16 December 2010: Recall of medical devices - DePuy ASR™ Hip Resurfacing System and DePuy ASR™XL Acetabular DePuy Orthopaedics conducted a global voluntary recall on 31 August 2010 of its DePuy ASRTM Hip Resurfacing System and DePuy ASRTM XL Acetabular System due to its association with higher rates of revision surgery. This is based on data from the National Joint Registry (NJR) of England and Wales which reflected that these medical devices have higher than anticipated rates of revision surgery in hip resurfacing and total hip replacement procedures. Patients who reported problems with the DePuy ASRTM systems and required revision surgeries within the first five years post-surgery presented with a variety of symptoms including pain, swelling and difficulty in walking. Healthcare professionals are encouraged to report adverse events suspected to be associated with the DePuy ASRTM systems or other medical devices to the Medical Device Branch of HSA.
16 December 2010: Bisphosphonates and atypical fracture HSA would like to draw healthcare professionals' attention to a recent implementation of label warnings regarding the risk of atypical femur fractures associated with the
bisphosphonate class of drugs that are used in the treatment of osteoporosis. This label change describes the uncertainty of the optimal duration of bisphosphonate use for the treatment of osteoporosis as this information has not been elucidated. Although the mechanism of this adverse event is not known, these atypical fractures may be related to long-term bisphosphonate use.
To date, there are 82 local ADR reports of subtrochanteric fractures associated with bisphosphonates. Healthcare professionals are encouraged to conduct periodic re-evaluation of the need for continued bisphosphonate therapy and to evaluate any patient
who presents with new thigh or groin pain so as to rule out a femoral fracture. Healthcare professionals are encouraged to keep in mind the MOH CPG Guidelines for Osteoporosis when prescribing bisphosphonates for the treatment of osteoporosis.
who presents with new thigh or groin pain so as to rule out a femoral fracture. Healthcare professionals are encouraged to keep in mind the MOH CPG Guidelines for Osteoporosis when prescribing bisphosphonates for the treatment of osteoporosis.
HSA would like to update healthcare professionals on the local adverse drug reaction (ADR) reports and recent international developments related to varenicline (Champix®) that have taken place since our last report1 on this issue in July 2008. This article includes regulatory updates from international agencies, reports from literature and updates on local ADR reports.
HSA is working with GlaxoSmithKline (GSK) to implement restrictions on the use of rosiglitazone in Singapore following the review of additional data about its associated cardiac ischaemic risks made available since our earlier review in 2007. This recommendation arose after an in-depth review, in consultation with the HSA Pharmacovigilance Advisory Committee (PVAC) and an expert panel of cardiologist and endocrinologists, taking into consideration the findings of the various scientific analyses, including data from meta-analyses US Food and Drug Administration, clinical trials, and observational studies. In addition, restrictions to the label are added to significantly limit the use of rosiglitazone to a group of patients who are unable to effectively control their blood glucose despite the use of alternative anti-diabetic medications.
HSA would like to bring to the attention of healthcare professionals the potential risk of patients developing eosinophilic pneumonia during treatment with daptomycin (Cubicin®, AstraZeneca). The US Food and Drug Administration had in July 2010, conducted a review of its Adverse Event Reporting System (AERS) which identified six cases of eosinophilic pneumonia most likely associated with Cubicin® reported between 2004 and 2010. One additional case was identified in the medical literature. HSA is working with the company to strengthen the local package insert for Cubicin® to include warnings that reflect the above safety issue. Physicians are advised to monitor their patients carefully for signs and symptoms of eosinophilic pneumonia after initiating Cubicin® treatment, including new onset or worsening fever, dyspnoea, hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates on chest imaging studies.
16 December 2010: Lamotrigine and aseptic meningitis
The US Food and Drug Administration has in August 2010 issued a drug safety communication to warn that aseptic meningitis has been associated with the use of lamotrigine. This observation arose from routine adverse event monitoring where a total of 40 cases of aseptic meningitis occurring in adults and paediatric patients taking Lamictal® were reported from the period December 1994 to November 2009. To date, HSA has not received any local reports of aseptic meningitis associated with lamotrigine. Healthcare professionals are advised to be vigilant to the potential development of aseptic meningitis in subjects taking lamotrigine.
16 November 2010: Voluntary recall of "Oral Guard Antiseptic-Antiplaque Mouthwash"
The Health Sciences Authority (HSA) would like to update healthcare professionals on the voluntary consumer level recall of all batches of “Oral Guard Antiseptic-Antiplaque Mouthwash” which was found to be contaminated with Burkholderia cepacia (B. cepacia), a gram-negative bacillus. The recall was initiated as a precautionary measure as the contaminated product may pose a health risk to susceptible individuals. Healthcare professionals are advised to stop prescribing “Oral Guard Antiseptic-Antiplaque Mouthwash” to patients and encouraged to be vigilant to possible adverse effects which may arise from the use of the contaminated mouthwash, especially in individuals who are immunocompromised or have chronic lung diseases.
The Health Sciences Authority (HSA) would like to update healthcare professionals on the voluntary consumer level recall of all batches of “Oral Guard Antiseptic-Antiplaque Mouthwash” which was found to be contaminated with Burkholderia cepacia (B. cepacia), a gram-negative bacillus. The recall was initiated as a precautionary measure as the contaminated product may pose a health risk to susceptible individuals. Healthcare professionals are advised to stop prescribing “Oral Guard Antiseptic-Antiplaque Mouthwash” to patients and encouraged to be vigilant to possible adverse effects which may arise from the use of the contaminated mouthwash, especially in individuals who are immunocompromised or have chronic lung diseases.
11 October 2010: Suspension of sales of sibutramine
The Vigilance Branch of HSA would like to update healthcare professionals on its regulatory decision to suspend the sales of sibutramine products with effect from 11 October 2010 following a benefit-risk assessment, which took into consideration the findings from the Sibutramine Cardiovascular Outcomes (SCOUT) study, the use of the product in the local context and developments in other international jurisdictions. The Vigilance Branch had consulted with its Pharmacovigilance Advisory Committee and a panel of external experts before arriving at this regulatory decision.
24 September 2010: HSA's advisory on the use of rosiglitazone
The Health Sciences Authority (HSA) has reviewed the recent scientific analyses conducted to determine the cardiovascular (CV) risk associated with the use of rosiglitazone (Avandia®) and concluded on its recommendations on the use of rosiglitazone. Based on the data reviewed and the recommendations of the Pharmacovigilance Advisory Committee and the expert panel of endocrinologists and cardiologists, HSA has assessed that a possible increased risk of myocardial ischaemic events associated with rosiglitazone cannot be excluded. However, for a group of patients who cannot effectively control their blood sugar using alternative medications, the benefits of rosiglitazone may exceed these risks. Hence, additional contraindications and restrictions would be implemented to mitigate any possible CV risks associated with the use of rosiglitazone.
The Vigilance Branch of HSA would like to update healthcare professionals on its regulatory decision to suspend the sales of sibutramine products with effect from 11 October 2010 following a benefit-risk assessment, which took into consideration the findings from the Sibutramine Cardiovascular Outcomes (SCOUT) study, the use of the product in the local context and developments in other international jurisdictions. The Vigilance Branch had consulted with its Pharmacovigilance Advisory Committee and a panel of external experts before arriving at this regulatory decision.
24 September 2010: HSA's advisory on the use of rosiglitazone
The Health Sciences Authority (HSA) has reviewed the recent scientific analyses conducted to determine the cardiovascular (CV) risk associated with the use of rosiglitazone (Avandia®) and concluded on its recommendations on the use of rosiglitazone. Based on the data reviewed and the recommendations of the Pharmacovigilance Advisory Committee and the expert panel of endocrinologists and cardiologists, HSA has assessed that a possible increased risk of myocardial ischaemic events associated with rosiglitazone cannot be excluded. However, for a group of patients who cannot effectively control their blood sugar using alternative medications, the benefits of rosiglitazone may exceed these risks. Hence, additional contraindications and restrictions would be implemented to mitigate any possible CV risks associated with the use of rosiglitazone.
The Vigilance Branch of HSA has from September 2009 to March 2010, received a clustering of reports on the lack of efficacy associated with the use of bupivacaine preparations (Marcain® 0.5% and Marcain® Spinal 0.5% Heavy Injection, AstraZeneca, AZ) when used during spinal anaesthesia. Analytical test results conducted on the affected batches indicated that the products were within the registered product specifications and that the products were stable during the specified shelf-life. Based on available literature and investigations conducted to date, HSA has assessed that the causes of failed spinal anaesthesia could be a combination of many factors. Global estimates on the incidence of failed spinal anaesthesia range from 0.5 – 17%. HSA will continue to monitor this situation and update our healthcare professionals when new information arises.
HSA would like to bring to the attention of healthcare professionals, post-marketing reports of renal impairment and renal failure associated with the use of intravenous zoledronic acid (Aclasta®). As of 14 August 2009, 139 post-marketing reports of renal impairment following Aclasta® infusion have been received by Novartis worldwide. Majority of these cases have been reported in patients with pre-existing medical conditions or risk factors or who had concurrent exposure to nephrotoxic agents. Rare cases of renal failure requiring dialysis or with a fatal outcome have been reported in patients with pre-existing renal impairment and concomitant risk factors. To date, HSA has received two reports of renal-related adverse reactions following Aclasta® infusion. One patient experienced acute renal failure and another patient on multiple concomitant medications developed renal impairment nine months after receiving Aclasta® infusion. Physicians are advised to consider their patient's renal function and assess their patient's serum creatinine before treatment with Aclasta® in view of the above safety information.
HSA is updating healthcare professionals on the post-marketing reports of liver injuries associated with the use of orlistat. Orlistat is registered in Singapore under the trade names of Alli® (GSK) and Xenical® (Roche). US FDA recently reviewed 13 reports of severe liver injury, which occurred over a period of 10 years, associated with the use of these orlistat-containing medicines. Of these 13 patients, two died from liver failure while three patients required liver transplantation. FDA reported that a causal relationship between severe liver injury and the use of orlistat has not been established. Moreover, some of these patients were on concomitant medications and have confounding medical conditions. A Europe-wide review also concluded that there was insufficient evidence to show that either Xenical® or Alli® was associated with serious liver disorders. Since 2000, HSA has received a case of jaundice and fulminant liver failure with massive hepatocellular necrosis and another case of elevated liver enzymes associated with the use of Xenical®. In view of the potential for rare but severe liver injuries, healthcare professionals are advised to consider the benefits and risks associated with the use of orlistat before prescribing orlistat and to advise patients to stop the use of orlistat and seek prompt medical attention if they experience symptoms associated with liver injury.
HSA would like to bring to the attention of healthcare professionals the potential risk of intravascular haemolysis (IVH) associated with Rho (D) Immune Globulin (Human) (WinRho® SDF) when used to treat Immune Thrombocytopenia Purpura (ITP). From March 1995 to March 2009, the manufacturer reported a total of 180 serious post-marketing reports of suspected and/or confirmed cases of IVH associated with the use of WinRho® SDF worldwide. Seventeen of the 58 definite IVH cases (29%) reported fatal outcomes. A disproportionate number of IVH cases has also been reported in patients with ITP secondary to haematological malignancies or active viral infections. The local package insert (PI) for WinRho® SDF has been updated to include new contraindications and monitoring information. Physicians are advised to be vigilant for signs and symptoms of IVH, including back pain, shaking chills, fever, and discoloured urine or haematuria in patients being treated with WinRho® SDF.
The Health Sciences Authority (HSA) has earlier informed healthcare professionals on the findings of DNA fragments of porcine circovirus 1 (PCV1) in Rotarix® and PCV1 and porcine circovirus 2 (PCV2) DNA fragments in RotaTeq®. HSA, in consultation with the MOH and its Expert Committee on Immunisation (ECI), would like to update healthcare professionals that they can continue to use Rotarix® and RotaTeq® as the benefits of vaccination outweigh the risk of PCV infectivity. Healthcare professionals can continue to use Rotarix® in patients who have previously deferred vaccination. Patients who have started or have been switched to the RotaTeq® vaccination schedule may wish to complete their course of vaccination with RotaTeq®. Parents should be made aware of the presence of the PCV DNA in these vaccines so that they can make an informed decision before their child is vaccinated.
The Health Sciences Authority (HSA) has on 23 March 2010, informed healthcare professionals on the findings of DNA fragments of porcine circovirus 1 (PCV-1) in the rotavirus vaccine, Rotarix®, by an independent research team from the University of California, San Francisco. Additional studies have since been performed by the companies manufacturing rotavirus vaccines to further assess the presence and findings of PCV DNA fragments in these vaccines. HSA would like to update healthcare professionals on the current findings from these studies as well as the interim local recommendations on the use of rotavirus vaccines until a decision is made following HSA's review of this matter
HSA would like to share with healthcare professionals information regarding the association of genetic variants of the enzyme uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) among the major ethnic groups in Singapore with a higher risk of irinotecan-induced severe neutropenia. The active metabolite of irinotecan, SN-38, is metabolized predominantly by UDP-glucuronosyltransferase (UGT). Patients who are homozygous (UGT1A1*6/*6 or UGT1A1*28/*28) or heterozygous (UGT1A1*6/*28) in allele UGT1A1*6, UGT1A1*28 of UGT may be at increased risk for serious adverse reactions (especially neutropenia) caused by reduced glucuronidation of SN-38. In view of the genotype distribution of UGT1A1*28 and UGT1A1*6 among the various ethnic groups in Singapore, added caution should be exercised when administering irinotecan to susceptible patients.
19 Apr 2010 : Increased myopathy with combination use of ER niacin/laropiprant (Tredaptive®) and simvastatin 40mg in Chinese patients
HSA would like to update healthcare professionals on the results of an interim analysis from an ongoing study, HPS2-THRIVE involving 25,000 patients, which suggest a higher incidence of myopathy observed in Chinese patients on concomitant extended release (ER) niacin/laropiprant 2g/40mg (Tredaptive®) and simvastatin 40mg (with or without ezetimibe) treatment as compared to Scandinavian and British patients. An interim analysis conducted by the independent safety monitoring committee revealed that the incidence of myopathy in 3,900 Chinese patients involved in the trial is higher than expected, with an approximate incidence of 0.9%. Clinical trial data from patients treated with simvastatin reported the incidence of myopathy to range from 0.02% to 0.53%, depending on the dosage used. Physicians prescribing the combined therapy of Tredaptive® with statins are advised to carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months or therapy and when dosage of either drug is increased.
19 Apr 2010 : Finasteride and potential risk of male breast cancer
HSA would like to bring to the attention of healthcare professionals the potential risk of male breast cancer associated with finasteride. In December 2009, the UK MHRA completed a review of data from clinical trials and post-marketing reports on the risk of breast cancer in men taking different strengths of finasteride for various medical conditions, and concluded that an increased risk of male breast cancer associated with finasteride use cannot be excluded. Healthcare professionals are advised to inform their patients taking finasteride to promptly report any changes in their breast tissue such as lumps, pain, gynaecomastia or nipple discharge to their doctors.
19 Apr 2010 : Sitagliptin- a new class of antidiabetic agents and acute pancreatitis
HSA would like to update healthcare professionals on the 88 cases of acute pancreatitis received by the US Food and Drug Administration (FDA) between October 2006 and February 2009 reported in patients treated with Sitagliptin (Januvia®) and Sitagliptin/Metformin (Janumet®). Fifty-eight patients were hospitalised, out of which four were critical cases, including two cases of hemorrhagic or necrotizing pancreatitis. The most common adverse events reported in the 88 cases were abdominal pain, nausea and vomiting. Physicians are encouraged to monitor their patients carefully for the development of pancreatitis after the initiation or dosage increments of Sitagliptin and to advise their patients taking Januvia® or Janumet® to look out for signs and symptoms of acute pancreatitis as early recognition is important in reducing adverse health outcomes. When pancreatitis is suspected, Januvia® or Janumet® should be discontinued.
19 April 2010 : Illegal product- Huo Luo Jing Dan [活絡金丹] adulterated with undeclared medicinal ingredients
In Dec 2009, HSA issued a press statement to warn consumers not to take an adulterated product labelled “Huo Luo Jing Dan [活絡金丹]” which was found to contain indomethacin, dexamethasone and prednisolone. A 54 year-old Chinese female who reportedly consumed this product for 12 years to relieve arthritic pain had Cushingoid features and was also diagnosed with supraglottic oedema caused by an aggravation of a neck abscess as her infection was not healing well. Healthcare professionals are strongly encouraged to ask their patients about the use of complementary medicine while taking their medication history.
19 Apr 2010 : Cessation of the marketing of Mediaxal® in Singapore
HSA would like to update healthcare professionals on the results of an interim analysis from an ongoing study, HPS2-THRIVE involving 25,000 patients, which suggest a higher incidence of myopathy observed in Chinese patients on concomitant extended release (ER) niacin/laropiprant 2g/40mg (Tredaptive®) and simvastatin 40mg (with or without ezetimibe) treatment as compared to Scandinavian and British patients. An interim analysis conducted by the independent safety monitoring committee revealed that the incidence of myopathy in 3,900 Chinese patients involved in the trial is higher than expected, with an approximate incidence of 0.9%. Clinical trial data from patients treated with simvastatin reported the incidence of myopathy to range from 0.02% to 0.53%, depending on the dosage used. Physicians prescribing the combined therapy of Tredaptive® with statins are advised to carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months or therapy and when dosage of either drug is increased.
19 Apr 2010 : Finasteride and potential risk of male breast cancer
HSA would like to bring to the attention of healthcare professionals the potential risk of male breast cancer associated with finasteride. In December 2009, the UK MHRA completed a review of data from clinical trials and post-marketing reports on the risk of breast cancer in men taking different strengths of finasteride for various medical conditions, and concluded that an increased risk of male breast cancer associated with finasteride use cannot be excluded. Healthcare professionals are advised to inform their patients taking finasteride to promptly report any changes in their breast tissue such as lumps, pain, gynaecomastia or nipple discharge to their doctors.
19 Apr 2010 : Sitagliptin- a new class of antidiabetic agents and acute pancreatitis
HSA would like to update healthcare professionals on the 88 cases of acute pancreatitis received by the US Food and Drug Administration (FDA) between October 2006 and February 2009 reported in patients treated with Sitagliptin (Januvia®) and Sitagliptin/Metformin (Janumet®). Fifty-eight patients were hospitalised, out of which four were critical cases, including two cases of hemorrhagic or necrotizing pancreatitis. The most common adverse events reported in the 88 cases were abdominal pain, nausea and vomiting. Physicians are encouraged to monitor their patients carefully for the development of pancreatitis after the initiation or dosage increments of Sitagliptin and to advise their patients taking Januvia® or Janumet® to look out for signs and symptoms of acute pancreatitis as early recognition is important in reducing adverse health outcomes. When pancreatitis is suspected, Januvia® or Janumet® should be discontinued.
19 April 2010 : Illegal product- Huo Luo Jing Dan [活絡金丹] adulterated with undeclared medicinal ingredients
In Dec 2009, HSA issued a press statement to warn consumers not to take an adulterated product labelled “Huo Luo Jing Dan [活絡金丹]” which was found to contain indomethacin, dexamethasone and prednisolone. A 54 year-old Chinese female who reportedly consumed this product for 12 years to relieve arthritic pain had Cushingoid features and was also diagnosed with supraglottic oedema caused by an aggravation of a neck abscess as her infection was not healing well. Healthcare professionals are strongly encouraged to ask their patients about the use of complementary medicine while taking their medication history.
19 Apr 2010 : Cessation of the marketing of Mediaxal® in Singapore
In May 2009, the French Medicines Agency (AFSSAPS) identified very rare cases of cardiac valvular disorders associated with the use of benfluorex (Mediaxal®) during its routine post-marketing surveillance. This prompted the re-evaluation of the benefit-risk ratio of the product by the AFSSAPS, which led to the agency's decision to suspend the marketing authorisation of Mediaxal® in France on 24 November 2009 and cease exportations of the product from 30 November 2009. In view the above decision, Servier has voluntarily ceased the marketing of this product locally with effect from 30 November 2009. Physicians who have prescribed Mediaxal® to their patients were advised to re-evaluate the treatment of their patients and to switch to appropriate alternative therapies.
19 Apr 2010 : Erythropoietin stimulating agents (ESAs): A safety update
HSA would like to remind healthcare professionals of key safety issues associated with the use of erythropoietin stimulating agents (ESAs). In several studies, certain cancer patients were treated with ESA to achieve haemoglobin levels > 12 g/dL. In these patients, it was documented that the time to tumour progression was shorter. In 2006, two clinical studies (CHOIR and CREATE) on patients with chronic renal failure and not on dialysis reported that patients who were randomised to receive an ESA to achieve higher haemoglobin levels (13.5g/dL in CHOIR and 13.0 to 15.0g/dL in CREATE) experienced more serious adverse cardiovascular outcomes. The result of another study at 80 centres and published in 2009 documented a higher incidence of deep vein thrombosis and similar rates of other clinically relevant thrombovascular events in subjects who did not receive prophylactic anticoagulation before spinal surgery and using epoetin alfa. Healthcare professionals are advised that the target haemoglobin concentration for all indications of ESAs should not exceed 12 g/dL.
HSA would like to remind healthcare professionals of key safety issues associated with the use of erythropoietin stimulating agents (ESAs). In several studies, certain cancer patients were treated with ESA to achieve haemoglobin levels > 12 g/dL. In these patients, it was documented that the time to tumour progression was shorter. In 2006, two clinical studies (CHOIR and CREATE) on patients with chronic renal failure and not on dialysis reported that patients who were randomised to receive an ESA to achieve higher haemoglobin levels (13.5g/dL in CHOIR and 13.0 to 15.0g/dL in CREATE) experienced more serious adverse cardiovascular outcomes. The result of another study at 80 centres and published in 2009 documented a higher incidence of deep vein thrombosis and similar rates of other clinically relevant thrombovascular events in subjects who did not receive prophylactic anticoagulation before spinal surgery and using epoetin alfa. Healthcare professionals are advised that the target haemoglobin concentration for all indications of ESAs should not exceed 12 g/dL.
HSA would like to remind healthcare professionals of the risk of osteonecrosis of the jaw (ONJ) associated with the use of oral and intravenous bisphosphonates and additionally provide an update on local cases of bisphosphonates related ONJ. According to a recent study published in the Journal of Oral Maxillofacial Surgery, the risk of bisphosphonates-related ONJ is between 1 in 10,000 and 1 in 100,000. This incidence may increase to 1 in 300 after dental extraction. Another study investigating the prevalence of oral bisphosphonate-related ONJ in Asian population estimated the prevalence of oral bisphosphonate-related ONJ to be 0.05% to 0.07%. To date, the Vigilance Branch of HSA has received one report of possible osteomyelitis with zoledronic acid use and 11 reports of osteonecrosis associated with several types of bisphosphonates. Healthcare professionals should consider the need for dental examination with appropriate preventive dentistry for patients with concomitant risk factors for ONJ. Physicians are advised to inform patients to avoid invasive dental procedures if possible, while on treatment with bisphosphonates. Dental surgery may exacerbate the condition in patients who develop ONJ while on bisphosphonate treatment.
23 Mar 2010 : Update on the recent finding of porcine circovirus-1 (PCV-1) DNA fragment in rotavirus vaccine (Rotarix®)
The Health Sciences Authority (HSA) would like to update healthcare professionals on the recent finding by researchers from the University of California, San Francisco regarding the presence of DNA fragment of porcine circovirus (PCV-1) found in the rotavirus vaccine, Rotarix® (GSK) and HSA's interim position on this matter. While HSA is reviewing the significance of this new finding, healthcare professionals are advised to consider deferring immunisation with Rotarix® or consider an alternative vaccine till more information becomes available.
23 Mar 2010 : Update on the recent finding of porcine circovirus-1 (PCV-1) DNA fragment in rotavirus vaccine (Rotarix®)
The Health Sciences Authority (HSA) would like to update healthcare professionals on the recent finding by researchers from the University of California, San Francisco regarding the presence of DNA fragment of porcine circovirus (PCV-1) found in the rotavirus vaccine, Rotarix® (GSK) and HSA's interim position on this matter. While HSA is reviewing the significance of this new finding, healthcare professionals are advised to consider deferring immunisation with Rotarix® or consider an alternative vaccine till more information becomes available.
26 Jan 2010 : Sibutramine and cardiovascular risk – an interim regulatory update
The Vigilance Branch, HSA would like to provide healthcare professionals with an interim regulatory update concerning the recommendation by the European Medicines Agency (EMA) to suspend the marketing authorisation of sibutramine across the European Union on the basis of a large clinical trial, the Sibutramine Cardiovascular OUTcomes (SCOUT) study.
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