Carrie S. Oliphant

Does heart failure exacerbation increase response to warfarin?A critical review of the literature

ABSTRACT Background: Numerous factors, such as other drugs, diet, and age, are well documented as altering response to warfarin. Less attention has been focused on the effect of disease states on the response to oral anticoagulants. Decompensated heart failure is reported to increase response to warfarin, but documentation is limited. Objective: The purpose of this review is to critically examine the evidence of a possible effect of heart failure exacerbations on response to warfarin. Research design and methods: A literature search was completed of the last 60 years using several databases, including PubMed, MEDLINE, EMBASE, and SCOPUS. Key terms in our search included ‘warfarin’ AND ‘heart failure’ and ‘heart failure exacerbation’ (or ‘decompensated heart failure’) AND ‘effect on warfarin’. When relevant citations were found, the references cited by those authors were checked. Results: Several reports from 1946–1989 suggested that decompensated heart failure increases response to oral anticoagulants. Unfortunately, these early reports have important limitations. More recent reports, since the widespread use of the international normalized ratio (INR), also suggest that heart failure exacerbations are associated with increased response to warfarin. Patient populations are small in these reports. Conclusions: Heart failure exacerbations may be associated with an increased response to warfarin and other vitamin K antagonists, but many reports are inadequate, and it appears that not all patients are susceptible to this effect. More frequent monitoring of INR in patients with decompensated heart failure is warranted. It is prudent to initiate warfarin at lower doses in patients with a history of heart failure and to monitor INR every 1–2 weeks during times of instability in ambulatory patients, and daily INRs in hospitalized patients. Given the large number of variables that impact on warfarin dose requirement, it is difficult to clearly establish the effect of decompensated heart failure on response to warfarin. Further studies must take all of these variables into account.

Treatment of Warfarin-related intracranial hemorrhage: A comparison of prothrombin complex concentrate and recombinant activated factor VII

OBJECTIVE Warfarin-related intracranial hemorrhage (ICH) is a devastating complication of warfarin therapy. Several studies have demonstrated successful correction of the international normalized ratio (INR) using prothrombin complex concentrate (PCC) or recombinant activated factor VII (rFVIIa). To our knowledge, no study has directly compared these agents for treatment of warfarin-related ICH. METHODS We retrospectively reviewed the charts of 15 patients who received rFVIIa and 9 who received PCC for treatment of warfarin-related ICH over a 2-year period. The primary objective was to compare the efficacy of rFVIIa and PCC in correcting the INR to 1.3 or less. Baseline INR was compared to INR obtained within 1, 3, 6, 12, and 24 hours after rFVIIa or PCC administration. RESULTS Six patients in the rFVIIa group and five in the PCC group had a follow-up INR within 1 hour of agent administration. In the rFVIIa group, the mean INR decreased from 6.1 to 1.1 and from 2.3 to 1.48 in the PCC group. At 6 hours, all rFVIIa patients and six (67%) PCC patients had at least one subsequent INR, with 93% and 50% correcting to an INR of 1.3 or less. Mean dose for all patients included was 53.4 ± 17.5 μg/kg and 27.8 ± 15.4 units/kg for rFVIIa and PCC, respectively. CONCLUSION Correction of the INR is more reliably obtained with rFVIIa when compared to PCC. Larger, prospective studies comparing these therapies for warfarin-related ICH are needed.

Clinical Efficacy and Safety of Cilostazol: A Critical Review of the Literature

Cilostazol is a unique antiplatelet agent that has been commercially available for over two decades. As a phosphodiesterase III inhibitor, it reversibly inhibits platelet aggregation yet also possesses vasodilatory and antiproliferative properties. It has been widely studied in a variety of disease states, including peripheral arterial disease, cerebrovascular disease, and coronary artery disease with percutaneous coronary intervention. Overall, cilostazol appears to be a promising agent in the management of these disease states with a bleeding profile comparable to placebo; even when combined with other antiplatelet agents, cilostazol does not appear to increase the rate of bleeding. Despite the possible benefit of cilostazol, its use is limited by tolerability as some patients often report drug discontinuation due to headache, diarrhea, dizziness, or increased heart rate. To date, it has been predominantly studied in the Asian population, making it difficult to extrapolate these results to a more diverse patient population. This paper discusses the evolving role of cilostazol in the treatment of vascular diseases.

Ivabradine: A Review of Labeled and Off-Label Uses

Ivabradine is a unique medication recently approved in the USA for the treatment of select heart failure patients. It was first approved for use in several countries around the world over a decade ago as an anti-anginal agent, with subsequent approval for use in heart failure patients. Since ivabradine has selective activity blocking the If currents in the sinus node, it can reduce heart rate without appreciable effects on blood pressure. Given this heart-rate-specific effect, it has been investigated in many off-label indications as an alternative to traditional heart-rate-reducing medications such as beta blockers and calcium channel blockers. We conducted searches of PubMed and Google Scholar for ivabradine, heart failure, HFrEF, HFpEF, angina, coronary artery disease, inappropriate sinus tachycardia, postural orthostatic hypotension, coronary computed tomography angiography and atrial fibrillation. We reviewed and included studies, case reports, and case series published between 1980 and June 2016 if they provided information relevant to the practicing clinician. In many cases, larger clinical trials are needed to solidify the benefit of ivabradine, although studies indicate benefit in most therapeutic areas explored to date. The purpose of this paper is to review the current labeled and off-label uses of ivabradine, with a focus on clinical trial data.

Evaluation of warfarin dose requirements in patients with chronic kidney disease and end-stage renal disease.

The effect of chronic kidney disease (CKD) on warfarin has gained attention because of an increased risk of thromboembolism and an increased risk of bleeding associated with warfarin treatment in these patients. Data suggest that patients with reduced kidney function require lower warfarin doses; however, relatively few patients with end‐stage renal disease (ESRD) were included in previous studies. The goal of this study was to evaluate warfarin dosing requirements and time to reach therapeutic international normalized ratio (INR) in patients with CKD stages 3–5 and ESRD compared with patients with normal kidney function (NKF).

Dual Antiplatelet Therapy After Coronary Artery Bypass Grafting in the Setting of Acute Coronary Syndrome

After acute coronary syndrome (ACS), dual antiplatelet therapy (DAPT) is the standard of care for both invasive management with percutaneous intervention and noninvasive (medical) management. Conversely, studies using dual antiplatelet in the population of patients presenting with ACS who undergo coronary artery bypass grafting (CABG) are conflicting. The appropriate antiplatelet regimen after CABG remains an area of controversy. Plaque stability, prevention of graft closure, and secondary thrombosis form the basis for using a second antiplatelet drug, whereas the additional risk of bleeding and lack of conclusive evidence should also be considered. After an extensive literature search, 12 clinical trials with efficacy outcomes were identified. Most of the studies are retrospective, nonrandomized single-center trials. A few large patient populations have been examined using database information. To date, there is only 1 prospective, multicenter, randomized trial published. Recommendations from national guidelines differ, proposing single antiplatelet therapy with aspirin or DAPT with the combination of aspirin and clopidogrel. The purpose of this report is to review the available clinical trial data and provide guidance to practitioners when caring for this patient population. In conclusion, there is no clear consensus regarding the use of DAPT in patients after CABG. If not contraindicated, it is reasonable to use DAPT, starting in the postoperative period, in patients presenting with ACS. Large, multicenter, randomized clinical trials are needed to definitively investigate the role of DAPT in patients with ACS after CABG.

Clopidogrel Response Variability: Review of the Literature and Practical Considerations

Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor is standard therapy following acute coronary syndrome and percutaneous coronary intervention. Despite the use of potent antiplatelet agents, vascular events continue to occur. Lack of response to clopidogrel therapy has been widely investigated using various methods of platelet function testing. These studies have consistently found an association between poor clopidogrel response and an increased risk of vascular events. Strategies to overcome this problem include higher clopidogrel doses or the use of an alternative P2Y12 agent. To date, the majority of studies investigating tailored antiplatelet therapy have failed to show any reduction in clinical events likely due to the low-risk population studied. Despite this lack of benefit from altering therapy, platelet function testing may be done in certain patient populations. Patients at high risk of deleterious outcomes from stent thrombosis may be an appropriate patient population for platelet function testing to ensure adequate response to therapy. In addition, emerging data suggests a potential role for platelet function testing to assess for bleeding risk. The purpose of this article is to review the key studies demonstrating response variability to clopidogrel therapy, strategies to overcome variability, and practical considerations for the clinician.

Colchicine for the Treatment of Acute and Recurrent Pericarditis

Objective: To evaluate the literature with colchicine for the acute treatment of pericarditis and prevention of recurrent pericarditis. Data Sources: Searches of MEDLINE (1966-March 2014) and Cochrane Database (1993-March 2014) were conducted using the search terms pericarditis and colchicine. Limits were set for articles written in English with human subjects. Additional data were identified through bibliographic reviews. Study Selection and Data Extraction: Case series and clinical trials identified from the data sources were evaluated. Data Synthesis: A total of 16 case series and 5 prospective controlled trials were identified in the search. Early observational studies examined the use of colchicine, as an adjunct to aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs), in patients with multiple cases of recurrent pericarditis. These studies showed decreased rates of recurrence after the initiation of colchicine therapy and formed the basis of the only available guidelines for the treatment of pericarditis. Since then, 5 randomized controlled trials have been published; 3 trials studied colchicine therapy for 6 months in patients with recurrent pericarditis, and the other 2 studied colchicine therapy for 3 months in patients with acute pericarditis. All 5 trials showed decreased rates of recurrence and symptom persistence, with similar rates of adverse events between study groups. Conclusions: Clinical controlled trials have shown that colchicine, as an adjunct to aspirin or NSAIDs, is effective in the prevention of recurrent pericarditis and in the management of acute symptoms. Colchicine was generally well tolerated with a low incidence of adverse events.

Direct oral anticoagulant use in nonvalvular atrial fibrillation with valvular heart disease: a systematic review

Direct oral anticoagulants (DOACs) are indicated for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF), which, according to the American College of Cardiology/American Heart Association/Heart Rhythm Society atrial fibrillation (AF) guidelines, excludes patients with rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair. However, the data regarding use of DOACs in AF patients with other types of valvular heart disease (VHD) are unclear. We aimed to summarize and evaluate the literature regarding the safety and efficacy of DOAC use in NVAF patients with other types of VHD. After an extensive literature search, a total of 1 prospective controlled trial, 4 subanalyses, and 1 abstract were identified. Efficacy of the DOAC agents in NVAF patients with VHD mirrored the overall trial results. Bleeding risk was significantly increased in VHD patients treated with rivaroxaban, but not for dabigatran or apixaban. Of the bioprosthetic valve patients enrolled in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, no safety or efficacy concerns were identified. In conclusion, subanalyses of DOAC landmark AF trials revealed that dabigatran, rivaroxaban, and apixaban may be safely used in AF patients with certain types of VHD: aortic stenosis, aortic regurgitation, and mitral regurgitation. More evidence is needed before routinely recommending these agents for patients with bioprosthetic valves or mild mitral stenosis. Patients with moderate to severe mitral stenosis or mechanical valves should continue to receive warfarin, as these patients were excluded from all landmark AF trials.

Fever as a Risk Factor for Increased Response to Vitamin K Antagonists: A Review of the Evidence and Potential Mechanisms

Numerous factors affect the response to vitamin K antagonists (VKA) including age, dietary vitamin K, other drugs, pharmacogenetics, and disease states. In antithrombotic guidelines, fever is mentioned as a factor that may increase response to VKA. The purpose of this article is to review the available evidence regarding the effect of fever on response to VKA, and to discuss possible mechanisms of this effect. We performed a search of the English literature from 1943 to June 2014, using the key words fever AND warfarin, acenocoumarol, phenprocoumon, coumarin anticoagulants and VKA; fever AND vitamin K dependent clotting factors II, VII, IX, and X. One animal investigation and 6 studies in humans suggest fever increases response to VKA, but one study did not find a significant effect. The magnitude of this effect is variable. Possible mechanisms for the increased effect of VKA associated with fever are increased catabolism of vitamin K dependent clotting factors, decreased vitamin K intake, and inhibition of VKA metabolism. More rigorous studies are needed to confirm that fever increases response to warfarin and other VKA.