1: US Supreme Court Upholds the ACA; Re-Election of President Obama Ensures ACA Continuity
On June 28, 2012, the US Supreme Court ruled that the Patient Protection and Affordable Care Act of 2010 (ACA) is constitutional. The ruling stated that the law’s controversial individual mandate provision was permissible under Congress’s taxation powers as defined by the Constitution. The individual mandate to obtain insurance coverage or else pay a penalty was the core of a lawsuit against the ACA that was filed by 26 states, which claimed the individual mandate violated the Constitution’s Commerce Clause. Before it was considered by the Supreme Court, a federal district court in Florida and a federal appeals court in Georgia had sided with the plaintiffs and invalidated the individual mandate. The Supreme Court upheld the individual mandate in a 5 to 4 decision, with Chief Justice John Roberts writing for the majority that the penalty for failure to obtain insurance could be viewed as a tax, which Congress is authorized to levy. The justices largely preserved the law’s expansion of the Medicaid program, which the plaintiffs had asserted was a usurpation of states’ rights. The re-election of President Obama in November ensures that the ACA remains law.
2: Patent on Plavix Expires
Plavix (clopidogrel) became available as a generic drug in May 2012 after its patent expired. Plavix, a product of Bristol-Myers Squibb/ Sanofi, was for years the second-best-selling drug in the world, with more than $9 billion in global sales in 2010 alone. Approved in 1997 on the basis of the CAPRIE trial, clopidogrel’s indications expanded over the years to include patients with acute coronary syndrome (ACS) including non-ST-segment-elevation MI (NSTEMI) and STEMI patients, as well as in combination with aspirin in patients treated with a coronary stent. Dr John Tsai, VP of US Medical at Bristol- Myers Squibb, noted that clopidogrel has benefited more than 115 million patients worldwide, including 50 million in the United States. The FDA approved 300-mg and 75-mg generics.
3: Rivaroxaban Approved for PE, DVT
Rivaroxaban (Xarelto) was approved in November 2012 by the FDA for treatment of acute deep vein thrombosis (DVT) and pulmonary embolism (PE) and for prevention of recurrences. The new indications are in addition to previous approval for prevention of thromboembolism and stroke in patients with nonvalvular atrial fibrillation (AF) and for DVT prevention in patients undergoing joint surgery. Earlier in the year, an FDA advisory committee voted against approving rivaroxaban to reduce the risk of secondary cardiovascular events in patients with ACS in combination with standard antiplatelet therapy because panel members were concerned about missing data in the ATLAS ACS 2 TIMI 51 trial of the drug.
Rivaroxaban is a product of Janssen Pharmaceuticals Inc.
4: Intensive BP Targets in T2DM: No Evidence of Reduced Risk for Mortality or MI
Treatment of hypertension in patients with type 2 diabetes mellitus (T2DM) has been shown to improve cardiovascular outcomes, but the value of intensive versus standard blood pressure (BP) targets has been uncertain. Researchers therefore wanted to determine the effectiveness and safety of treating BP to intensive targets (upper limit, 130 mm Hg systolic and 80 mm Hg diastolic), compared with standard targets (upper limit, 140-160 mm Hg systolic and 85-100 mm Hg diastolic) in patients with T2DM. They conducted a systematic review and meta-analysis to identify randomized trials that enrolled adults diagnosed with T2DM and analyzed 5 randomized controlled trials with 7312 patients. All the trials used stepped antihypertensive therapy to achieve prespecified BP targets. Random-effects models were used to pool relative risks (RRs) and risk differences for mortality, MI, and stroke. The study found that the use of intensive BP targets was not associated with a significant decrease in the risk for mortality (RR difference, 0.76; 95% confidence interval [CI], 0.55-1.05) or MI (RR difference, 0.93; 95% CI, 0.80-1.08), but was associated with a decrease in the risk for stroke (RR, 0.65; 95% CI, 0.48-0.86). The study found that the use of intensive BP targets resulted in a small absolute decrease in the risk of stroke; there was no statistically significant difference in the risk of mortality or MI.
5: Favorable Trends in US Lipid Levels
Data from 3 National Health and Nutrition Examination Surveys (NHANES), nationally representative surveys of the noninstitutionalized US population spanning the period between 1988 and 2010, show that there have been favorable trends in lipid levels across the nation in the last 2 decades. Total cholesterol fell by 10 mg/dL over the study period, low-density lipoprotein (LDL) fell by 13 mg/dL, and high-density lipoprotein (HDL) levels rose by 2 mg/ dL. Triglycerides fell by 8 mg/dL over the period. Positive changes may be due to a reduction in smoking rates and a decrease in the consumption of trans fats, as well as an increase in the number of people taking statins, noted study coauthor Brian Kit, MD, MPH, of the US Centers for Disease Control and Prevention. Dr Kit noted that obesity levels have risen over the same period, however.
Carroll MD, Kit BK, Lacher DA, Shero ST, Mussolino ME. Trends in lipids and lipoproteins in US adults, 1988-2010. JAMA. 2012;308:1545-1554.
6: Dabigatran Use in US Climbing
According to a study of national trends in oral anticoagulant use in the United States, by the end of 2011, dabigatran (Pradaxa) had become “the drug of choice” at about 19% of office visits for oral anticoagulation, compared with 81% for warfarin. Dabigatran was approved for an AF indication in October 2010 and had reached the 19% share in 1 year. In November 2011 the FDA approved rivaroxaban for the same indication. Senior study author G. Caleb Alexander, MD, MS, of Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, noted that the approval of dabigatran for AF did not achieve the goal of decreased rates of undertreatment of AF because only about 40% of patients eligible for oral anticoagulation for AF were receiving it. The study also found that the growth in dabigatran use was partially due to non-AF indications. Over time, there were increasing rates of off-label use of dabigatran, including venous thromboembolism, coronary disease, and stroke or transient ischemic attack.
Kirley K, Qato DM, Kornfield R, et al. National trends in oral anticoagulant use in the United States, 2007 to 2011. Circulation: Cardiovasc Qual Out-comes. 2012;5:615-621. Dr Alexander discloses support from the Agency for Healthcare Research and Quality and serving as a consultant to IMS Health.
7: Hypoglycemia and Risk of Death in Critically Ill Patients
Researchers set out to find whether hypoglycemia in critically ill patients leads to death, a question that has long been debated. The NICE-SUGAR study investigators examined the associations between moderate and severe hypoglycemia (blood glucose [BG], 41-70 mg/dL and ≤40 mg/dL , respectively) and death among 6026 critically ill patients in intensive care units (ICUs). It is the largest multicenter trial to examine intensive glycemic control in ICU patients. Patients were randomly assigned to intensive (target BG, 81-108 mg/dL) or conventional (≤180 mg/dL) glucose control; Cox regression analysis with adjustment for treatment assignment and baseline and postrandomization covariates was used. The adjusted hazard ratios (HRs) for death among patients with moderate or severe hypoglycemia, compared with those without
hypoglycemia, were 1.41 (95% CI, 1,21-1.62; P <0.001) and 2.10 (95% CI, 1.59-2.77, P <0.001), respectively. The association with death was increased among patients who had moderate hypoglycemia on more than 1 day, those who died from vasodilated shock, and those who had severe hypoglycemia in the absence of insulin treatment. The researchers concluded that in critically ill patients, intensive glucose control leads to moderate to severe hypoglycemia, both of which are associated with an increased risk of death. While the data cannot prove a causal relationship, the NICE-SUGAR researchers noted a dose-response relationship that is strongest for death from vasodilated shock. The results of NICESUGAR contradicted the trend toward intensive glycemic control in the ICU that has been in place for the last decade.
The NICE-SUGAR Study Investigators. Hypoglycemia and risk of death in critically ill patients. N Engl J Med. 2012;367:1108-1118. Supported by grants from the Australian National Health and Medical Research Council, the Health Research Council of New Zealand, and the Canadian Institutes of Health Research.
8: Repercussions of Fungal Meningitis Outbreak Continue
On September 25, 2012, the US Centers for Disease Control and Prevention (CDC) notified the FDA that it was investigating a cluster of meningitis cases at a single Tennessee clinic that might be associated with product contamination. The FDA joined the investigation of what began as a voluntary recall by the New England Compounding Center (NECC) of 3 implicated lots of injectable methylprednisolone acetate (MPA), which were traced to that compounding pharmacy. The CDC has reported 36 deaths and over 500 cases of fungal meningitis from the outbreak as of November 26, 2012. Approximately 14,000 patients may have received injections with contaminated MPA from NECC. In an interview with NBC News on November 21, 2012, FDA Commissioner Dr Margaret Hamburg stated that FDA officials know little about US compounding pharmacies, how much they are making, and where they are sending their products. Dr Hamburg said it was likely there could be another outbreak of infections similar to the spread of fungal meningitis in the contaminated MPA. She told the Senators that even as FDA inspectors found NECC to be violating rules and operating with filthy conditions, FDA regulators were arguing about how much they could actually do to shut them down given ambiguities in the law. State regulators in Massachusetts were said to have done little, while other states took prompt action. Congress and the FDA are pushing for federal legislation to clarify how the FDA can regulate compounding pharmacies.
9: FFR-Guided PCI Versus Medical Therapy in Stable Coronary Disease
The FAME 1 trial demonstrated the superiority of fractional flow reserve (FFR)-guided PCI over angiography-guided PCI. For the FAME 2 trial, researchers hypothesized that in patients with functionally significant stenoses (as determined by FFR measurement), PCI plus the best available medical therapy would be superior to the best available medical therapy alone. Their primary end point was a composite of death, MI, or urgent revascularization. Recruitment in FAME 2 was halted early after enrollment of 1220 patients because of a significant between-group difference in the percentage of patients who had a primary end-point event: 4.3% in the PCI group and 12.7% in the medical therapy group (HR with PCI, 0.32; 95% CI, 0.19-0.53, P <0.001). The difference was driven by the lower rate of urgent vascularization in the PCI group than in the medical therapy group (1.6% vs 11.1%; HR, 0.13; 95% CI, 0.06-0.30, P <0.001). The researchers concluded that in patients with stable coronary artery disease and functionally significant stenoses, FFR-guided PCI plus the best available medical therapy—as compared with the best available medical therapy alone—decreased the need for urgent revascularization. In patients without ischemia, the outcome appeared to be favorable with the best available medical therapy alone.
De Bruyne B, Pijls NHJ, Kalesan B, et al. Fractional flow reserve-guided PCI versusmedical therapy in stable coronary disease. N Engl J Med. 2012;367:991- 1001. This study was funded by St Jude Medical; ClinicalTrials.gov number NCT01132495.
10: New Strategy for Discontinuation of Dual Antiplatelet Therapy: RESET
Few prospective randomized clinical studies have been published comparing the safety and efficacy of shorter-duration dual antiplatelet therapy (DAPT) after DES implantation. The goal of the RESET trial was to evaluate shorter duration (3-month) DAPT after implantation of a DES. A total of 2117 patients with coronary artery stenosis were randomly assigned to 2 groups according to DAPT duration and stent type: 3-month DAPT following Endeavor zotarolimus-eluting stent (E-ZES) implantation (E-ZES+3-month DAPT; n = 1059) versus 12-month DAPT following the other DES implantation (standard therapy; n = 1058). The researchers correctly hypothesized that the E-ZES+3-month DAPT would be noninferior to the standard therapy for the primary composite end point of cardiovascular death, MI, stent thrombosis, target vessel revascularization, or bleeding at 1 year. The primary end point occurred in 40 (4.7%) patients assigned to E-ZES+3-month DAPT compared with 41 (4.7%) patients assigned to standard therapy (difference, 0.0%; 95% CI, -2.5 to 2.5; P = 0.84; P <0.001 for noninferiority).
Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET trial (REal safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol. 2012;60:1340-1348.