel IV). As internal deliberations continue, it’s a good time to consider abandoning cholesterol targets as the central focus of the recommendations.
Statins are the lipid lowering drugs with the strongest evidence of benefit (some medications, like ezetimibe, have yet to be shown to improve patient outcomes). Statins reduce risk across the spectrum of LDL values. The first generation drugs reduce risk about 20% and the higher potency and high dose statins reduce it by about another 15%. If you bluntly target LDL, you will be:
- treating some patients with low risk (those without other risk factors and LDL that is not exceptionally high)
- neglecting some high-risk patients (those without elevations in LDL but with many other risk factors).
Maybe it is time to decide about treatment based on risk. No trial has ever tested the target strategy—the major trials tested fixed doses of drugs—so it is not that we are abandoning RCT evidence. Rod Hayward and I have written an open letter to the Guideline writing committee in Circulation: Cardiovascular Quality and Outcomes.
What do you do in your practice? How would you recommend that the committee tackle this issue?
January 18th, 2012
New Enrollment in FAME II Halted After Interim Analysis Shows Benefits of FFR
Larry Husten, PHD
Following a positive interim analysis showing that fractional flow reserve-guided PCI was superior to optimal medical treatment, an independent data and safety monitoring board (DSMB) has recommended that patient enrollment in the ongoing FAME II trial be stopped. The news was announced by the trial sponsor, St. Jude Medical.
FAME II (Fractional Flow Reserve-Guided Percutaneous Coronary Intervention Plus Optimal Medical Treatment Versus Optimal Medical Treatment Alone in Patients with Stable Coronary Artery Disease) investigators had planned to randomize 1832 patients with stable coronary artery disease to either PCI guided by FFR plus optimal medical treatment (OMT) or OMT alone. At the time of the announcement, 1219 patients had been randomized.
According to the company, the DSMB recommendation was based on an increase in the risk of major adverse cardiac events in patients randomized to OMT alone. “In particular, patients receiving OMT alone experienced a highly statistically significant increased risk of hospital readmission and urgent revascularization, and the DSMB determined that this difference was highly unlikely to change with inclusion of more patients,” the company stated. There were no significant differences between the groups in the rates of death or MI.
It should be noted that all patients in FAME II underwent FFR prior to randomization, according to the original announcement of the trial. Patients who had hemodynamically significant lesions as assessed by FFR were then randomized to PCI or OMT. The trial was designed to address the limitations of COURAGE, in which CAD patients as documented by angiography were randomized to PCI or OMT. However, the follow-up to COURAGE, the ISCHEMIA trial, will randomize ischemic patients to PCI or OMT without prior angiography. FAME II does not appear to address the question of which patients should undergo angiography in the first place.
January 18th, 2012
Cangrelor and Alaska’s “Bridge to Nowhere”
Richard A. Lange, MD, MBA and L. David Hillis, MD
The Gravina Island Bridge (also known as The Bridge to Nowhere) was a proposed bridge to replace the ferry that currently connects Ketchikan, Alaska (population, 14,000) to the Ketchikan International Airport on Gravina Island (population, 50) at a projected cost of $398 million. The bridge was to have been nearly as long as the Golden Gate Bridge and taller than the Brooklyn Bridge.
A study published yesterday, entitled “Bridging Antiplatelet Therapy With Cangrelor in Patients Undergoing Cardiac Surgery,” showed that in patients who discontinue thienopyridine therapy before cardiac surgery, the use of cangrelor compared with placebo resulted in a higher rate of maintenance of platelet inhibition, as assessed with the VerifyNow P2Y12 platelet assay. (See also our CardioExchange news coverage here.)
Cangrelor, an intravenously administered P2Y12 receptor antagonist with a rapid offset effect (half life, 3-6 minutes), was used to “bridge” patients to surgery after irreversible platelet P2Y12 inhibitors (i.e., clopidogrel or prasugrel) were discontinued. Cangrelor infusion was initiated a median of 29 hours (IQR, 11-38) after thienopyridines were discontinued and was administered for up to 7 days until shortly (1-6 hours) before surgical incision. Cangrelor was associated with a numerical increase in minor, but not major, bleeding before CABG, and with no increase in CABG-related bleeding events.
What’s the connection?
It is the rare person who flies from Ketchikan…or experiences a serious ischemic event after cessation of clopidogrel 5 days before CABG. As a result, the benefits of the Alaskan bridge — and of bridging antiplatelet therapy with cangrelor — are unlikely to justify its cost. Both the bridge to Gravina Island and the VerifyNow platelet assay are models in search of rationales. Certainly, we can build (or perform) it, but does it have a meaningful impact?
In your patients referred for CABG, do you need to give “bridging antiplatelet therapy?”
If so, when and how often?
Would you support the approval of cangrelor for “bridging therapy”?
January 17th, 2012
Cangrelor Proposed as Bridge to Surgery
Larry Husten, PHD
As a potent and reversible platelet inhibitor, cangrelor has been proposed for use in a bridging strategy for patients scheduled for surgery who are currently taking clopidogrel or another thienopyridine. To test this strategy, the BRIDGE investigators randomized 210 ACS or stent patients awaiting CABG and taking a thienopyridine to receive either cangrelor or placebo for at least 48 hours prior to surgery.
During the treatment period, platelet reactivity was lower in the cangrelor group than in the placebo group. There was no significant difference in the rate of surgery-related bleeding.
- Platelet inhibition (defined as PRU <240) occurred in 98.8% of patients in the cangrelor group compared with 19.0% of patients in the placebo group (RR 5.2, CI 3.3-8.1, p< 0.001).
- Excessive CABG surgery–related bleeding occurred in 11.8% of the cangrelor group compared with 10.4% of the placebo group (RR 1.1, CI 0.5-2.5, p=0.763).
Writing in JAMA, the researchers conclude:
Our data support the hypothesis that intravenous cangrelor is a feasible management strategy in patients waiting for cardiac surgery who require prolonged platelet P2Y12 inhibition after thienopyridine discontinuation.
(For our Interventional Cardiology co-moderators’ take on this study, click here.)
January 17th, 2012
Selections from Richard Lehman’s Weekly Review: Week of January 16th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint selections from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. A British general practitioner, Dr. Lehman writes in an engaging, sometimes provoking, style that conveys his generalist point of view on what matters for patients. These chosen summaries are relevant to our audience, but we encourage members to engage with the entire blog.
Week of January 16th
(click here to read the full review at BMJ.com)
JAMA 11 Jan 2012 Vol 307
157 There’s a general feeling among cardiologists that low potassium is a bad thing, but this interesting observational study of 38,689 patients with acute myocardial infarction shows that high potassium can be even worse. On admission with AMI, potassium levels are normally distributed (figure 1): mortality in relation to potassium levels thereafter follows a classic U-shaped distribution, bottoming out under 10% between 3.5 and 4.5 mmol/L but hitting an alarming 60+% by the time you reach the pretty modest level of 5.5 mmol/L. The strength of the association on both sides of the curve really is quite dramatic, which presumably is why JAMA is releasing the full text of this paper free online. What it means for clinical practice is not for me to guess: go instead to the learned editorial.
NEJM 12 Jan 2012 Vol 366
130 The Greek word for fennel is marathon, and it was on a fennel-covered field that the Greeks repulsed the army of Persia — a most regrettable encounter which has retarded the progress of civilization to this day. To quote Wikipedia: “The traditional story relates that Pheidippides (530 BC–490 BC), an Athenian herald, was sent to Sparta to request help when the Persians landed at Marathon, Greece. He ran 240 km (150 mi) in two days. He then ran the 40 km (25 mi) from the battlefield near Marathon to Athens to announce the Greek victory over Persia in the Battle of Marathon (490 BC) with the word “Νενικήκαμεν” (Nenikékamen, “We have won”) and collapsed and died on the spot from exhaustion.” Serves him right: it was a very foolish thing for a forty-year-old man to do. Moreover, if he was so out of breath, he did not need to use the reduplicative perfect tense. Male marathon runners continue to drop dead at an increasing rate (2 per 100,000), and this study identifies the chief causes as atherosclerotic coronary disease in the older runners and hypertrophic cardiomyopathy in the younger. If only the Persians had won: we might have a world free of marathons, Olympic games and unhelpful Greek medical terms like hypertrophic cardiomyopathy (or such really exotic examples as paragonimiasis).
Lancet 14 Jan 2011 Vol 379
123 Idrabiotaparinux is a word which belongs to no known human language: it is made up of “idraparinux” (perhaps inspired by the characters in Astérix, as this is a French drug) and biotin, sometimes known as vitamin H (a Greek root sneaks back in here). You will, I am afraid, have to memorize this word, because idrabiotaparinux marks a breakthrough in anticoagulation. It is a safe, effective anticoagulant which inhibits factor Xa: it has a terminal half-life of 66 days and a simple antidote in the form of avidin (an egg-derived substance). In this study, it was given by weekly subcutaneous injection, but there seems no reason why that could not be monthly. Patients with acute symptomatic pulmonary embolism were started on enoxaparin and then allocated (with complex blinding) either to idrabiotaparinux or to INR-adjusted warfarin. As usual in The Lancet, the manufacturers are allowed to sneak statistically non-significant claims for their product into the abstract: but the fact remains that idrabiotaparinux is non-inferior to warfarin in preventing VTE following PE, and probably a lot more convenient for most patients.
BMJ 14 Jan 2012 Vol 344
The Hypertension in the Very Elderly Trial (HYVET) recruited 3,845 subjects over the age of 80 using a huge team of investigators from 11 countries, dominated by Bulgaria, Tunisia, and China, between 2000 and 2003. Indapamide was the main intervention used to get the systolic BP under 160mm Hg — a strange choice since there are so many other thiazide diuretics that cost practically nothing. The second-line drug was perindopril, also made by the co-sponsor of the trial, Servier. Oh well: there are no doubt plenty of people still taking these drugs in the centres chosen. And they continue to benefit, as the BMJ shows us in this paper about an open-label follow-up cohort; though I imagine the subject who was 105 at the start may no longer be among them.
January 12th, 2012
The Safety of the Long Distance Runner
Larry Husten, PHD
Long distance runners may be lonely but they are not at high risk for sudden cardiac arrest, according to a study published in the New England Journal of Medicine. The RACER (Race Associated Cardiac Arrest Event Registry) investigators analyzed data from 10.9 million registered participants in marathons and half-marathons that took place in the U.S. during the first decade of this century.
They identified 59 cases of cardiac arrest; 40 occurred during marathons and 19 during half-marathons. The mean age of the runners with cardiac arrest was 42 years; 51 were men and 8 were women.
The rate of cardiac arrest was 1 per 184,000 participants; the rate of death was 1 per 259,000 participants. The authors describe this event rate as “relatively low” and compared it with rates in collegiate athletics (1 death per 43,770), triathlons (1 death per 52,630 participants), and previously healthy middle-aged joggers (1 death per 7620 participants).
Event rates were higher for marathons than for half-marathons and for men than for women. Most events occurred during the last quarter of the race. One possibly disturbing trend – for men but not women – was that the incidence of cardiac arrest increased during the second half of the decade.
The cause of cardiac arrest was determined in 31 cases – hypertrophic cardiomyopathy and possible HCM were the most frequent underlying causes of death. The authors express surprise at the absence of any subjects with coronary plaque rupture. By contrast, in a separate correspondence published in NEJM, Alfred Albano and colleagues describe 3 male athletes who developed acute coronary thrombosis after finishing the 2011 Boston Marathon. They note that all 3 had arrived in Boston after a flight lasting longer than 4 hours.
January 12th, 2012
Selections from Richard Lehman’s Weekly Review: Week of January 9th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to be able to reprint selections from Dr. Richard Lehman’s journal review: a weekly blog at BMJ.org offering commentary on the latest literature. Dr. Lehman is a British general practitioner who started these reviews 14 years ago as brief notes to encourage further reading discussion among friends and colleagues. In his own words, they are still written in a style that tries to provoke and engage the reader while conveying the message of the articles from the point of view of a generalist trying to work out what matters for patients.
Each week, we’ll pull out a couple of his summaries that are relevant to this audience, but we encourage members to engage with the entire blog.
Week of January 9th
(click here to read the full review at the BMJ)
JAMA 4 Jan 2012 Vol 307
56 If you look at obesity measured by BMI, and then adjust for insulin resistance, hyperlipidaemia and high blood pressure, weight as such is actually a weak predictor of cardiovascular risk. Which may explain why the absolute benefit of bariatric surgery is not enormous, and is probably non-existent for obese individuals without other risk factors. This is a report from the Swedish Obese Subjects (SOS) study at a median of 14.7 years, and it shows a halving of cardiovascular events in the group treated with bariatric surgery. That sounds impressive, but absolute mortality difference actually amounts to 1.3% in favour of surgery. And the benefit was not related to baseline BMI in this study. Even longer term data are needed.
66 I have spent several afternoons over the last few months listening to presentations on readmission rates in US hospitals, wondering all the while how these compare with other health systems. For myocardial infarction, they are very high compared with other developed countries. “However,” say the authors, “this difference was greatly attenuated after adjustment for length of stay.” In other words, the facts that the US has the shortest stays for MI, and the highest readmission rates, are not unconnected.
NEJM 5 Jan 2012 Vol 366
9 A new era in secondary prevention after acute coronary syndrome is the headline of one birthday editorial, celebrating the success of low-dose rivaroxaban in reducing a composite end-point of death from cardiovascular causes, myocardial infarction, or stroke in 15,526 patients with recent ACS. And to be fair, this amounted to an actual (small) tally of lives saved: total mortality was reduced from 4.5% to 2.9%. It would take any competitor a comparable amount of effort to show benefit from its own fixed-dose anticoagulant, and two have already tried and failed (apixaban and dabigatran), perhaps because the dosing was wrong. Rivaroxaban also failed at a dose of 5mg b.d., but by halving this it was changed from an agent that caused too many bleeds to one which prevented more events than it caused. Good news for Johnson & Johnson and Bayer shareholders, then: but for post-ACS patients and health systems struggling to contain costs? For these, the “new era” is a mixed blessing: someone will need to interrogate the individual patient data from this vast 766-centre trial, and then we will have to wait at least a decade for evidence from trials of equal size to find out the optimal anticoagulant/antiplatelet cocktail for post-ACS patients.
20 But at least we can cross vorapaxar off the list right away: this new oral protease-activated–receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation simply caused more bleeds in post-ACS patients, without any countervailing benefit. That’s a pity: I rather like the name. (I took a shine to vorapaxar: What a shame we had to axe her).
January 11th, 2012
ASSERT Sheds Light on the Role of Subclinical AF in Stroke
Larry Husten, PHD
A new study published in the New England Journal of Medicine sheds some much-needed light on the precise role of subclinical atrial fibrillation (AF) in the prognosis and development of ischemic stroke. ASSERT (Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial) followed 2580 patients with a newly implanted pacemaker or ICD and with no previous diagnosis of AF.
At 3 months, subclinical AF lasting longer than 6 minutes had been detected in 10.1% (261) of the subjects. During 2.5 years of follow-up, 51 patients in the study had an ischemic stroke or systemic embolism. Of these, 11 were in the group with subclinical AF by 3 months. Patients with subclinical AF had more than double the risk for stroke or systemic embolism:
- HR 2.49; CI 1.28 – 4.85, p = 0.007
Subclinical AF accounted for 13% of the population attributable risk for ischemic stroke or systemic embolism, according to the ASSERT investigators. Patients with subclinical AF and a CHADS-2 score above 2 had nearly a 4% per year risk for stroke or systemic embolism.
In a second portion of the study, half of the patients with pacemakers were randomized to continuous atrial overdrive pacing, but this intervention had no significant impact on any of the endpoints in the study.
In an accompanying editorial, Gervasio Lamas praises the study but argues that the clinical implications are unclear: “The current evidence simply does not address the question of whether treatment with warfarin or other anticoagulants is justifiable for the asymptomatic patient who has had a 6-minute episode of atrial fibrillation.” Lamas recommends the CHADS-2 score as an aide in deciding which patients should receive anticoagulation.
January 11th, 2012
Director of UConn CV Research Center Accused of Scientific Misconduct
Larry Husten, PHD
Following an extensive investigation, Dipak Das, a professor in the Department of Surgery and director of the Cardiovascular Research Center at the University of Connecticut Health Center, has been accused of serious scientific misconduct. UConn has informed 11 scientific journals about the investigation.
Das had numerous publications on resveratrol and other nutrition-related cardiovascular subjects. According to an online biography, he was a founding editor and editor-in chief of the journal Antioxidant and Redox Signaling, and also served as associate editor of the American Journal of Physiology: Heat and Circulatory Physiology and consulting editor of Molecular and Cellular Biochemistry.
The news was announced by the UConn Health Center and has been reported by Retraction Watch, the Associated Press, and the Connecticut Mirror.
The University said the investigation had been sparked by an anonymous allegation of research irregularities in 2008, resulting in a 60,000 page report that found Das guilty of 145 counts of fabrication and falsification of data. UConn said it worked closely with the U.S. Office of Research Integrity during the investigation. UConn is now preparing to dismiss Das.
“While we are deeply disappointed by the flagrant disregard for the University’s Code of Conduct, we are pleased the oversight systems in place were effective and worked as intended,” said Philip Austin, interim vice president for health affairs at UConn. “We are grateful that an individual chose to do the right thing by alerting the appropriate authorities. Our findings were the result of an exhaustive investigation that, by its very nature, required considerable time to complete.”
Retraction Watch reported further details about Das, including the following:
Das appears to have had a relationship with a Las Vegas resveratrol maker called, unsurprisingly, Longevinex. The company has promoted his research, and Das also shows up in a lengthy video touting the nutrient as the next aspirin. The infomercial is guided by an “investigative reporter” named Gailon Totheroh, who is affiliated with the Christian Broadcasting Network.
Here is the list of journals notified by UConn:
- American Journal of Physiology – Heart & Circulatory
- Antioxidants & Redox Signaling
- Cellular Physiology & Biochemistry
- Free Radical Biology
- Free Radical Research
- Journal of Agriculture and Food Chemistry
- Journal of Cellular & Molecular Medicine
- Journal of Nutritional Biochemistry
- Journal of Pharmacology and Experimental Therapeutics
- Molecular & Cellular Cardiology
- Molecular & Cellular Chemistry
January 10th, 2012
Researchers Find Lower Sweet Spot for Potassium Levels in MI
Larry Husten, PHD
Current guidelines for the treatment of acute MI recommend that serum potassium be maintained between 4.0 and 5.0 mEq/L, and some believe that the upper limit could be raised to 5.5, but evidence is based on small, outdated studies. Now a study published in JAMA suggests that the ideal potassium range should be adjusted downward.
Abhinav Goyal and colleagues performed a retrospective cohort study of 38,689 MI patients. They found a U-shaped relationship between the postadmission potassium level and in-hospital mortality, with the lowest rate of death found in patients with potassium levels between 3.5 and 4.5.
Postadmission potassium level and mortality rate (adjusted odds ratio):
- <3.0: 46.2% (8.11)
- 3.0- <3.5: 11.4% (1.45)
- 3.5- <4.0: 4.8% (1)
- 4.0- <4.5: 5.0% (1.25)
- 4.5- <5.0: 10% (1.96)
- 5.0- <5.5: 24.8% (3.27)
- ≥5.5: 61.4% (6.44)
The authors point out that the clinical status of the patient may have been a cause rather than an effect of the potassium level. Since large randomized trials of this topic are unlikely, they recommend that “overly aggressive repletion of potassium levels (which is often automated through the implementation of hospital order sets) may not be advisable in patients with AMI (particularly in those with levels between 3.5 and 3.9 mEq/L), as potassium levels of at least 4.5 mEq/L are associated with harm.”
In an accompanying editorial, Benjamin Scirica and David Morrow acknowledge the limitations of the available data but support the recommendations of the study authors and state that for patients with potassium levels below 3.5, potassium repletion “remains reasonable,” but repletion for levels between 3.5 and 4.0 and target levels greater than 4.5 “do not appear justified.”
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