Clinical and Industry News

Low-Molecular-Weight Heparin Preferable Anticoagulation Therapy For Procedure To Re-Establish Heart Rhythm Using the low-molecular-weight heparin drug enoxaparin (Clexane®/Lovenox®) to prevent blood coagulation while performing cardioversion of atrial fibrillation to re-establish a normal heart rhythm is preferred to conventional antithrombotic drugs. Enoxaparin is more reliable and easier to use while performing effectively and safely, according to the multicenter Anticoagulation in Cardioversion Using Enoxaparin (ACE) trial data presented at the European Society of Cardiology (ESC) Congress 2002. Enoxaparin is an attractive alternative to conventional anticoagulation therapy. While demonstrating efficacy and safety in the setting of cardioversion, it can be given on an outpatient basis and provides almost immediate, reliable anticoagulation without the need for rigorous anticoagulation checks in most patients. The anticipated reduction in hospitalization stays and anticoagulation monitoring may make enoxaparin treatment cost-effective. Along with its proven performance this should make enoxaparin a preferred therapy among physicians, says ACE investigator Christoph Stellbrink, MD, FESC, from the Department of Cardiology at the University of Aachen. Current guidelines recommend treating atrial fibrillation that lasts longer than 48 hours with cardioversion and anticoagulation therapy. Most physicians employ a transesophageal echocardiography (TEE) test to determine if atrial blood clots are absent before cardioversion. This permits early restoration of normal heart rhythm using intravenous unfractionated heparin (UFH) as an antithrombotic during the procedure, followed by four weeks of oral anticoagulation (OAC) therapy. If the TEE test is not performed, patients receive OAC for at least three weeks before and four weeks after cardioversion. Stringent anticoagulation monitoring is necessary with OAC, especially when therapy is initiated. ACE shows that enoxaparin, which does not need to be administered in a hospital setting, allows quick and safe cardioversion, at least as well as a regimen of UFH/OAC, either with or without a TEE, said Dr. Stellbrink. Also, previous studies documented the superiority of enoxaparin as an anticoagulant to UFH in patients with unstable, severe chest pain and heart attacks. In ACE, investigators evaluated and compared cardioversion in 496 patients from 56 German medical centers with previously documented atrial fibrillation who received either enoxaparin (248 patients) or a combination of intravenous UFH followed by the OAC phenprocoumon (248). Patients received an initial assignment to cardioversion with (431, including 213 in the enoxaparin group) or without (65, including 35 in the enoxaparin group) TEE and then to either of the two therapy regimens. During the trial, investigators excluded 68 patients because of protocol deviations. During ACE, enoxaparin performed at least equivalently to the UFH/OAC therapy based on the cumulative incidence of strokes, death or major bleeding complications. Specifically, 3.2 percent of the enoxaparin patients, seven of 216, had such complications, while 5.6 percent of the UFH/OAC group, 12 of 212 patients, experienced such events. No statistically significant difference occurred for any of the strokes, death or major bleeding complications between the two treatment groups. Also, Stellbrink notes, previous studies report that the risk of a heparin-induced reduction in platelet count associated with severe embolic complications, is lower with low-molecular weight heparin than with UFH. Results of EuroSPAH Intravascular Sonotherapy® Trial Presented at European Society of Cardiology (ESC) Meeting PharmaSonics, Inc. announced the presentation of the results of the EuroSPAH clinical trial, a European double-blind, multi-center randomized study of anti-restenotic treatment in de novo stented patients. The results were reported at the European Society of Cardiology (ESC) Congress by principal investigator Professor Patrick Serruys, MD, PhD. The reduction of 40% in re-intervention by Sonotherapy in EuroSPAH is very significant, especially considering the true double-blind nature of the trial, stated Professor Serruys. PharmaSonics’ Intravascular Sonotherapy® treatment uses therapeutic ultrasound energy to inhibit restenosis. This treatment is applied after a stent is implanted within the artery. The Sonotherapy system has received CE Mark approval. Boston Scientific Corporation holds the exclusive distribution rights throughout Europe and all other regions outside the U.S., Canada, and Japan. The endpoints of the EuroSPAH study are in-stent angiographic late loss (reduction in minimum lumen or blood vessel diameter) and Major Adverse Cardiac Events (MACE). A total of 403 patients were enrolled from 23 European Centers. The EuroSPAH protocol required one month of anti-platelet therapy. Sonotherapy treatment after stenting reduced the re-intervention rate by 40% (p=0.045) at seven months when compared to stenting alone, the control arm. The re-intervention rate in the Sonotherapy arm was 10.4%, versus 17.4% in the control arm. This reduced rate of re-intervention resulted in a 27% reduction in MACE. The MACE rate for the Sonotherapy arm was 18.8%, versus 25.9% for the control arm. The angiographic in-stent late loss, the trial's primary endpoint, showed a difference in favor of Sonotherapy but did not reach statistical significance. The expected difference in late loss was 0.21mm; the actual difference was 0.09mm (p=0.09). According to Professor Serruys, EuroSPAH is one of the very few double-blind studies in interventional cardiology. This is important to understand, especially when reviewing the variance observed between the clinical and angiographic results. That is, the physicians in this trial, who were truly blinded, chose to reduce interventions by over 40% based on their clinical and angiographic assessment. Professor Serruys continued, The EuroSPAH protocol requires that all 403 patients undergo IVUS analysis. Three-dimensional volumetric analysis using IVUS may provide the answer to this previously unseen variance between clinical and anatomical assessment. In addition, the analysis from the SWING trial should help clarify the variance observed in EuroSPAH. The SWING clinical trial is designed to establish the long-term safety and efficacy of Sonotherapy treatment in reducing the incidence of restenosis in coronary de novo stented patients. SWING is a 1,200-patient, prospective, double-blinded, randomized study. The results will be released on November 18 at the American Heart Association Meeting by the principal investigator, Richard E. Kuntz, MD, MSc. Dr. Kuntz stated, The EuroSPAH clinical results are exciting. I look forward to the results of SWING, which should most likely confirm the strong clinical findings of EuroSPAH. Regarding the angiographic and clinical variance observed in EuroSPAH, I am anxious to explore the possibility of a favorable re-narrowing pattern that may reduce clinical ischemia after Sonotherapy. As clinicians, we rely on clinical endpoints to guide therapy, and the FDA requires demonstration of clinical utility for product approval. Nevertheless, SWING will have a comprehensive angiographic, IVUS, and clinical array of data and analyses to help clarify these provocative findings of EuroSPAH. The EuroSPAH trial also confirmed the feasibility (95.3% device delivery success) and safety of Sonotherapy treatment, with no reported incidences of early or late thrombosis, edge effect, or aneurysm observed with other device- or drug-based anti-restenotic therapies. The high safety profile is also reflected in the short duration of anti-platelet therapy required following Sonotherapy treatment. Patients in the EuroSPAH clinical trial received one month of anti-platelet therapy, a shorter time period than that used with other anti-restenotic therapies, which may require up to six months. Anti-platelet therapy is prescribed after interventional medical procedures in order to prevent the formation of blood clots. The standard anti-platelet therapy following stenting is one month. The EuroSPAH results are good news for the European interventional cardiology community because physicians, patients, and governments may have more clinical and economic choices for treating patients with coronary restenotic disease, commented Professor Serruys. A safe and cost-effective therapy like Sonotherapy could complement the potentially more costly drug-eluting stents in patients in several situations, such as patients requiring more than one stent. EuroSPAH was designed to include these patients. Dr. Kuntz added, Assuming that SWING demonstrates similar positive results possibly leading to FDA approval next year, Sonotherapy will give U.S. physicians more clinical and economic choices for reducing stent restenosis, especially in situations where bare stents are used, multiple stents are required, and in treating recurring in-stent restenosis. Menahem Nassi, PharmaSonics CEO and President, commented, The EuroSPAH trial results provide the momentum to pursue the financing that is necessary for PharmaSonics to introduce Sonotherapy into the U.S. market, assuming FDA approval in 2003. Based on the EuroSPAH clinical results, I am optimistic about the upcoming SWING results scheduled to be released at the 2002 AHA in November in Chicago, Illinois. The Medicines Company Completes Enrollment of 6000-Patient REPLACE-2 Angioplasty Trial The Medicines Company has completed the target enrollment of 6,000 patients its REPLACE-2 study. REPLACE-2 was conducted in patients undergoing percutaneous coronary intervention procedures. The study is evaluating the use of The Medicines Company's lead product, Angiomax®, as the foundation anticoagulant for angioplasty within in the context of modern therapeutic products and technologies, including coronary stents. The Cleveland Clinic and The Medicines Company coordinated REPLACE-2 with Eric J. Topol, MD as chairman and A. Michael Lincoff, MD, as the principal investigator. The Company expects to announce the primary post-marketing data results by the end of 2002. REPLACE-2 is a randomized double-blind trial that enrolled patients at 233 clinical sites in the United States, Canada, Western Europe and Israel. One randomized group of patients received heparin plus a GP IIb/IIIa inhibitor. A second randomized group of patients received Angiomax (bivalirudin) plus the provisional use of a GP IIb/IIIa inhibitor, administered to patients in certain circumstances. GP IIb/IIIa inhibitors are antiplatelet products commonly used in the modern angioplasty setting. Sites selected a GP IIb/IIIa inhibitor based on institutional practice, reflecting current practices in providing patient care. The study will evaluate the standard clinical endpoints of death, myocardial infarction, revascularization and clinically significant bleeding at 30-days. The study is also examining the total cost of care of the two arms up to 30-days post PCI. Additional follow-up will be conducted at six months and one year. Research Shows New CT Can Help Physicians Diagnose Heart Disease in Early Stages The SOMATOM Sensation 16 from Siemens Medical Solutions is the first and only 16-slice computed tomography (CT) scanner commercially available and installed as a released product in U. S. facilities. The SOMATOM Sensation 16 can help physicians diagnose heart disease in its earliest stages, without the need for surgery or angiography. Proven in the clinical environment, doctors believe the cardiac imaging capability of the new scanner will be a critical tool in early diagnosis and may improve the effectiveness of treatment of coronary heart disease, a known cause of heart attacks. The SOMATOM Sensation 16 was first seen at the Radiological Society of North America's (RSNA) Annual Conference last fall, followed by the introduction of the SOMATOM Sensation Cardiac, a 16-slice scanner for cardiology, at the meeting of the American College of Cardiology (ACC). The Siemens CT scanner uses 16-slice technology to allow for four-times more speed, real-time reconstruction, and higher image resolution than today's standard 4-slice CT machines. With a speed of 0.4s for a full revolution, the image capture system provides up to 100ms acquisition time per image, making this multi-slice CT system among the fastest in the industry. This increased speed provides a dramatic difference, particularly when imaging moving organs such as the heart. Because more images are gathered in one rotation of the CT gantry, and because real-time reconstruction is possible, doctors are now able to gather more information in a shorter period of time enabling them to make decisions faster. The improved image quality of the 16-slice scanner additionally allows doctors to see small vessels and other fine anatomical details that could not be seen before without surgery. Dr. Christoph Becker from the Grosshadern Clinic in Munich recently presented the first clinical case studies that show the new scanner can visualize and differentiate coronary lesions in early, possibly pre-clinical stages. Based on the performance of this new technology, cardiac CT has the potential to become a complementary tool to invasive coronary catheterization and may allow for effective control of pharmaceutical treatment like lipid-lowering agents, Dr. Becker noted. Dr. Becker demonstrated that, for the first time, even small coronary arteries with less than one-millimeter diameter could be assessed with the new CT scanner. Soft coronary plaques, associated with coronary artery disease and possibly acute heart attacks, may be visualized at an early stage of the disease. The high potential of cardiac CT as a new tool for non-invasive and earlier diagnosis of coronary heart disease also has been outlined by studies performed with Siemens CT equipment and presented by Dr. Schroder from the Tubingen University at the 2001 American Heart Association conference in the fall. Over 12 million Americans have a history of coronary heart disease, and every year about 7.5 million suffer a heart attack. In fact, approximately half a million people die because of coronary heart disease and half of these without even being hospitalized, said Dr. Erich Reinhardt, president and chief executive officer of Siemens Medical Solutions. There is a clear need here for a reliable, non-invasive and economical tool to diagnose heart disease at an early stage, and to track progression of disease in order to allow for successful medical care. The SOMATOM Sensation 16 is capable of acquiring over 32 slices per second when operating at its maximum rotation speed. The new CT system is a member of the Siemens SOMATOM family and based on a 16-slice detector platform with optimized performance for cardiac and cardiovascular applications. The technology uses cutting-edge cardiac reconstruction and cardiac function analysis software, as well as newly developed concepts for electrocardiogram (ECG)-correlated acquisition. The new technology also uses anatomy-based and ECG-based dose optimization techniques to allow for radiation exposure reductions of up to 50% higher than previous CT technology. Early Intervention Superior Over Watch and Wait Strategy For Unstable Heart Disease Patients The early use of an angiography and a revascularization procedure cuts the frequency of severe chest pain known as refractory angina in half, with no increased risk of deaths and heart attacks in patients at moderate risk of dying from their unstable heart disease, according to the Randomized Intervention Trial of Unstable Angina 3 (RITA 3). Physicians now have scientific proof that using an angiography and revascularization procedure provides a significant health benefit for unstable coronary artery disease patients at moderate risk of death. It is preferable to current ‘watch and wait’ medical management standards, which call for these procedures only when a patient has ischaemia or a higher risk of death from heart disease, says study chairman Keith Fox, MB, ChB, FRCP, FESC, Duke of Edinburgh Professor of Cardiology and Head of the Department of Medical and Radiological Sciences at the University of Edinburgh. In RITA 3, investigators at 45 centres in the United Kingdom enrolled 1,810 patients. The study evaluated and compared an intervention strategy of the early use of angiography with, as needed, a revascularization procedure such as percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) to a conservative strategy of using only as clinically indicated an angiography and PCI or CABG. Patients in both the intervention and conservative arms of the study received the antithrombin low-molecular-weight heparin enoxaparin (Clexane®/Lovenox®) to prevent blood coagulation, based on its superiority over unfractionated heparin in previous trials. The hazards of intervention and angiography appear to be more than counterbalanced by the subsequent reduction in non-procedure related heart attacks among the RITA 3 study participants. For patients with unstable angina at moderate risk, an interventional strategy is preferable to waiting for ischemic symptoms to provoke the procedure," says Fox. "Moreover, physicians should feel comfortable using enoxaparin in patients proceeding to angiography and PCI, as no significant change in bleeding frequency occurred among the RITA 3 participants who underwent these procedures, regardless of their initial strategy. In RITA 3, the invasive strategy significantly reduced the likelihood of death, heart attack, or treatment-resistant (refractory) angina after four months. Such events occurred in 86 (9.6 percent) patients, compared to 133 (14.5 percent) of those on conservative strategy, p = 0.001. This significant difference remained at 12 months as well, p = 0.003. Most significantly, intervention reduced the occurrence of refractory angina by half at four months, with 39 (4.4 percent) of patients experiencing it compared to 85 (9.3 %) of conservative patients, p Scientists Create Biological Heart Pacemaker Scientists in the United States have made a breakthrough that could revolutionize heart surgery by replacing electronic pacemakers with a biological equivalent. Our results indicate that genetically engineered pacemakers could be developed as a possible alternative to implantable electronic devices, comment the researchers at Johns Hopkins University, Baltimore. The Johns Hopkins’ scientists discovered that by altering the potassium balance in ordinary heart cells in guinea pigs, they could trick them into behaving like pacemaker cells. We can envision a day when it will be possible to recreate an individual’s pacemaker cells or develop hybrid pacemakers part electronic, part biologic, said cardiologist Eduardo Marban, one of the Johns Hopkins' team. Likening the process to creating a hot rod car out of a junk heap, he said the scientists had tinkered with the cells' genetic toolbox to manipulate their functions. Warning that clinical applications in humans were still some way off, Marban said what he termed the biopacemaker could have vital uses in patients either too weak or too young to face implantation surgery. A biologic pacemaker should also be able to adjust to the body's changing needs, whereas an electronic pacemaker at least in its simplest form does not, he said. The heart normally has two sets of pacemaker cells that trigger their neighbors to contract and send blood round the body. Other cells are inhibited from aping these starter-motor cells by the presence of potassium. The scientists used a virus to carry a gene that altered the potassium balance, and injected it into the guinea pigs' hearts and quickly found the affected cells began acting as pacemakers. However, Marban warned that their understanding of the process still needed a lot of work. We've created a biologic pacemaker in the guinea pig, but now the hard work comes, he said. We need to fine-tune it develop controlling strategies, find the optimum place to re-engineer the cells in the heart, control the frequency of the new pacemaker. But there is light at the end of the tunnel, Marban added. Innercool Initiates Acute Myocardial Infarction Clinical Trial Innercool Therapies today announced it has initiated a clinical trial to investigate the use of its Celsius Control System in the treatment of acute myocardial infarction (AMI). Innercool received an investigational device exemption (IDE) from the Food and Drug Administration and has begun enrolling patients into the ICE-IT (Intravascular Cooling Adjunctive to Primary Coronary Intervention) clinical trial, which is designed to investigate the safety and feasibility of treating AMI patients with the Celsius Control System. In addition, Innercool completed patient enrollment in its TCAS (Temperature Control During Aneurysm Surgery). TCAS is a multi-center trial designed to induce hypothermia, maintain a target temperature and subsequently restore normothermia during surgical repair of unruptured brain aneurysms. John Dobak, MD, President and CEO of Innercool, notes, We plan to randomize over 400 patients at 30 sites across the country. Clinical research suggests the induction of hypothermia during periods of ischemia may protect tissue from damage, said Cindy Grines, MD, FACC, Director of the Cardiac Catheterization Laboratory at William Beaumont Hospital and principal investigator of the ICE-IT clinical trial. We have seen evidence of this protection in stroke and during brain aneurysm surgery. The cardiology community has long sought methods to protect the heart from tissue damage that results from heart attacks. Stenting and angioplasty are effective methods to open occluded arteries and we are now focused on finding methods to better protect heart muscle damage, thereby protecting heart function. We are encouraged by the initial clinical data regarding hypothermia and believe this is a very promising method in the treatment of acute myocardial infarction. Physicians currently induce and reverse hypothermia with cooling blankets and other body surface cooling devices, which are difficult to control and have limited efficacy. Innercool’s Celsius Control System consists of an endovascular catheter, circulating set and console. The tip of the catheter incorporates a proprietary, alloy-based Temperature Control Element (TCE) that is cooled or warmed with saline solution circulated from the console. When placed in the inferior vena cava, the TCE exchanges heat directly with the blood flowing in the vessels of the body resulting in cooling or rewarming of the downstream organs and body. The System does not require fluids to be perfused into the patient, nor does it require blood to be circulated outside the body. Doctors Not Sure Why Elders Halt Cholesterol Drugs Several recent studies have shown that senior citizens often stop taking statins, and researchers don’t know exactly why. Many elderly patients aren't sticking with the statins they are prescribed, according to two studies. In one study, Dr. Joshua S. Benner, a research fellow at Brigham and Women’s Hospital, and several colleagues found that only 53% of patients 65 or older prescribed statins were still taking them 6 months later, and only 35% were taking them 5 years later. In the second study, Cynthia Jackevicius of Toronto General Hospital and colleagues looked at patients aged 66 and older. They found that only 40% of patients who had a heart attack or chest pain were still taking their medicine two years later, compared with 36% of those with chronic heart disease and 25% prescribed the drugs to prevent heart disease. So why do seniors stop taking statins? Benner said steep drop-offs in the first few months aren't surprising. When people are asked to try something new no matter what medication they usually quickly make up their minds as to whether it makes them feel funny, and if they are committed to taking it, he said. In his trial, cost did not seem to influence compliance, Benner said, noting that most people only paid $5 or less for their statins. In the Canadian study, medications were free. In reality, elderly people do stop taking statins because of price $50 to $100 a month. The physicians also said side effects were not likely a major reason for discontinuation. We know that side effects for statins are relatively low, said Applegate. Side effect worries were fueled by last August’s recall of Baycol (cerivastatin), a statin that was associated with severe muscle weakness, and several deaths from rhabdomyolysis, in which the muscle breaks down. Just after that, the consumer advocacy group Public Citizen petitioned the US Food and Drug Administration to add a large warning to all statins about the potential for severe muscle weakness and wasting. Nothing has come of the request. The American College of Cardiology, the American Heart Association, and the National Heart, Lung and Blood Institute recently issued clinical guidelines that say that despite the problems with Baycol, statins are safe, and one of the best weapons against high cholesterol and reducing stroke and heart attack risk. Physicians say the main reason people don't take statins not just the elderly is because they can't feel that they have high cholesterol. When patients are asymptomatic, it's harder to get them to focus their attention on continued consistent compliance, said Applegate. When they’ve had a heart attack or other coronary event, people are much more likely to stick to their regimens, he said. Benner found in his study that patients who began statin therapy after a heart attack, or who had active heart-related chest pain, were more likely to stay on the medications. Cook Wins Approval To Sell Second Paclitaxel-Eluting Stent In Europe Just days after receiving clearance to sell its ACHIEVE Drug Eluting Stent System in Europe, Cook® now has received CE Mark approval to market its paclitaxel-coated V-Flex Plus PTX Coronary Stent System in the European Union. Cook will begin selling the V-Flex Plus PTX stent to European medical institutions immediately. The V-Flex Plus PTX, manufactured using Cook stent components with the company’s proprietary polymer-free paclitaxel coating, received CE Mark approval following a comprehensive review by both the Medicines Control Agency (MCA) and Lloyd’s Register Quality Assurance (LRQA). Animal testing and human clinical data from the ELUTES trial supported the regulatory submission. Cook has no plans at this time to introduce the V-Flex Plus PTX stent to the U.S. market. In Cook’s ELUTES clinical trial, the V-Flex Plus PTX demonstrated a restenosis rate of just 3.1 percent due to its paclitaxel coating, which acts to prevent excessive cell regrowth at the site of the stent placement. Cook’s polymer-free, paclitaxel-eluting V-Flex Plus PTX stents are not approved for sale in the U.S. at this time. Cook Group Incorporated and Guidant Corporation jointly announced on July 30, 2002 that Guidant has agreed to acquire Cook Group Incorporated in a stock-for-stock transaction. The parties anticipate closing in early 2003, subject to the satisfaction or waiver of conditions. Reciting Poetry Calms the Heart While the rhythmic sounds of poetry may woo a lover’s heart, it might also be healthy for the heart of the speaker, according to recent study findings. Our findings suggest that the stress-releasing effect of guided recitation of old poetry can lead to a deep relaxation afterwards, said Dietrich von Bonin of the University of Berne in Switzerland and Dr. Henrik Bettermann of the University of Witten/Herdecke in Germany. This effect could be beneficial not only in stress management but also for the prevention of heart disease and other illnesses related to irregular breathing, they added. The researchers investigated the effects of poetry on heart rate in a study of seven individuals. After having their heart rates measured for a 15-minute period, the study participants recited poetry for 30 minutes, or spent the same amount of time engaged in conversation. Then their heart rates were measured again, also for 15 minutes. After reciting poetry, the study participants’ heart rates slowed to match their breathing rates in harmonic interaction, according to the researchers. Further, this effect persisted for up to 15 minutes after the recitation exercises, the investigators report. No similar effects were observed when the individuals engaged in everyday conversation, the researchers noted. In light of the findings, we recommend fostering old skills like recitation of rhythmic poetry not only in therapy but also in education, in order to optimize early prevention of heart disease and other stress-related problems, von Bonin and Bettermann said. These findings may also help explain the calming effect of chanting, the researchers note, since chanting of calming songs also generates slow and deeper breathing. Completion of Patient Enrollment for Study In Emerging Field of Heart Attack Prevention Guidant Corporation announced that a company-supported optical coherence tomography (OCT) study of complex lesions recently completed enrollment. The study examined images of lesions in patients with coronary artery disease at Massachusetts General Hospital in Boston, Mass. A newly established body of evidence shows that as many as 85 percent of heart attacks are triggered by complex vulnerable lesions vulnerable plaque that suddenly cause blood to clot and occlude the artery. Research suggests that local therapies may be effective in treating vulnerable plaque as a component of optimal patient management. Optical coherence tomography is a new coronary imaging technology that provides resolution ten times greater than intravascular ultrasound. Investigators in the Guidant-supported study used this new technology to gather highly detailed information about the unique characteristics of complex lesions that may lead to a heart attack. The OCT system used in the study was developed at Wellman Laboratories of Photomedicine, based at Massachusetts General Hospital within the Department of Dermatology at Harvard Medical School. With 63 patients enrolled, this is likely the largest study of its kind, and I expect the results will stimulate discussion in the interventional cardiology community about the best ways to find and treat vulnerable plaque, said Ik-Kyung Jang, MD, PhD, interventional cardiologist at Massachusetts General Hospital, associate professor of medicine at Harvard Medical School, and principal investigator for the study.

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