Primecuts – This Week In The Journals

By Caroline Srisarajivakul, MD

Peer Reviewed

In a historic election marked by a 97% voter registration rate, Scotland elected to remain a part of the United Kingdom with a 55% majority; while promises of increased power for Scottish lawmakers were promised by the British government, supporters of Scottish independence remain skeptical that the Westminster parliamentary parties will be able to come to a resolution[1].

Medical news this week included a study looking at the differences between anticoagulation treatments for acute venous thromboembolism (VTE), investigations into both new and old cardiovascular drugs, and a study that sheds light on some alternative medicine.

Is there a best management strategy for acute VTE?

In a meta-analysis published this week in JAMA, investigators examined 45 randomized trials with a total of almost 45,000 patients comparing a large variety of anticoagulation strategies for treating acute VTE [2]. The regimens investigated included combination unfractionated heparin (UFH)-vitamin K antagonist (VKA), low molecular weight heparin (LMWH)-VKA, fondaparinux–VKA, LMWH–dabigatran, and LMWH–edoxaban; as well as lone drug regimens including only rivaroxaban, apixaban, or LMWH. The primary outcomes of included studies was recurrent VTE confirmed with imaging and major bleeding. As compared with LMWH-VKA, there were no significant differences in recurrent VTE with one notable exception; the investigators found that UFH-VKA therapy was associated with significantly more recurrent VTE events as compared to LMWH-VKA (1.84% in the UFH-VKA group compared to 1.30% in the LMWH-VKA group, number needed to harm = 188). Rivaroxaban and apixaban were associated with fewer major bleeds as compared to LMWH-VKA (0.49% and 0.28% respectively, as compared to 0.89% in LMWH-VKA). In contrast, more bleeding events were associated with use of UFH-VKA as compared to LMWH-VKA. UFH-VKA is a staple for treatment of VTE in the inpatient setting and is safe and effective, but these findings cast doubt on whether it should be the first-line therapy in patients who would be a candidate for an alternative, especially among those more prone to bleeds or predisposed to the highest risk of recurrent thromboembolic disease.

Ivabradine in stable CAD

Ivabradine, a drug that inhibits the If pacemaker current of the sinoatrial node to reduce heart rate, has been shown to decrease cardiac death and hospital admissions in patients with heart failure [3]; it has also been shown to be noninferior to atenolol for making angina attacks less frequent [4] and when in combination with atenolol, can further improve exercise duration in patients with chronic stable angina as compared to atenolol alone [5]. Ivabradine was investigated again in the SIGNIFY trial, published this past week in The New England Journal of Medicine [6], which examined its effect on mortality and incidence of nonfatal MIs in patients with stable CAD but without heart failure. The 19,102 patients needed to have stable coronary artery disease without heart failure and a resting heart rate of >70 in sinus rhythm to be included; they were then randomized either to ivabradine or a placebo, with a nearly 4-year follow-up period. Overall, there was no difference in the composite endpoint of cardiovascular deaths or nonfatal MIs between ivabradine and placebo. Predictably, there was a significantly greater amount of adverse effects in the drug group, including symptomatic and asymptomatic bradycardia, atrial fibrillation, and phosphenes, which are spots of light seen on the visual field as a result of the medication. Significantly more patients also withdrew from the study due to the adverse effects. Pre-specified subgroup analysis did reveal that a significant interaction was present between more severe baseline angina (CCS class greater or equal to II) and the effect of ivabradine; interestingly, in this particular group, there was an increased risk of both cardiovascular death and nonfatal MI (7.6% vs 6.5% in placebo). Ivabradine, while a drug that has shown benefits in other studies, is not one that has a mortality benefit and due to its significant adverse effects, it likely would not be a staple of a cardiac medication regimen outside of its indication for heart failure and reduction of angina.

Generic vs Brand-Name Statins

An observational cohort study published in the Annals of Internal Medicine this week examined the differences between patients who initiate therapy with a generic or brand-name statin and if there was an effect on adherence or cardiovascular outcome [7]. The primary endpoint was a composite of cardiovascular outcomes (hospitalization for ACS or stroke) and all-cause mortality. The study included 90,111 patients, 93% of which were started on a generic statin during the study period. Adherence was determined by calculating the proportion of days covered, derived by dividing the number of days of medication supplied by the time interval (1 year in this case). Adherence to therapy was significantly greater for the generic statin group as compared to the brand-name (77% in the generic group vs 71%). In addition, patients in the generic group also had a reduced rate of the primary composite end point, however when broken down by components, ACS hospitalization was the only one that had a statistically significant reduction. While an outcome linking improved adherence with improved outcomes is not entirely surprising, what remains to be elucidated further is why exactly patients on generic statins show greater adherence. In addition, while propensity matching was used in this study to help control for confounding variables, it is possible that the difference is driven by something unmeasured given this is an observational study. It is, however, postulated that the cheaper drug cost would allow the drug to be more accessible to those who would otherwise be unable to obtain their medications.

Back-related leg pain and home exercise

One of the most common diagnoses worldwide, low back pain has a profound impact on quality of life and has economic consequences, accounting for millions of lost workdays in the US alone. This study examines the effect of chiropractic spinal manipulation and exercise on chronic back-related leg pain [8], defined as pain radiating to any part of the lower extremity (with or without neurologic signs) lasting for 4 or more weeks which has not been relieved by a month of stable medications. The interventions in this study were 12 weeks of chiropractic spinal manipulation (SMT) with home exercise and advice (HEA) versus HEA alone; the effect of these interventions was examined for the primary outcome of leg pain as reported by patients using an 11-point scale. At 12 weeks, 37% of patients who had undergone SMT with HEA had a 75% reduction in pain level as compared to the 19% of patients in the HEA group . 20% of patients in the SMT-HEA group had a complete resolution of pain whereas there was only 5% of patients with complete resolution in the HEA group. After a year of follow-up, the SMT-HEA group had better satisfaction and ”global improvement” scores as determined by a questionnaire, though there was not a statistically significant difference in pain score. There also were no differences seen in mental health or disability.  This information sheds light on the usefulness of chiropractic in showing a benefit to spinal manipulation by experienced practitioners in this setting. Medical doctors can better advise patients seeking alternative treatments for a debilitating disease such as back-related leg pain.

In other medical news:

Select replacement valves carefully [9] — an analysis of Medicare patients undergoing concurrent aortic valve replacement and CABG showed a higher risk of death both at surgery and 30-day post-op mortality in patients receiving a mechanical valve as compared to a bioprosthetic valve. Notably, this difference was not present in patients undergoing isolated aortic valve replacement.

In a randomized trial evaluating patients with suspected nephrolithiasis, there was no difference in complications, adverse events, pain, hospitalizations, or recurrent ED visits between patients who had an initial ultrasound compared to those who had an initial CT [10].

JAMA published an article this week examining the benefit of initiating a long-acting beta agonist (LABA) versus LABA with inhaled corticosteroids [11] with therapy continuing for 5 years in patients with COPD. The combination therapy was found to be associated with significantly reduced risk of the combined endpoint of COPD hospitalization and death. An NEJM study, reported in Primecuts last week, looked at tapering inhaled corticosteroids after at least 6 weeks of LABA+corticosteroid therapy [12]; it showed that tapering the corticosteroid was noninferior to continuation of combination therapy, a result that somewhat contradicts the former study. It is unclear what is driving this difference in results, though there are major differences between the two studies. The NEJM study was a randomized controlled trial whereas this study is observational. The NEJM study had a shorter period of follow-up and thus there is a large difference in duration of inhaled corticosteroid therapy between these two studies.  An RCT with a longer period of follow-up may be useful in elucidating the relationship of these drugs to improvement in COPD.

Dr. Caroline Srisarajivakul is a second year resident at NYU Langone Medical Center

Peer reviewed by Mark H. Adelman, MD, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References

1. BBC. Scottish referendum: Scotland votes ‘No’ to independence. Published online 9/19/2014. Available at http://www.bbc.com/news/uk-scotland-29270441.

2. Castellucci AL, et al. Clinical and Safety Outcomes Associated With Treatment of Acute Venous Thromboembolism: A Systematic Review and Meta-analysis. JAMA. 2014;312(11):1122-1135. http://jama.jamanetwork.com/article.aspx?articleid=1904827

3. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875-85. http://www.sciencedirect.com/science/article/pii/S0140673610611981

4. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J 2005;26:2529-36. http://eurheartj.oxfordjournals.org/content/26/23/2529.long

5. Tardif JC, Ponikowski P, Kahan T. Efficacy of the I(f) current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month, randomized, placebo-controlled trial. Eur Heart J 2009;30:540-8. http://eurheartj.oxfordjournals.org/content/30/5/540.long

6. Fox, K, et al. Ivabradine in Stable Coronary Artery Disease without Clinical Heart Failure. N Engl J Med 2014; 371:1091-1099. http://www.nejm.org/doi/full/10.1056/NEJMoa1406430

7. Gagne JJ, Choudhry NK, Kesselheim AS, et al. Comparative effectiveness of generic and brand-name statins on patient outcomes: a cohort study. Ann Intern Med. 2014 Sep 16;161(6):400-7. http://annals.org/article.aspx?articleid=1905128

8. Bronfort, G, et al. Spinal Manipulation and Home Exercise With Advice for Subacute and Chronic Back-Related Leg Pain: A Trial With Adaptive Allocation. Ann Intern Med. 2014;161(6):381-391. http://annals.org/article.aspx?articleid=1905126

9. Du, D, et al. Early Mortality After Aortic Valve Replacement With Mechanical Prosthetic vs Bioprosthetic Valves Among Medicare Beneficiaries. JAMA Intern Med. Published online September 15, 2014. http://archinte.jamanetwork.com/article.aspx?articleid=1904759.

10. Smith-Bindman, R, et al. Ultrasonography versus Computed Tomography for Suspected Nephrolithiasis. N Engl J Med 2014; 371:1100-1110. http://www.nejm.org/doi/full/10.1056/NEJMoa1404446

11. Gershon AS, et al. Combination Long-Acting ?-Agonists and Inhaled Corticosteroids Compared With Long-Acting ?-Agonists Alone in Older Adults With Chronic Obstructive Pulmonary Disease. JAMA. 2014;312(11):1114-1121. http://jama.jamanetwork.com/article.aspx?articleid=1904829

12. Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of Inhaled Glucocorticoids and Exacerbations of COPD. N Engl J Med. 2014 Sep 8. [Epub ahead of print] http://www.nejm.org/doi/full/10.1056/NEJMoa1407154

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