Top POEMs of 2013: Cardiovascular Disease

Fasting Not Necessary Before Lipid Panels

Clinical question: Do patients have to fast before obtaining a lipid panel?

Bottom line: Forget fasting as a requirement for cholesterol screening or monitoring. Cholesterol levels, with the exception of triglycerides, are similar when drawn after fasting or soon after a meal. Even triglyceride levels will be elevated by less than 20% if the patient has not fasted. Similarly, hemoglobin A1c determinations for the diagnosis or monitoring of type 2 diabetes can be drawn at the visit regardless of a recent meal (Diabetes Care 2012;35 Suppl 1:S11-63). If you get some push back from your lab tech, ask him or her to fast until 10:30 some morning, which is what I had to do before my last visit. The resulting grumpiness may generate some empathy. (LOE = 2b)

Reference: Sidhu D, Naugler C. Fasting time and lipid levels in a community-based population. A cross-sectional study. Arch Intern Med 2012;Nov 12:1-4 [Epub ahead of print].

Study design: Cross-sectional

Funding source: Self-funded or unfunded

Setting: Population-based

Synopsis: These Canadian investigators looked at lipid levels for 209,180 individuals (111,048 women and 98,132 men), which comprised all the lipid panels reported for a 6-month period in Calgary (a single laboratory provides all testing for the city). The authors also recorded, as a matter of practice, the length of time of the fast before blood was drawn. The huge number of patients should present an average with only small variation (confidence interval); as a result, any differences found by stratifying results by the duration of the fast should indicate an effect of recent food ingestion on measurements. Although the majority of serum levels were drawn after at least 10 hours of fasting, the average result was remarkably similar when compared across hours of fasting. The mean cholesterol levels varied by less than 2% for total cholesterol and high-density lipoprotein cholesterol, by less than 10% for calculated low-density lipoprotein cholesterol, and by less than 20% for triglycerides over the fasting times.

Allen F. Shaughnessy, PharmD, MMedEd
Professor of Family Medicine
Tufts University
Boston, MA

NSAIDs and COX-2 Agents, but Not Naproxen, Pose Vascular Risk to Adults

Clinical question: How common are adverse vascular and gastrointestinal events among nonsteroidal anti-inflammatory drugs?

Bottom line: Diclofenac, ibuprofen, and COX-2 inhibitors (coxibs) cause more vascular complications than placebo. (LOE = 1a)

Reference: Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013, early online publication May 30, 2013. http://dx.doi.org/10.1016/S0140-6736(13)60900-9

Study design: Meta-analysis (randomized controlled trials)

Funding source: Government

Setting: Outpatient (any)

Synopsis: These authors (who have an impressive list of ties to industry) searched multiple databases to find published and unpublished randomized trials of at least 4 weeks' duration that compared a nonsteroidal anti-inflammatory drug (NSAID) against placebo, open controls, or another NSAID. In addition to analyzing the studies using standard meta-analytic approaches, the researchers also tried to obtain patient-level data. They evaluated the rate of major vascular events (defined as nonfatal myocardial infarction, nonfatal stroke, or death from a vascular cause), major coronary events (nonfatal myocardial infarction or death from coronary disease), stroke, hospitalization, and upper gastrointestinal complications (bleeding, perforation, or obstruction). Two authors independently assessed studies for inclusion and extracted study characteristics and data. The authors don't describe how discrepancies were resolved or whether they formally assessed study quality. Ultimately, they included 280 placebo-controlled trials (with more than 124,000 patients) and 470 trials comparing NSAIDs to NSAIDs (nearly 230,000 patients). Most of the trials lasted less than 1 year. The included trials provided approximately 90% of the available data to the researchers. Compared with placebo, patients taking a coxib expereinced more major vascular events (1.2% per year) than patients taking placebo (0.8% per year; number needed to treat to harm [NNTH] = 250 per year), more admissions for heart failure (0.7% vs 0.3% per year; NNTH = 250), deaths from all causes (1.7% vs 1.4% per year; NNTH = 417), and upper gastrointestinal (GI) complications (0.4% vs 0.2% per year; NNTH = 527). In studies comparing a coxib with diclofenac, the patients taking coxibs had lower annual rates of major vascular events (0.8% vs 1.1%; number needed to treat [NNT] = 358); heart failure admissions (0.9% vs 1.7%; NNT = 117); and upper GI complications (0.7% vs 1.2%; NNT = 193). Compared with ibuprofen, patients taking coxibs were less likely to be admitted for heart failure (0.4% vs 1.6% per year; NNT = 82) and upper GI complications (0.2% vs 0.6% per year; NNT = 257). Finally, in studies comparing coxibs and naproxen, patients taking coxibs had lower annual rates of heart failure admissions (0.8% vs 1.8%; NNT = 98) and upper GI complications (0.3% vs 0.5%; NNT = 477).

Henry C. Barry, MD, MS
Professor
Michigan State University
East Lansing, MI

NSAID Use Associated with Increased Risk of Death Following AMI

Clinical question: Does the increased risk of death following acute myocardial infarction associated with nonsteroidal anti-inflammatory drug use decline over time?

Bottom line: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an increased risk of death for up to 5 years following acute myocardial infarction (AMI). The risk was somewhat lower with naproxen, so if NSAIDs must be used, naproxen should be the preferred agent. (LOE = 2b)

Reference:
Olsen AM, Fosbøl EL, Lindhardsen J, et al. Long-term cardiovascular risk of nonsteroidal anti-inflammatory drug use according to time passed after first-time myocardial infarction: a nationwide cohort study. Circulation 2012;126(16):1955-1963.

Study design: Cohort (retrospective)

Funding source: Government

Setting: Population-based

Synopsis: American Heart Association guidelines recommend that patients with cardiovacular disease avoid NSAID use, because they increase the risk of adverse events. Whether this increase in risk persists years after an AMI or if it differs by drug is not well established. The authors of this Danish study identified patients who had experienced an AMI betweeen 1997 and 2009, and linked this information to a pharmacy database to determine whether they had filled a prescription for an NSAID. Only ibuprofen (200 mg, no more than 100 at a time) was available over the counter in Denmark during the study period. The authors also gathered information on comorbidities, other medications, and demographic variables, so they could attempt to adjust for differences between groups using multivariate analysis. Patients who died during hospitalization, those with a prior AMI, those younger than 30 years, and those who died within 30 days of discharge were excluded. The final study population included 99,187 participants with a mean age of 69 years; 36% were women. The authors found a significant increase in the likelihood of death among NSAID users during each of the 5 years following the index AMI; while the absolute risk declined, the relative increase in risk with NSAID use was similar (hazard ratio = 1.59 - 1.84). The increase in risk was similar for rofecoxib, celecoxib, and ibuprofen, and was somewhat higher for diclofenac and lower for naproxen. Limitations of the study including that dosage and duration of treatment were estimated from the pharmacy data, and that patients may have also gotten ibuprofen 200 mg over the counter in addition to the prescribed NSAIDs.

Mark H. Ebell, MD, MS
Associate Professor
University of Georgia
Athens, GA

Sustained Modest Reduction in Daily Salt Intake: Reduced BP, No Adverse Effect on Lipids or Hormones

Clinical question: Does a modest reduction of salt intake over 4 weeks or more affect blood pressure, lipid, or hormone levels?

Bottom line: A modest reduction of salt intake over time leads to lower blood pressure (BP) in both hypertensive and normotensive people without adversely affecting lipid levels or hormone levels. A greater reduction in salt intake results in a greater reduction in systolic BP. These authors suggest a goal of 3 g per day salt intake for the overall population, a target that is lower than the current recommendations in most countries of 5 g to 6 g per day. (LOE = 1a)

Reference: He FJ, Li J, MacGregor GA. Effect of longer term modest salt reduction on blood pressure: Cochrane systematic review and meta-analysis of randomized trials. BMJ 2013;346:f1325.

Study design: Meta-analysis (randomized controlled trials)

Funding source: Self-funded or unfunded

Allocation: Uncertain

Setting: Outpatient (any)

Synopsis: A recent systematic review suggested that a large reduction in salt intake can adversely affect lipids and hormones, thus counteracting the benefits of reduced BP (Graudal et al. Cochrane Database Syst Rev 2011 Nov 9;(11):CD004022). This review, however, included many short-term trials with drastic reductions in daily salt intake over only a few days. These investigators searched multiple databases including MEDLINE and EMBASE to find randomized trials that studied the effect of reduced salt intake by 2 g to 7 g per day over 4 weeks or more on BP, lipids, and hormones such as renin and aldosterone. Two authors independently selected the studies and assessed study quality using the criteria of allocation concealment, masking, and completeness of follow-up. Discrepancies were resolved by discussion with the third author. A total of 34 trials were included in the meta-analysis (N = 3230): 22 included hypertensive patients and 12 included normotensive patients. The majority of the studies had adequate concealment of allocation and almost all were either double-blinded or blood pressure observer-blinded. Study duration ranged from 4 weeks to 3 years. The median salt intake in the control group was estimated at 9.4 g per day and the median BP was 141/86 mmHg. The intervention group reduced salt intake by 4.4 g per day, resulting in a decrease in systolic BP of 4 mmHg (95% CI, 3.18-5.18; P < .001) and in diastolic BP of 2 mmHg (1.45-2.67; P < .001). Results were similar when restricted to the trials of hypertensive patients only and normotensive patients only with decreases in BP of 5/3 mmHg and 2/1 mmHg, respectively. Further analysis showed a dose-response relation between the reduction in salt intake and the reduction in systolic BP. After adjusting for age, ethnicity, and the presence of baseline hypertension, a reduction in salt intake by 6 g per day corresponded to a reduction in systolic BP by 6 mmHg. There were no clinically important changes in lipid or hormone levels with long-term reduced salt intake.

Nita Shrikant Kulkarni, MD
Assistant Professor in Hospital Medicine
Northwestern University
Chicago, IL

Mediterranean Diet Reduces Cardiovascular Events (PREDIMED)

Clinical question: Is a Mediterranean diet more effective than a low-fat diet at preventing cardiovascular events?

Bottom line: In a high-risk population, a Mediterranean diet, either supplemented with nuts or olive oil, reduces the likelihood of a composite outcome of cardiovascular events or death over a 5-year follow-up period (number needed to treat = 70). The relative risk reduction is approximately 30%. This is the strongest evidence yet to support any particular approach to diet. Best of all, what's not to like about seafood, red wine, paella, nuts, fresh fruit, and chicken? (LOE = 1b)

Reference: Estruch R, Ros E, Salas-Salvadó J, et al, for the PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013; Feb 25. [Epub ahead of print]. Doi:10.1056/NEJMoa1200303

Study design: Randomized controlled trial (single-blinded)

Funding source: Government

Allocation: Concealed

Setting: Population-based

Synopsis: Most studies of diet are underpowered or are only observational. This large Spanish study identified men between the ages of 55 and 80 years and women between the ages of 60 and 80 years (n = 7447) who either had type 2 diabetes mellitus or who had 3 or more of the following risk factors: hypertension, smoking, low-density lipoprotein cholesterol > 160 mg/dL (4.1 mmol/L), high-density lipoprotein cholesterol < = 40 mg/dL (1.0 mmol/L, body mass index (BMI) >= 25 kg/m2, or a family history of premature cardiovascular disease. Patients were randomized to follow 1 of 3 diets: (1) a Mediterranean diet supplemented with olive oil, (2) a Mediterranean diet supplemented with nuts, or (3) a low-fat diet. The Mediterranean diets emphasized fresh fruit, vegetables, fish, legumes, sofrito (love that paella!), white meat, and wine with meals. Red meat, commercially baked goods, soda, and spreadable fats were discouraged. The olive oil group was given 1 liter of oil per week, the nut group received 30 grams of mixed nuts per day, and the low-fat group just got a small nonfood gift (so they didn't feel bad). The low-fat group focused on low-fat food, lots of carbohydrates, fresh fruits, vegetables, and lean fish and seafood. Sofrito, fatty fish, spreadable fats, nuts and fried snacks, vegetable oils, commercially baked goods, and red meats were discouraged. End points were adjudicated by a committee unaware of treatment assignment. The participants had an average age of 67 years, 97% were European whites, and 57% were women. Only 8% had a BMI of less than 25 kg/m2, and approximately 50% had type 2 diabetes. Participants were followed up for 4.8 years, and the authors assessed compliance with the diet in all 3 groups using self-reported intake and biomarker analysis. For 12 of the 14 items on the Mediterranean diet screener, the Mediterranean diet groups had higher scores. The primary outcome was a combined end point of myocardial infarction, stroke, and cardiovascular death. This end point was less likely for both of the Mediterranean diet groups than for the low-fat control diet group; there were approximately 3 fewer events per 1000 person-years, which corresponds to a number needed to treat of approximately 70 for the 4.8-year study to prevent one adverse event. However, there was no difference in deaths due to any cause or deaths due to cardiovascular events; the only individual outcome for which there was a statistically significant benefit was strokes (4.1% for the Mediterranean diet with olive oil, 3.1% for the Mediterranean diet with nuts, and 5.9% for low-fat diet). One limitation is that the control group received fewer counseling visits and had a higher dropout rate than either of the intervention groups.

Mark H. Ebell, MD, MS
Associate Professor
University of Georgia
Athens, GA

POEMs are provided by Essential Evidence Plus, a point-of-care clinical decision support system published by Wiley-Blackwell. For more information, please see http://www.essentialevidenceplus.com(www.essentialevidenceplus.com).

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