ACC 2006 part 2: Where's the controversy?

ACC 2006 part 2: Where's the controversy? Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical CenterNew York, NY Christopher Cannon MD Staff cardiologist Brigham and Women's HospitalBoston, MA Melissa Walton-Shirley MDCardiologist TJ Samson Community HospitalGlasgow, KY

Four controversial studiesfrom the recent ACC meeting • ASTEROID • A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden • UNLOAD • Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure • BASKET-LATE • Basel Stent Cost-Effectiveness Trial–Late Thrombotic Events • MIST • Migraine Intervention with STARflex Technology Valentin Fuster

ASTEROID: Study design • Between November 2002 and October 2003, 507 patients were enrolled in this intravascular ultrasound (IVUS) study • All patients were treated with 40-mg rosuvastatin daily • There was no control group • Participants were followed for 24 months, at which time they were reevaluated with IVUS • Baseline and 24-month IVUS data were available for 349 patients Nissen SE. ACC 2006 Scientific Sessions; March 13, 2006; Atlanta, GA. Abstract 411-8.Nissen SE, et al. JAMA 2006;295:1556. Valentin Fuster

ASTEROID:Lipid results (mean values)

ASTEROID: Primary efficacyparameters The mean change in the percent of atheroma volume was borderline because it was of an entire vessel • Average decrease in volume was 3.1% Results were significant at p=0.001 Valentin Fuster

ASTEROID: Conclusions • It appears that 40-mg rosuvastatin daily not only prevented progression of the disease but also slightly enhanced regression • However • The patient population was not high risk. • There was no control group. • The changes are minimal. Valentin Fuster

ASTEROID: Exciting results • The results really match up nicely with everything we know • There are limitations to the study • Not having a control group • Results show • Intensively modifying lipids has a dramatic effect on LDL-C levels • A trend toward a significant (15%) increase in HDL-C • For the first time in a single statin study, these factors are shown to be important in the regression of plaque Christopher Cannon

ASTEROID: Goals of therapy • This study is not too different from the GREACE study • Lower the LDL-C as much as possible • Raise the HDL-C as much as possible • Rosuvastatin does just that • There is no progression of disease over 24 months, which is very attractive Valentin Fuster GREACE: Athyros VG et al. J Clin Pathol 2004;57:728.

ASTEROID: Tempered enthusiasm • Rosuvastatin is not an equal-opportunity therapy • Many patients cannot tolerate statins at any dose • Even more patients cannot afford statins • Some patients are noncompliant • Will physicians subconsciously push patients who are suffering from myalgia or other side effects to stay on statins? • Future studies should include strategies aimed at improving tolerability • Simultaneous coenzyme-Q10 use • High-dose pulse therapy Melissa Walton-Shirley

ASTEROID: Patient population • Issues important to the general clinician • Patients in this study did not necessarily have significant progression • There was no control group • Only 13% of the patients had diabetes • A large proportion of patients just had unstable angina Valentin Fuster

1.8 REVERSALpravastatin CAMELOTplacebo 1.2 0.6 A-Plusplacebo REVERSALatorvastatin Mean change in percentatheroma volume, % 0 –0.6 r2=0.97p<0.001 ASTEROIDrosuvastatin –1.2 50 60 70 80 90 100 110 120 ASTEROID: Figure 3 Relationship between mean LDL-C levels and median change in percent atheroma volume for several intravascular ultrasound trials Mean LDL-C (mg/dL) Nissen SE, et al. JAMA 2006;295:1556.

ASTEROID: Limitations • The different duration of this trial makes comparison difficult • ASTEROID was 24 months • Previous IVUS studies done by Nissen et al were 18 months • Measuring atherosclerosis in different patient populations makes comparisons difficult to interpret • People with not-too-severe atherosclerosis • Higher-risk patients • Although this trial has limitations, the results seem to fit with everything we know about intensive statin therapy Christopher Cannon

ASTEROID: Data needed • REVERSAL used IVUS to show that lowering LDL-C significantly with atorvastatin stopped the progression of disease in a relatively high-risk population • PROVE IT–TIMI 22 showed that there were significantly fewer cardiovascular events with atorvastatin • ASTEROID showed that rosuvastatin is very effective in modifying lipid profiles and in preventing progression of disease and maybe some regression • However, there are no clinical data correlating rosuvastatin and IVUS Valentin Fuster REVERSAL: Nissen SE et al. JAMA 2004; 291:1071.

JUPITER trial • Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial • More than 9000 patients enrolled • Lower-risk population • A primary-prevention trial • Positive C-reactive protein (CRP) as an entry criterion • JUPITER results are probably two years away, but clinical data are coming Christopher Cannon Ridker PM et al. Circulation 2003;108:2292-2297

Rosuvastatin: Side effects? • A few months ago, there was a lot of discussion about whether rosuvastatin caused side effects • What was reported • What was not reported Valentin Fuster

The trouble with statins • Simvastatin becomes generic in late 2006 • We don't know whether data from simvastatin translate or extrapolate to other statins • Patients are still reluctant to take statins • It's up to the practitioner to convince patients that statins are safe as long as they monitor side effects and communicate with their practitioner Melissa Walton-Shirley

ASTEROID: Summary • There are many people who should be taking statins that are not • We must look for strategies to increase their use • ASTEROID trial • 40 mg rosuvastatin daily proves that lower LDL-C and higher HDL-C is better • Some degree of regression was shown over 24 months Valentin Fuster

ASTEROID: Key message • In five years, our LDL-C target in a high-risk population will probably be around 50 mg/dL • One of the messages from ASTEROID is that lower is better Christopher Cannon

LDL-C target in five years • Prediction • An LDL-C of 50 mg/dL in a high-risk population • An LDL-C of 75 mg/dL in a lower-risk population Valentin Fuster

UNLOAD: Study design • 200 patients with acute decompensated heart failure at 28 institutions • Randomized to either • Peripheral ultrafiltration using a commercially available system • Standardized IV diuretic therapy • Patients were evaluated at 48 hours and at 90 days • Patients required up to two sessions of ultrafiltration over a period of a couple of days • 4 L of fluid were removed in each eight-hour session • A total of 8 L of fluid were removed altogether Costanzo MR et al. ACC 2006 Scientific Sessions; March 14, 2006; Atlanta, GA. Abstract 418-7. Valentin Fuster

UNLOAD: Results • Fewer patients in the ultrafiltration group than in the diuretic-treated group subsequently required vasoactive drugs at 90-day follow-up • The ultrafiltration group did better • More fluid lost in the first 48 hours. • Potassium levels were more stable. • No increase in creatinine levels. Valentin Fuster

UNLOAD: Results at 90 days • Rehospitalization at 90 days: • 18% of the ultrafiltration group. • 32% of the diuretic-treated group. • Number of rehospitalization days: • 1.4 days in the ultrafiltration group. • 3.8 days in the diuretic-treated group. • Emergency-room visits: • 21% in the ultrafiltration group. • 44% in the diuretic-treated group. Valentin Fuster

UNLOAD: Questions • Do all these patients need ultrafiltration? • Were diuretics used appropriately in UNLOAD? • Resistance to diuretics such as Lasix [furosemide] can develop • Is ultrafiltration necessary, or could diuretics, which are much cheaper, be used more effectively? Valentin Fuster

UNLOAD: Effect on therapy • Of all the data that were presented at ACC 2006, the UNLOAD findings have the greatest potential to affect acute hospital-based therapy • From a clinical standpoint, ultrafiltration allows patients to fit into their shoes and to go home with the same creatinine levels they came in with • This was a natural next step for cardiologists dealing with CHF • It is nearly impossible to motivate nephrologists to manage fluid in the nonuremic patient Melissa Walton-Shirley

UNLOAD: Cost effectiveness • Reducing the cost of DRG 127 [heart failure and cardiac shock] is the holy grail of CHF management • The $19 000 this device costs is a pittance compared with other technology purchases hospitals make • Shortening the length of hospital stay and preventing readmission of just two patients pays for the device Melissa Walton-Shirley

UNLOAD: Cost of ultrafiltration • Each ultrafiltration session costs close to $1000 • Decreasing the number of hospital days and the number of visits to the emergency room saves money • Despite being somewhat expensive, is ultrafiltration cost effective? Valentin Fuster

UNLOAD: Cost effective • We have to be careful not to buy into the "just-plug-them-into-a-machine" mentality • Ultrafiltration should not replace good dietary instruction and fluid restriction • We should take a hard look at the medical regimen of volume-overloaded patients • Are we doing anything to offend them? • Are we keeping them on dihydropyridine calcium-channel blockers? • Do we have them on glitazones (which, for some patients, means a 40-lb weight gain)? • We must carefully select which patients are offered ultrafiltration Melissa Walton-Shirley

UNLOAD: Diuretic resistance • When I see a patient on a dose of Lasix over 300 mg, I drop the dose and prescribe Zaroxolyn [metolazone] • In general, there is a significant change in the diuresis of these patients • Ultrafiltration is a significant move forward, but I'm not convinced that most of the patients we see on a daily basis need this device Valentin Fuster

UNLOAD: Heart failure • As coronary disease is treated successfully in more and more patients, more and more patients are left with heart failure • Diuresis takes an enormous amount of time • Ultrafiltration offers another option to people on high doses of Lasix who are still fluid-overloaded • The savings in length of hospital stays and rehospitalizations leads to an overall cost benefit • A formal cost-effectiveness analysis is still needed Christopher Cannon

UNLOAD: Chemistry • Why does all the chemistry continue to be fantastic, even after 8 L of fluid is removed? Valentin Fuster

UNLOAD: Chemistry explained • The fluid that's removed is isotonic, so there's no activation of the renin angiotensin system • There was not a lot of hypotension in UNLOAD patients so, unfortunately, patients left the hospital feeling about the same, with shortness of breath • However, they could wear their clothing and had significant weight loss, which is really the goal for these patients • The reason for the lack of improvement in dyspnea is unclear Melissa Walton-Shirley

UNLOAD: A significant advance • Ultrafiltration is a significant advance for patients with significant cardiac failure and volume load Valentin Fuster

UNLOAD: Nesiritide alternative • Ultrafiltration is a perfect solution for patients excluded by the nesiritide-clinic situation • Our nesiritide clinic, which ran for several months, was closed when the controversy began • Patients who no longer have access to the nesiritide clinic on a weekly basis are looking forward to trying this device Melissa Walton-Shirley

BASKET LATE: Study design • The original BASKET trial randomized a relatively complex patient group to a bare-metal stent or to a drug-eluting stent, either paclitaxel (Taxus) or sirolimus (Cypher) • BASKET LATE followed 746 BASKET patients who were free of major adverse coronary events (MACE) at six months for an additional 12 months PfistererME et al. ACC 2006 Scientific Sessions;March 14, 2006; Atlanta, GA. Abstract 422-11. Valentin Fuster

BASKET LATE: Study design • Thrombosis-related events in the two groups (bare-metal or drug-eluting stents) were compared • Thrombosis-related events comprised angiographically confirmed stent thrombosis, sudden cardiac death, and target-vessel myocardial infarction PfistererME et al. ACC 2006 Scientific Sessions;March 14, 2006; Atlanta, GA. Abstract 422-11. Valentin Fuster

BASKET LATE: Results • MACE rates were no different between the bare-metal and drug-eluting stent groups • The rates of nonfatal MI plus cardiac death and of nonfatal MI alone were significantly higher with drug-eluting stents than with bare-metal stents • Nonfatal MI: 4.1% in the drug-eluting-stent group vs 1.3% in the bare-metal-stent group • Cardiac death and nonfatal MI: 4.9% in the drug-eluting-stent group vs 1.3% in the bare-metal-stent group Valentin Fuster

BASKET LATE: Surprising results • The design of BASKET LATE led to a unique opportunity to look at planned discontinuation of clopidogrel six months after stent placement • The dramatic findings have immediate implications • They aren't definitive because only ~100 patients were studied, but the data are compelling Christopher Cannon

BASKET LATE and clopidogrel • What does the fact that most of the BASKET LATE patients stopped taking clopidogrel at six months tell us? Valentin Fuster

BASKET LATE: Clopidogrel debate • This study shows that discontinuation of clopidogrel six months after drug-eluting-stent placement is not a good idea • Package-insert information, based on the elective single-vessel stenting that earned these stents initial approval: • Taxus stent: Clopidogrel for six months • Cypher stent: Clopidogrel for three months • The BASKET LATE population comprised high-risk patients at high risk for recurrent events • Many interventionalists are considering two years of clopidogrel to prevent stent thrombosis related to drug-eluting stents • This study will extend the duration of clopidogrel treatment after drug-eluting-stent placement Christopher Cannon

BASKET LATE: The trade-off • In 100 patients with drug-eluting stents: • Five restenotic phenomena will be prevented. • There will be 3.3 late deaths from MI. Valentin Fuster

BASKET LATE: Implications • After seeing a couple of case reports in the literature of late and ultralate thrombosis (one of which was 18 months out), I started advising patients who have received drug-eluting stents to stay on clopidogrel indefinitely • These results are concerning because many patients cannot afford a year's worth of clopidogrel • At our facility, 100% of the patients who are implanted are STEMI patients, who are at higher risk Melissa Walton-Shirley

BASKET LATE: Choosing a stent • It's not the up-front cost of the stent anymore that determines which stent will be used, it's the ability of the patient to pay for the long-term Plavix prescription and the expectation of compliance by the patient • We need to do a better job of taking a good general medical review of systems before stent implantation • Many patients are coming back within three months of implant needing a cholecystectomy or with gut bleeding • We need to do a better job of defining who should and who should not get a drug-eluting stent • A patient who knew he was facing a biopsy for a chest mass received a drug-eluting stent when he underwent PCI Melissa Walton-Shirley

BASKET LATE:Appropriate use of clopidogrel • Based on this study, perhaps we should prescribe clopidogrel for 18 to 24 months • The significant drop in the rate of restenosis means we should not discount drug-eluting stents • Perhaps the appropriate use of clopidogrel over a longer period of time is required Valentin Fuster

BASKET LATE:Clopidogrel and surgery • The preprinted letter that comes from the surgeon advising patients to stop all anticlotting drugs for 10 days before surgery must be carefully considered • We may need to time clopidogrel more like warfarin • New data suggest discontinuing clopidogrel three days before surgery and then monitoring the level of platelet inhibition so that people are not putting themselves at risk for thrombotic events by discontinuing clopidogrel Christopher Cannon

MIST: Study design • 147 migraine patients, between 18 and 60 years, previously found to have a patent foramen ovale (PFO) • All patients were refractory to at least two classes of migraine medications and had a one-year history of migraine • All patients had contrast transthoracic echocardiography to establish shunt size • Half were treated with a PFO closure device implantation, the STARflex septal-repair implant • Half underwent a sham procedure consisting of general anesthesia and a groin incision • All patients were prescribed aspirin and clopidogrel for three months Taaffe M. ACC 2006 Scientific Sessions;March 12, 2006; Atlanta, GA. Abstract 945-109. Valentin Fuster

MIST: Results • Three patients in each arm achieved the primary end point—complete cessation of headaches • More PFO-closure than sham patients had a 50% or greater reduction in headache days • 42% of PFO-closure patients vs 23% of sham patients achieved a 50% reduction in headache days • More PFO-closure than sham patients had a reduction in headache burden (calculated as headache frequency × duration) • PFO closure might help headaches by preventing platelets from releasing serotonin, which causes headaches Valentin Fuster

MIST: Jury still out • I sent a patient two years ago for PFO closure who presented with a transient neurologic deficit; she happened to also have a history of severe migraines • She was 100% migraine free immediately after the procedure and continues to be two years later • The presenters have not yet finished the calculations for the shunt data, and therein might lie the explanation • These patients had exceptionally large communications; if the closures were not complete, improvement would not be expected • Any migraine sufferer would jump at the chance for a 50% reduction in the number of headaches or the number of trips to the emergency room • It would be nice if the primary end point in MIST II were the reduction in migraines instead of a cure Melissa Walton-Shirley

MIST: Cause of headaches • Are platelets crossing the PFO and getting into the head and releasing serotonin, which causes the headaches? Valentin Fuster

MIST: More data needed • The pathophysiology explaining this is unclear • If data from MIST II are consistent, then the two trials together would show this benefit • One concern about PFO or atrial septal-defect closure is with fractured parts of the devices causing strokes • Is this device different than atrial septal-defect closure devices? • We need to see all the safety data, beyond half of 147 patients Christopher Cannon

MIST: Course of action • If a patient presents tomorrow with constant headaches and a PFO, would you close it? Valentin Fuster

ACC 2006 part 2: Where's the controversy?