CardioExchange Archive

Low Diagnostic Yield for Angiography: Coronary angiography as practiced in the U.S. has a startlingly low diagnostic yield, according to an important new study by Patel et al. in the New England Journal of Medicine using data from the ACC National Cardiovascular Data Registry. In 398,978 patients undergoing elective catheterization who did not have known coronary artery disease (CAD), only 149,739 (37.6%) were found to have obstructive disease. Nearly 40% had no evidence of CAD. The authors conclude that “current strategies that are used to inform decisions regarding invasive angiography, including clinical assessment of risk and noninvasive testing, need to be improved substantially to increase the diagnostic yield of cardiac catheterization in routine clinical practice.”
   
In an accompanying editorial, David Brenner notes that cardiac imaging is responsible for as much as 30% of radiation exposure from diagnostic imaging. “Ironically, there is evidence that, in many situations, a better gatekeeper test may be yet another radiographic imaging technique” —  CT angiography.

Is Acute MI Disappearing? From 2002 to 2007, the rate of hospitalization for acute MI among Medicare fee-for-service patients declined by 23.4%, according to a study by Chen et al. (led by CardioExchange editor-in-chief Harlan Krumholz) in Circulation. The rate of decline was slower among blacks, however. In an accompanying editorial, Russell Luepker and Alan Berger note that this observation is consistent with other data in different populations and ask: “Is acute myocardial infarction disappearing?”

Clopidogrel After DES: In a retrospective analysis of more than 9,000 patients who received a drug-eluting stent, Petersen et al. found that at 12 months, high use of clopidogrel was associated with a significant reduction in the risk of death or nonfatal MI but at the cost of more bleeding. Low use of clopidogrel was associated with an increase in death and nonfatal MI but with less bleeding. In their paper in the American Heart Journal, the authors write that the optimal duration of dual antiplatelet therapy can only be determined by “a dedicated randomized controlled trial.” In the meantime, “the decision to use drug-eluting stents in percutaneous coronary intervention should be made after consideration of the risks of ischemic events and bleeding in addition to the risk of restenosis.”

Obama’s Calcium Scan: In an early-release editorial in Archives of Internal Medicine, Rita Redberg writes that although she was “pleased to learn” about the results of President Obama’s recent physical examination, she “was troubled to read that the President’s physical examination included an electron beam computed tomographic (CT) scan for coronary calcium.” She points out that this test is not recommended for men in Obama’s risk category, and that “the most powerful way for President Obama to reduce his cardiac risk is to stop smoking.”

Zero Calcium: What is the “warranty period” for a zero calcium score? Min et al. studied 422 people who had a normal calcium scan (CAC=0) and who then received annual screens. One quarter of the patients had a subsequent calcium score >0 within 5 years, according to the report in the Journal of the American College of Cardiology, but the rate of conversion to abnormal was “nonlinear: extremely low in the first 2 years of serial scanning and accelerating substantially in year 4 to 5.”

In an accompanying editorial comment, Harvey Hecht writes that the study “paves the way for a fresh approach to a large segment of the primary prevention population” that will help prevent “overtreatment” in patients with zero calcium scores.

Click here to see this blog, originally posted on December 2, 2009.

Apixaban, a new factor Xa inhibitor under development, was compared with enoxaparin for thromboprophylaxis following knee replacement surgery in the ADVANCE-2 trial. The new report appears in the Lancet. In the primary efficacy analysis, the primary outcome — the composite of asymptomatic and symptomatic deep vein thrombosis, nonfatal pulmonary embolism, and all-cause death during treatment — was reached in 15% of apixaban patients compared with 24% of enoxaparin patients, a highly significant difference. Major or other clinically relevant bleeding was reported in 4% of the apixaban group versus 5% of the enoxaparin group. 
    In an accompanying comment, Jawed Fareed and Russell Hull note that in the previously published ADVANCE-1 trial, apixaban did not demonstrate noninferiority when compared to a different enoxaparin regimen, although it was associated with a lower bleeding rate. (ADVANCE-2 used the enoxaparin regimen most commonly employed outside the U.S.; ADVANCE-1 used the standard U.S. regimen.) The editorialists write that ADVANCE-2 brings us “potentially a step closer to the unmet need of oral antithrombotic therapy without need for monitoring.” Other new agents, including rivaroxaban and dabigatran, may also fill this need, they say.

Norepinephrine and dopamine are both recommended as first line drugs for the treatment of shock. In a report by De Backer et al in the New England Journal of Medicine, 1,679 shock patients were enrolled in the SOAP II trial and randomized to initial vasopressor therapy with one of the drugs. At 28 days there was no significant difference in mortality between the two groups (52.5% in the dopamine group versus 48.5% in the norepinephrine group). However, patients treated with dopamine had more arrhythmic events, and dopamine was associated with increased mortality in the subgroup of patients with cardiogenic shock. In an accompanying editorial,  Jerrold Levy writes that the study should “put an end to the outdated view that the use of norepinephrine increases the risk of death.”

We welcome Sanjay Kaul, MD, lead author of a recent American Heart Association/American College of Cardiology science advisory about the cardiovascular risks of thiazolidinedione drugs, to answer our questions about rosiglitazone. We encourage you to ask yours.

You and your coauthors call the evidence on the cardiovascular risks of rosiglitazone “inconclusive.” When you prescribe a thiazolidinedione, which agent do you choose and why?

For diabetic patients with known ischemic heart disease — particularly older, high-risk patients who take nitrates, ACE inhibitors, or insulin — I prefer pioglitazone over rosiglitazone. Indeed, the FDA has warned about the risk for myocardial ischemia from rosiglitazone (but not pioglitazone) in some of these high-risk patients. That said, for a diabetic patient without high-risk characteristics and with well-controlled blood sugar on rosiglitazone, I see no compelling reason to switch to pioglitazone. However, I don’t object if such a patient wants to switch to pioglitazone or any other antidiabetic drug. 
 
Notably, both rosiglitazone and pioglitazone are contraindicated in patients with NYHA class III or IV congestive heart failure (CHF). Given that the drugs are associated with weight gain and fluid retention, caution is warranted in all CHF patients and in patients with signs and symptoms of CHF.
 
What is your threshold for accepting that the cardiovascular risk is real — for example, if an estimate showed a clinically important risk increase of 20% to 30%?
 
Let me answer this important question using rosiglitazone.
 
First, we have the RECORD trial, an open-label, industry-funded study in which about 4500 patients with inadequate glucose control while taking metformin or a sulfonylurea were randomized to receive either both drugs (controls) or add-on rosiglitazone. Compared with controls, rosiglitazone recipients showed no significant difference in the primary endpoint of time to first cardiovascular hospitalization or cardiovascular death (ranging from a 15% risk reduction to a 16% risk increase) or for myocardial infarction (ranging from a 20% risk reduction to a 63% risk increase). In a prespecified subgroup of patients with preexisting ischemic heart disease, the lack of a primary-endpoint difference between rosiglitazone and the control regimen persisted, although subgroup analyses are inherently limited. Indeed, this entire trial has well-known limitations, so its findings are inconclusive.
 
Next, we have evidence from an FDA meta-analysis that focused only on diabetes trials; assessed robust outcomes of cardiovascular death, MI, or stroke; and used stringent analytical and statistical methods. With regard to the risk for CV death, MI, or stroke, rosiglitazone had a nonsignificant odds ratio of 1.15 (ranging from a 20% risk reduction to a 60% risk increase, compared with control). Thus, a 15% elevated risk is the most plausible point estimate we have.
 
If we use a probabilistic approach based on Bayes’ theorem, the likelihood of a 20% to 30% clinically important risk associated with rosiglitazone is less than 50% — lower than the “preponderance of the evidence” threshold used in civil court trials and nowhere near the 95% level of certainty that one would want. Ultimately, risk-benefit assessments are something of an art practiced by a clinician as he or she carefully considers the scientific evidence along with the clinical profile and the wishes of an individual patient.
 
What should we do when years have passed since FDA approval of a drug but we still don’t know whether it is safe?

In the face of insufficient evidence, patients, providers, and insurers often find themselves at odds with one another, frequently confused, and sometimes distrustful despite the presumed good intentions of industry sponsors, investigators, and regulators. As Jerry Avorn wrote in the NEJM in 2007, “The approval, prescribing, and safety surveillance of prescription drugs involve a complicated mix of science, regulatory law, clinical judgment, business, and politics.” I hope that the quiet, dispassionate voice of science will be allowed to render verdicts through its natural but rigorous course of refutation or confirmation. Meanwhile, the Hippocratic Oath compels us as clinicians to avoid (even potentially) harmful interventions, especially if we have alternatives.

The story of rosiglitazone, like that of ezetimibe, is a cautionary tale that highlights key shortcomings inherent in drug/device development, evaluation, and approval. The FDA approved rosiglitazone more than a decade ago, and we still lack conclusive evidence about its effects on cardiovascular outcomes. I believe that all the major stakeholders bear responsibility for this evidence vacuum: drug developers, regulators, investigators, physicians, payors, patients, and the U.S. Congress.

A potential remedy is the so-called “lifecycle evaluation” of a drug. Ideally, the FDA should grant only “provisional approval” when surrogate endpoints are used (rosiglitazone was approved on the basis of glycemic control, as other diabetes drugs have been). The conditions for full approval should be timely demonstration of efficacy and safety in large, well-designed clinical-outcomes trials that examine cardiovascular endpoints. Furthermore, Congress should empower the FDA to enforce postmarketing commitments. Only then can we hope to avoid controversies like those rosiglitazone has brought us.

Aspirin for Primary Prevention: Aspirin did not reduce the risk for cardiovascular disease in asymptomatic people with a low ankle brachial index (ABI) in the Aspirin for Asymptomatic Atherosclerosis trial. According to the report in JAMA, investigators screened nearly 30,000 men and women from Scotland and randomized 3,350 who had a low ABI to either aspirin or placebo. After 8.2 years of follow-up, there were no significant differences in outcomes between the two groups. An accompanying editorial by Jeffrey Berger concludes that “aspirin appears to have marginal benefits for reducing initial cardiovascular events when used for patients without clinically evident CVD and is associated with higher rates of bleeding events in these patients.”


ICDs and Cognitive Problems: Hallas et al. administered neuropsychological tests to 52 patients before, 6 weeks, 6 months, and 12 months after ICD implantation. In a study published in Circulation: Arrhythmia and Electrophysiology, 31%-39% of patients had evidence of cognitive problems at some point following the procedure. Most but not all of the problems were resolved by 12 months. The authors assume the cause of the problem is ventricular defibrillation testing of the device following implantation.

Secondary Smoke and 13-Year-Olds: Arterial damage caused by secondhand exposure to smoke is evident as early as the age of 13, according to a new report from Finland’s ongoing prospective randomized Special Turku Coronary Risk Factor Intervention Project (STRIP), appearing in Circulation: Cardiovascular Quality and Outcomes.