Doac Essay Help

Abstract

Venous thromboembolism (VTE) is a serious medical condition associated with significant morbidity and mortality, and an incidence that is expected to double in the next forty years. The advent of direct oral anticoagulants (DOACs) has catalyzed significant changes in the therapeutic landscape of VTE treatment. As such, it is imperative that clinicians become familiar with and appropriately implement new treatment paradigms. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance for VTE treatment with the DOACs. When possible, guidance statements are supported by existing published evidence and guidelines. In instances where evidence or guidelines are lacking, guidance statements represent the consensus opinion of all authors of this manuscript and are endorsed by the Board of Directors of the Anticoagulation Forum.

The authors of this manuscript first developed a list of pivotal practical questions related to real-world clinical scenarios involving the use of DOACs for VTE treatment. We then performed a PubMed search for topics and key words including, but not limited to, apixaban, antidote, bridging, cancer, care transitions, dabigatran, direct oral anticoagulant, deep vein thrombosis, edoxaban, interactions, measurement, perioperative, pregnancy, pulmonary embolism, reversal, rivaroxaban, switching, \thrombophilia, venous thromboembolism, and warfarin to answer these questions. Non- English publications and publications > 10 years old were excluded. In an effort to provide practical information about the use of DOACs for VTE treatment, answers to each question are provided in the form of guidance statements, with the intent of high utility and applicability for frontline clinicians across a multitude of care settings.

Keywords: DOACs, NOACs, Direct thrombin inhibitors, Factor Xa inhibitors, Antidotes, Care transitions, Bridging anticoagulation, Drug interactions

Introduction

The availability of the new direct oral anticoagulants (DOACs) has significantly changed the therapeutic landscape of anticoagulation and these agents may eventually displace conventional VTE treatment with a rapid-acting parenteral anticoagulant overlapped with a vitamin K antagonist (e.g. warfarin) in appropriately selected patients. As a class, the DOACs exhibit comparable efficacy and a significantly lower bleeding risk compared to warfarin among patients with acute symptomatic VTE [1, 2]. For patients who need extended anticoagulation for secondary VTE prevention, the safety record of the DOACs is strong [3–5].

In this paper we will examine key questions pertaining to the practical management of DOACs for VTE treatment, summarize the evidence (where it exists) pertaining to those questions, and finally, provide guidance that may be applied to real-world practice by frontline clinicians.

Methods

To provide guidance on the practical management of the DOACs, we first developed a number of pivotal practical questions that apply to DOACs as they might be used in the treatment of VTE. (Table 1). Questions were developed by consensus of the authors. The medical literature was reviewed using PubMed for topics and key words including, but not limited to, adherence, anticoagulant, apixaban, appropriate patient selection, bleed, bridging, care transitions, adherence, CYP, dabigatran, deep venous thrombosis (DVT), direct, edoxaban, education, follow-up, hemorrhage, initiation, interaction, measurement, monitoring, novel, oral, peri-operative, p-glycoprotein, practical management, prothrombin complex concentrate (PCC) pulmonary embolism (PE), reversal, rivaroxaban, safety, switching, target-specific, temporary interruption (TI), and venous thromboembolism (VTE). Non-English language publications and publications >10 years old were excluded. Guidance provided in this document is, whenever possible, based on the best available evidence. For some issues, however, published evidence is lacking. In all instances, guidance statements represent the consensus opinion(s) of all authors and are endorsed by the Anticoagulation Forum’s Board of Directors.

Guidance

  1. Which VTE patients are (and are not) good candidates for DOAC therapy?

The DOACs have been studied extensively in clinical trials and the results demonstrate they are at least as safe and effective as conventional treatment in the majority of typical VTE patients. However, many specific subgroups were excluded or underrepresented in these studies and the safety and efficacy of DOACs within these subgroups has yet to be established. The inclusion criteria for the VTE treatment trials included patients age ≥18 (no pediatric studies have been published) with an acute symptomatic proximal DVT and/or PE. Exclusion criteria varied slightly among the trials, but in general, patients were excluded if they had any of the following: need for thrombolytic therapy, another indication for anticoagulation, high risk of bleeding, clinically significant liver disease (acute or chronic hepatitis, cirrhosis, or alanine aminotransferase level greater than three times the upper limit of normal), creatinine clearance (CrCl) <30 mL/min (for apixaban the threshold was 25 mL/min), life expectancy of <3–6 months, aspirin use >100 mg/day, using interacting medications, uncontrolled hypertension, breastfeeding or pregnant or of childbearing potential without appropriate contraceptive measures [3–10]. Table 2 represents potential advantages and disadvantages of DOACs in comparison to conventional therapy that should be considered by both clinicians and patients before deciding on an anticoagulant regimen. Table 3 provides selection criteria for patients suitable for DOAC therapy. Table 4 provides further considerations regarding patient-controlled aspects, such as adherence, values and preferences as each of these will have a direct impact on outcomes with DOAC therapy.

Pregnancy and breastfeeding

Animal studies of dabigatran and rivaroxaban demonstrated pregnancy loss and fetal harm [11, 12], and one study demonstrated that dabigatran does cross the human placenta [13]. A case report of maternal rivaroxaban use during weeks 1–19 of pregnancy (when pregnancy discovered at week 19, the patient was switched to enoxaparin) resulted in a full-term, low growth percentile, otherwise healthy infant [14]. Apixaban has no human data in pregnancy, but showed no maternal or fetal harm in animal studies [15]. Edoxaban animal studies demonstrated no fetal harm. The edoxaban VTE treatment trial reported 10 pregnancies, with edoxaban exposure during the first 6 weeks of gestation (4 full-term births, 2 pre-term births, 1 first-trimester spontaneous abortion, and 3 elective pregnancy terminations) [16]. It is unknown whether any of the DOACs are excreted in breast milk. Because of the potential for infant harm, a decision should be made to either avoid breastfeeding or use an alternative anticoagulant, such as warfarin, in these women.

Body weight extremes

Patients at extremes of weight represented a very small proportion of subjects in DOAC VTE treatment trials. [3–10]. The mean weight was around 84 kg, with the majority of patients weighing between 60 and 100 kg. Underweight patients (<50–60 kg) comprised 2–13 % of the study populations and roughly 14–19 % of patients were >100 kg. Approximately 30 % of patients in the EINSTEIN, AMPLIFY and RE-COVER studies had a BMI ≥ 30 kg/m2, and in the AMPLIFY and RE-COVER studies, only 12 % of subjects had a BMI ≥ 35 kg/m2. Based on very limited data, extremes of weight do not appear to affect peak concentrations or bioavailability of dabigatran [17]. The pharmacokinetics and pharmacodynamics of factor Xa inhibitors may be affected by weight [10, 15, 18–20], but the clinical impact of these effects remains unknown. Pending further evidence in patients at extremes of weight (e.g., <50 kg, >120 kg or BMI ≥ 35 kg/m2) it is advisable to limit DOAC use to situations where vitamin K antagonists cannot be used.

Thrombophilia

Patients with thrombophilias represented 2–18 % of DOAC VTE clinical trial populations [3–9]. A posthoc subgroup analysis of thrombophilia patients within the RE-MEDY trial was recently presented [21]. Results showed that the frequencies of VTE-related death and PE did not differ between dabigatran and warfarin patients. The authors concluded that dabigatran’s efficacy in preventing recurrent VTE is not influenced by the presence of thrombophilia. Conversely, six cases citing possible failure of rivaroxaban or dabigatran to prevent thrombosis in patients with antiphospholipid antibody syndrome were recently published [22, 23]. While it is possible the DOACs may be a viable option for VTE treatment in patients with weaker underlying thrombophilias (e.g., heterozygous Factor V Leiden), caution or avoidance, especially in highly pro-thrombotic states such as antiphospholipid antibody syndrome or heparin-induced thrombocytopenia, is suggested until further evidence becomes available.

Cancer

Four meta-analyses of DOAC VTE clinical trials including approximately 1000 cancer patients (patients with a history of cancer or some with active cancer) demonstrated similar efficacy and safety for the DOACs compared to conventional therapy of a vitamin K antagonist overlapped with LMWH [24–27]. Previous trials, which included approximately 2000 patients with active cancer (many in advanced stages), indicate that vitamin K antagonists are inferior to long-term LMWH monotherapy for treatment of cancer-related VTE [28–31]. While most evidence to date is with dalteparin, the recent CATCH study [32] showing a trend (p = 0.07) towards superiority of tinzaparin over warfarin for prevention of recurrent symptomatic DVT and reduction in clinically relevant non-major bleeding suggests this may be a class effect of the LMWHs. Whether DOACs convey similar benefit as LMWH monotherapy for VTE treatment in cancer patients remains unknown. Data from head-to-head randomized controlled trials or robust comparative effectiveness studies is needed and future research in this area is encouraged. Until then, among patients with cancer-associated VTE, long-term LMWH is the preferred first-line therapy for anticoagulant treatment (see chapter by Khorana et al.). However, for those patients who cannot (or will not) use long term LMWH, either a DOAC or VKA could be prescribed as a second-line option. Given their improved safety profile compared to warfarin, DOACs may well be preferred in these instances, particularly among patients with a perceived increased risk for bleeding. However, it is important to emphasize the lack of experience with DOACs compared to warfarin in cancer patients who may have profound thrombocytopenia and other clinical challenges pertaining to anticoagulation. The lack of readily available measurement assays for DOACs may be particularly problematic in the setting of drug interactions, nephrotoxic chemotherapy, and potential disruption in absorption due to short gut or malnutrition, common issues in a cancer population.

History of bleeding

Much of the available data on DOACs and gastrointestinal (GI) bleeding is from atrial fibrillation trials, which generally consisted of older patients with more comorbidities than the VTE treatment populations. In a real- world study of Medicare claims data among new users of dabigatran or warfarin for non-valvular atrial fibrillation [33], there was a 28 % overall increased risk for gastrointestinal bleeding among dabigatran patients compared to warfarin patients. This was most pronounced in women ≥75 years of age (HR 1.5; 95 % CI 1.2–1.88), men ≥85 years of age (HR 1.55; 95 % CI 1.04–2.32) and in patients receiving the higher dose of 150 mg twice daily (HR 1.51; 95 % CI 1.32–1.73). A meta-analysis of 4 dabigatran trials of both NVAF and VTE treatment reported a 41 % increase in the risk of GI bleeding with dabigatran [34]. In the individual DOAC VTE treatment trials [3–10], GI bleeding event rates were too low to draw definite conclusions (dabigatran and rivaroxaban numerically higher rates of GI bleeding, apixaban and edoxaban numerically lower rate of GI bleeding) compared to conventional anticoagulation therapy. A meta-analysis of data from 11 phase-3 DOAC NVAF or VTE treatment trials found no significant difference in major gastrointestinal bleeding between DOACs and warfarin (2.09 vs. 1.7 %; RR 0.94; 95 % CI 0.75–1.99; p = 0.62, I2 71 %) [35]. Even so, careful consideration should be exercised in regards to DOAC use in patients with a history of gastrointestinal bleeding.

Intracranial hemorrhage (ICH) is the most feared complication of anticoagulant therapy. A significant advance with DOAC therapy over warfarin has been a reduction in the rates of ICH in atrial fibrillation. Numerically lower rates of both ICH and fatal bleeding were seen in all DOAC arms of the VTE trials [3–10], with the exception of intracranial hemorrhage in the EINSTEIN-DVT trial (2 events in the rivaroxaban arm vs. none in the warfarin arm) [4]. A systematic review and meta-analysis of 12 randomized controlled trials including over 100,000 patients with either NVAF or VTE showed that DOACs are associated with less major bleeding, fatal bleeding, intracranial bleeding, clinically relevant non-major bleeding, and total bleeding compared to warfarin [35]. This provides a compelling argument to favor these agents over conventional therapy for VTE treatment whenever possible.

Guidance statement

DOACs are suggested as an alternative to conventional therapy for VTE treatment in patients who meet appropriate patient selection criteria. For all other patients, we suggest VTE treatment with conventional therapy. Until further data are available, we suggest avoiding DOACs for VTE in patients with antiphospholipid antibody syndrome and patients at extremes of weight. LMWH monotherapy remains first line for patients with cancer-related VTE, but DOACs may be considered in select patients unwilling or unable to receive subcutaneous injections.

  • 2.

    How should DOACs be initiated for VTE treatment?

Before prescribing a DOAC, a thorough evaluation should be conducted to ensure the patient is a good candidate for DOAC therapy, as detailed in Tables 3 and ​4. Baseline labs should be performed, including serum creatinine, liver function tests, complete blood count, and coagulation assays such as aPTT and PT to ensure adequate organ function and rule out coagulopathy. In general, DOAC therapy should not be initiated in patients presenting with extensive VTE if there is potential need for an invasive procedure, such as thrombolysis or thrombectomy. Instead, preference should be given to a shorter-acting, reversible agent such as unfractionated heparin until no further immediate procedures are needed. Clinicians should consider characteristics of the individual agents when selecting which DOAC to initiate (detailed in Table 5). In addition, concomitant drug therapies and comorbidities should also be accounted for in DOAC dose management as detailed in Table 6. In clinical trials of edoxaban and dabigatran [6, 10] initial treatment consisted of open-label parenteral anticoagulation (median of 9 and 7 days in the dabigatran and edoxaban trials, respectively) overlapped with warfarin titrated to an INR of 2–3 in the control arm or overlapped with warfarin-placebo titrated to a sham INR in the intervention arms. Concomitant administration of a parenteral anticoagulant and a DOAC was not employed in either of these trials, as that would likely lead to excessive anticoagulation based on the rapid onset of the DOACs. Dabigatran was initiated at 150 mg BID. Edoxaban was initiated at 60 mg once daily, with a dose reduction to 30 mg once daily in patients with a creatinine clearance of 30–50 mL/min or a body weight of 60 kg or less or in patients who were receiving concomitant treatment with potent P-glycoprotein inhibitors. Package labelling for dabigatran and edoxaban also indicates the required 5–10 days of parenteral anticoagulation prior to their initiation for acute VTE, which closely approximates the conventional approach to VTE treatment.

Table 5

Drug characteristics to consider when deciding which DOAC to prescribe for VTE [3–12, 15, 16]

For patients with acute VTE selected for treatment with edoxaban or dabigatran, for lead-in therapy we suggest use of subcutaneous (SC) anticoagulants LMWH or fondaparinux over unfractionated heparin (UFH) when possible due to improved safety and efficacy [36, 37] and facilitation of outpatient therapy in eligible patients. (See care transitions section for more details). When switching from lead-in parenteral therapy within the acute VTE treatment phase, edoxaban or dabigatran should be initiated at the time that a heparin infusion is discontinued or the time the next dose of SC anticoagulant is due.

In clinical trials of apixaban [5] and rivaroxaban [4, 8], a single-drug approach was employed without parenteral anticoagulation. A higher dose was used in the initial period followed by a dose reduction(s). Apixaban was initiated with 10 mg BID for the first 7 days and reduced to 5 mg BID thereafter. Rivaroxaban was initiated at 15 mg BID for 21 days followed by 20 mg once daily. Less than 2 % of patients in apixaban and rivaroxaban VTE treatment trials received >2 days of parenteral anticoagulation before randomization which reinforces that these agents can be safely used as an oral, single-drug strategy for VTE treatment. Rivaroxaban and apixaban monotherapy should be initiated as soon as it is determined that no invasive procedures are needed. If the patient has been receiving empiric or temporary UFH or SC anticoagulant therapy for acute treatment of VTE, apixaban or rivaroxaban should be initiated at the time that the heparin infusion is discontinued or at the time the next dose of SC anticoagulant is due.

Guidance statement

We suggest that a thorough patient evaluation be conducted prior to DOAC initiation which should include assessment of baseline laboratory values, concomitant drug therapies, and comorbidities. We do not recommend initial DOAC therapy in patients who are hospitalized with extensive DVT or who have PE with hemodynamic instability in whom thrombolysis or thrombectomy may be indicated. We suggest that the unique characteristics of each DOAC, their distinct dosing for VTE treatment, and patient preferences should be considered when selecting a DOAC for VTE treatment.

  • 3.

    How should the anticoagulant activity of DOACs be measured?

The specificity, predictability and wide therapeutic index of the DOACs allow for fixed dosing without a need for routine monitoring. However, there are instances during which measurement of DOAC activity would be useful to direct therapy and inform long-term treatment decisions (Table 7) [38–40]. When these situations occur, clinicians need to be familiar with the role, limitations and local availability of various coagulation assays as they relate to DOACs (Tables 7, ​8; Fig. 1).

Fig. 1

Linearity and specificity of coagulation assays for measurement of DOACs [40]. Reproduced with permission from Cuker et al. [40]

The INR does not vary significantly from hour to hour due to the long half-life of warfarin and the timing of INR in relation to the last warfarin dose is not important. In contrast, the timing of last DOAC dose relative to the coagulation assay is important for interpretation given the relatively short half-life of the DOACs [39]. Most scenarios that would trigger laboratory testing for DOACs are urgent (e.g. bleeding or thrombosis) thus lab results will often be random out of necessity. In the bleeding patient, it is likely sufficient to have a rapidly available quantitative test that will reliably determine whether DOAC is present in measurable quantities (yes or no). In the setting of thrombosis or suspected treatment failure, the ideal test would indicate not only whether drug was present but also if the concentration was consistent with observed on-treatment levels. In the event of concern for DOAC accumulation due to renal insufficiency or drug interactions, trough levels are preferred [39]. For detailed information of the impact of individual DOACs on various anticoagulant assays, please refer to the pharmacology chapter of this compendium by Nutescu et al.

A systematic review regarding laboratory measurement of OAC activity was recently published and provides support for following guidance statements: [40]

Guidance statement

We suggest that clinicians do not routinely measure DOAC activity. If measurement of a DOAC is indicated, we suggest that clinicians use assays that are validated either locally or in a reference laboratory and that are readily available. The chosen assay should be suitable for the DOAC being used, as well as for the indication for measurement, as detailed in Table 8.

  • 4.

    How should VTE patients who require temporary interruption (TI) of DOAC therapy be managed?

Use of bridge therapy

Approximately 10 % of patients require temporary interruption (TI) of their anticoagulant for a procedure on an annual basis [41] with additional patients requiring interruption due to bleeding or other non-bleeding adverse events [42–44]. Relatively little direct medical literature exists on studies in the VTE treatment population and TI of DOACs; however, some information may be extrapolated from data in other populations as well as guidelines and other practical recommendations. [42–44]. In the RELY and the ROCKET atrial fibrillation (AF) trials, 25 and 33 % of enrolled participants underwent one or more TI during the study period with 17 and 8.2 % utilizing bridging with unfractionated heparin (UFH)/low molecular weight heparin (LMWH) therapy for dabigatran 150 mg and rivaroxaban, respectively [42, 43]. In the RELY trial, there were numerically more bleeding events among dabigatran patients who received bridging therapy compared to warfarin patients receiving bridging therapy (295 for dabigatran 150 mg BID vs. 276 for warfarin). There was no significant difference in the incidence of perioperative major bleeding (4.6 vs. 5.1 %) or the composite of cardiovascular death, ischemic stroke, and non-central nervous system and pulmonary embolism (1.2 vs. 1.5 %) for warfarin and dabigatran 150 mg BID, respectively. Other bleeding outcomes, including fatal bleeding, bleeding requiring reoperation or transfusion of red blood cells, and minor bleeding were also similar between groups [42]. For rivaroxaban, perioperative major bleeding (0.99 %/30 days vs. 0.79 %/30 days) and the composite of stroke/systemic embolism/myocardial infarction/death (0.66 %/30 days vs. 0.95 %/30 days) were not significantly different for the rivaroxaban and warfarin groups that received bridging therapy, respectively. Overall in the ROCKET AF trial in TI patients, there was numerically higher major/non-major clinically relevant bleeding for those who received bridging therapy versus those who did not (4.83 vs. 3.02 %) [43]. The data from these subanalyses suggests that bridging therapy with LMWH/UFH should be minimized or avoided in DOAC patients. The pharmacokinetic similarities of these two anticoagulant classes further support avoidance of overlapping therapies to prevent over anticoagulation.

Managing DOAC interruptions for invasive procedures

Determining the optimal approach to management of DOACs around elective invasive procedures involves addressing a few key clinical questions. For elective procedures, clinicians should first consider whether the procedure can be delayed until a time that the patient may not require a DOAC or is at least several months after the index event, since the risk of recurrent VTE is highest during the first 3 months. For patients who require long-term anticoagulation or in whom the invasive procedure cannot be delayed, the next step is to determine whether procedure-related bleeding risk is sufficiently high to warrant DOAC interruption. Some procedures, such as simple dental extractions, minor dermatologic procedures or cataract surgery, pose minimal bleed risk and do not require interruption of anticoagulation. Table 9 provides a list of procedures categorized by bleed risk. Table 10 lists additional characteristics that may predispose patients to bleeding.

When DOAC interruption is necessary, the cessation and resumption of the DOAC around the elective procedure is determined according to bleeding risk, renal function, and DOAC half-life (t1/2) (Table 11). The half-life of a drug is the time for the blood plasma concentration of a substance to reach one-half of its steady-state value as a result of elimination processes. It requires five half-lives to eliminate >95 % of a therapeutic drug concentration. When pathways of elimination are diminished (e.g. renal impairment), it will require more time to clear the drug and the half-life will increase. Among hospitalized VTE patients who develop acute kidney injury (AKI), the DOAC t1/2 may become significantly prolonged.

For urgent or emergent procedures, determination of time of last ingestion and rapid assessment of residual anticoagulant effect should be performed with an appropriate assay if possible before proceeding with invasive interventions. In deciding whether an urgent/emergent procedure should be delayed until after an appropriate amount of time has elapsed since the last administration of the DOAC, the increased risk of bleeding should be weighed against the urgency of the procedure.

Once hemostasis is achieved, the DOAC should be resumed approximately 24 h post-operatively in low bleed risk situations, and this should be delayed to 48–72 h in high bleed risk patients (Tables 9, ​10, and ​11). VTE prophylaxis with UFH, LMWH or DOAC may be employed, if necessary, until therapeutic doses of DOAC are resumed. If the risk of bleeding precludes even prophylactic-dose anticoagulation from being given, mechanical VTE measures should be considered. In situations where a patient cannot tolerate oral therapy post-operatively, apixaban or rivaroxaban may be administered via NG or a parenteral agent may be utilized until the DOAC can be administered. In post-operative patients with ongoing epidural anesthesia, DOACs should be avoided. Guidelines regarding neuraxial anesthesia and anticoagulants set forth by the American Society of Regional Anesthesia and Pain Medicine (ASRA) [45] should be strictly followed to avoid spinal or epidural hematoma. Only anticoagulants endorsed by ASRA should be utilized while the epidural remains in place.

Several guidelines and reviews pertaining to perioperative management of anticoagulants have been published and form the basis for our guidance statements [41, 46, 47].

Guidance statement

For VTE patients on DOAC therapy requiring TI for an invasive procedure, we suggest a carefully constructed, thoughtful approach that emphasizes communication between the provider managing the DOAC therapy, the clinician performing the procedure, and the patient and/or caregiver about the management of the DOAC. If TI is deemed necessary, we suggest that clinicians consider the patient’s renal function, the DOAC t1/2 and the associated bleeding risk when determining timing of cessation and resumption of the DOAC. We suggest avoiding routine use of bridge therapy during DOAC interruption.

  • 5.

    How should patients with DOAC drug–drug interactions be managed?

Currently, the majority of available DOAC drug interaction data only illustrate changes in drug exposure conducted in pharmacokinetic studies of healthy volunteers. Available pharmacokinetic drug interaction data in actual patients are limited to subsets of the larger atrial fibrillation population clinical trials. It is unknown if these pharmacokinetic changes translate to pharmacodynamic effect resulting in excess bleeding or thrombotic events.

Each of the DOACs is a substrate of permeability-glycoprotein (p-gp), an efflux transporter located in the membranes of the small intestine, blood–brain barrier, liver, and kidneys that regulates absorption of drugs into the bloodstream and tissues [48, 49] (Fig. 2). Hepatic enzyme Cytochrome 3A4 (CYP 3A4) metabolizes rivaroxaban and apixaban to varying degrees (33 and 25 %, respectively). Dabigatran is not a CYP3A4 substrate, and less than 4 % of edoxaban is metabolized via CYP3A4 (Table 12). Drugs that induce (increase the function of) p-gp and/or CYP3A4 may decrease DOAC plasma concentrations and increase the risk for thromboembolic events, while drugs that inhibit (decrease the function of) p-gp and/or CYP3A4 may increase DOAC concentrations and increase bleeding risk.

Fig. 2

P-gp effect on drug exposure. Reproduced with permission from Kaatz and Mahan [127]

Given that each of the DOACs has some proportion of renal elimination (dabigatran 80 %, rivaroxaban 33 %, apixaban 25 %, edoxaban 50 %) [49] (Table 12), patients with renal impairment or over age 75 years taking DOACs may be at a higher risk of bleeding complications [48, 50–56], especially if they also have potential concomitant drug interactions (e.g. taking a p-gp and/or CYP3A4 inhibitor). It is important to note that these same patient characteristics (increasing age, impaired renal function and drug interactions) have been shown to convey an increased bleeding risk with warfarin as well [57].

In VTE treatment trials, dyspepsia and gastrointestinal (GI) bleeding were more common in patients taking dabigatran as compared to warfarin or placebo [6, 7]. Patients with these adverse effects may be frequently prescribed proton-pump inhibitors (PPIs). Even though dabigatran requires an acidic gastric environment for absorption [58], pharmacokinetic studies have not shown a clinically significant reduction in dabigatran exposure with concomitant PPI [14, 59]. Therefore, PPIs may be safely co-administered with dabigatran without need for dose adjustment. Tables 13 and ​14 provide an evidence-based summary of drug interactions with dabigatran and the anti-Xa inhibitors. Additionally, the product labeling for each of the DOACs contains detailed dosing information and necessary adjustments that consider route of metabolism and elimination and degree of renal impairment.

Table 13

Permeability glycoprotein (p-gp) drug–drug interactions with dabigatran and edoxaban [16, 48, 59, 130–135] (list is not exhaustive)

Table 14

Permeability glycoprotein (p-gp) and Cytochrome 3A4 drug–drug Interactions with rivaroxaban and apixaban) [134–139] (list is not exhaustive)

Antiplatelet agents and non-steroidal anti-inflammatory drugs (NSAIDs)

When each of the DOACs were studied in combination with dual antiplatelet therapy (aspirin and clopidogrel) for acute coronary syndromes, investigators observed a clinically significant increase in major bleeding in patients taking triple therapy [60–62]. The DOAC VTE treatment trials permitted low-dose concomitant aspirin, and dual antiplatelet therapy was permitted in the dabigatran and rivaroxaban trials. The rate of low-dose aspirin use in the study populations for dabigatran, rivaroxaban, and apixaban ranged from 8 to 14 % and was not reported in the edoxaban trial [4, 5, 7–10, 63]. In a sub-analysis of the rivaroxaban VTE treatment trial, patients taking rivaroxaban and low-dose aspirin had a significantly higher risk of clinically relevant bleeding (hazard ratio (HR) 1.81, 95 % CI 1.36–2.41) and a non-significant increase in major bleeding (HR 1.50, 95 % CI 0.63–3.61) compared to rivaroxaban-only patients [63].

Each of the VTE treatment trials allowed concomitant NSAID use (the edoxaban trial restricted NSAID use to <4 days per week [4, 5, 7–10], with 43 % of dabigatran patients and 23 % of rivaroxaban patients reporting concomitant NSAID use) [7, 60]. Patients taking rivaroxaban and NSAIDs had a 2.5-fold higher rate of major bleeding (HR 2.56, 95 % CI 1.21–5.39) and a 2-fold higher rate of clinically relevant bleeding (HR 1.9, 95 % CI 1.45–2.49) compared to those not taking NSAIDs. In this study, 14 % of the clinically relevant bleeding events were gastrointestinal [63].

Potential drug interactions should be assessed to determine if an alternative non-interacting medication is available to treat the patient’s condition. The duration of interaction exposure should be evaluated, as well as the patient’s risk for a recurrent VTE or major bleeding. Patients at high risk of recurrent VTE (VTE event in the last 3 months or with ongoing VTE risk factors) or at a high risk of bleeding may be particularly vulnerable to DOAC drug interactions. Conversely, patients at a lower risk of recurrent VTE or bleeding may be able to tolerate a moderate drug–drug interaction combination without substantially increasing their risk of adverse events. As always, it is imperative to educate and involve the patient in the discussion. If there is no clear guidance from the literature regarding a specific drug interaction, explain this to the patient and the potential risks involved of each possible approach to management, including alternate therapy. Regular follow-up is advised to assess for adverse events.

Guidance statement

DOAC drug–drug interaction management must be patient-specific and incorporate multiple clinical parameters, such as concomitant renal impairment, extremes of body weight or advanced age. We suggest that clinicians avoid concomitant use of dabigatran and edoxaban with a strong inducer or inhibitor of p-gp and avoid use of rivaroxaban and apixaban with combined strong inducers and inhibitors of p-gp and CYP3A4.

For patients requiring concomitant DOAC therapy with a p-gp and/or CYP3A4 inhibitor, we suggest clinicians closely follow the detailed dose adjustments or avoidance provided in the product labeling. We suggest concomitant antiplatelet or NSAIDs be avoided during DOAC therapy unless the potential benefit clearly justifies the increased bleeding risk.

  • 6.

    How should patients transition between anticoagulants?

In general, the need to switch between agents exposes the patient to periods of increased thromboembolic and bleeding risks. In the ROCKET AF [64] and ARISTOTLE trials [65] of rivaroxaban and apixaban, respectively, a 4-fold increase risk of stroke or bleeding was seen at the end of the study period, attributable to lack of a structured approach to ensuring study patients did not have a “gap” in therapeutic levels of anticoagulation while transitioning to warfarin [66]. This underscores the importance of having a carefully constructed and thoughtful approach for anticoagulant transitions, especially for transition to warfarin.

A recent study from a large outpatient anticoagulation clinic showed approximately 4–6 % of their warfarin patients are being switched to a DOAC annually [67]. A Danish study among atrial fibrillation patients found that the majority (51.2 %) of patients prescribed a DOAC had switched to a VKA within 6 months. Reasons for the high rate of switching in this study are not known. However, these two studies collectively suggest that switches between anticoagulants are not infrequent and may be expected to increase [68].

There are a variety of reasons patients may switch between anticoagulants [66]. Patients may require a switch from parenteral anticoagulants to DOAC for longer-term outpatient management. Patients may also be switched from warfarin to a DOAC, or DOAC to DOAC, if they experience a therapeutic failure, have drug intolerance (e.g. rash, dyspepsia, etc.) or if they express a preference for DOAC therapy and are deemed to be an appropriate candidate based on criteria previously discussed [66].

In addition, there may be times when a patient needs to be switched from a DOAC to warfarin, for many of the same reasons, such as drug intolerance, failure or preference. Patients may also acquire a new condition or comorbidity that is a contraindication to DOAC therapy, such as pregnancy, severe renal impairment, placement of a mechanical valve or need for dual antiplatelet therapy that necessitates a switch [66].

Other situations that might warrant a switch include gastric bypass surgery where gastric absorption may be significantly altered or the need for new medication, such as protease inhibitor, that poses a major drug interaction with a DOAC. In these instances it may be best to maintain the patient on warfarin therapy so levels of anticoagulation can be readily monitored. Patients may also not be able to tolerate oral medications during the perioperative period (e.g. bowel resection or NPO status) and thus may need to be transitioned from a parenteral back to a DOAC or from prophylactic-dose DOAC to treatment-dose DOAC [66].

If a VTE patient requires a switch between anticoagulants, clinicians should employ a carefully constructed approach that takes into consideration the patient’s anticoagulation status at the time of the switch, their renal function and the pharmacokinetics of the individual DOAC to avoid significant under- or over anticoagulation of their patient.

Tables 15 and ​16 provide information regarding appropriate switching strategies for heparin, LMWH and the DOACs.

Guidance statement

Switching from warfarin to a DOAC:

When switchingfromwarfarin to dabigatran, apixaban, rivaroxaban or edoxaban, discontinue warfarin and start the DOAC when the International Normalized Ratio (INR) has decreased to <2 for dabigatran and apixaban (<3 for rivaroxaban, <2.5 for edoxaban) to avoid periods of inadequate or excessive anticoagulation. In cases where the target INR was 2.5–3.5 or higher due to recurrent VTE, initiate the DOAC when the INR is near 2.5 or the lower end of the specified range.

Switching from non-warfarin anticoagulant to a DOAC:

When switchingfrom a DOAC to a different DOAC orfrom LMWH/fondaparinux to a DOAC, start the new DOAC 0–2 h prior to the next scheduled administration of the original anticoagulant and then discontinue the original anticoagulant.

When switchingfrom IV UFH to a DOAC, stop the heparin infusion and begin administration of the DOAC at the time of UFH discontinuation.

When switchingfrom SC UFH treatment to a DOAC, stop the SC UFH and initiate the DOAC approximately 4–5 h after the last dose of SC UFH.

For additional information regarding switching from a DOAC to warfarin or a non-warfarin anticoagulant, readers are also referred to the respective chapters within this compendium by Wittkowsky and Witt.

  • 7.

    How should DOAC-associated bleeding be managed?

In both VTE treatment trials and atrial fibrillation trials, rates of major bleeding were shown to be comparable or lower with DOACs than with conventional approaches using LMWH and warfarin [3–10, 64, 65, 69, 70]. There is encouraging evidence to suggest that DOAC patients who develop a major bleed require less blood or factor products, have shorter lengths of hospital stay and potentially have better outcomes compared to patients experiencing VKA-associated major hemorrhage [71–73]. Despite early concerns regarding excessive bleeding with dabigatran, post-marketing surveillance data from the FDA supports a favorable risk–benefit profile [74].

Nevertheless, DOAC-treated patients may experience a hemorrhagic episode and require intervention (Fig. 3). Hospitals should develop evidence-based antithrombotic bleeding and reversal protocols that contain clinical decision support for providers and are easy to access and use in high-stress urgent or emergent situations. The general approach to a bleeding patient, regardless of anticoagulant, includes withholding the anticoagulant, hemodynamic monitoring, resuscitation with fluid and blood products, mechanical compression if possible, and definitive procedural intervention to identify and treat the source of bleed if indicated. In addition to supporting blood pressure, assertive fluid resuscitation will promote renal elimination of DOACs, particularly dabigatran. If DOAC ingestion within the last 6 h can be confirmed, clinicians may consider use of oral activated charcoal for any of the DOACs. In addition to determining time of last DOAC ingestion, clinicians should also rapidly evaluate the patient’s renal function to estimate remaining duration of drug exposure, and potential need for additional interventions, such as hemodialysis. Hemodialysis may be considered for dabigatran patients, particularly if they have impaired renal function and will have prolonged exposure to dabigatran without the aid of extracorporeal removal. Hemodialysis is not an effective option for removal of direct Xa inhibitors due to their extensive protein binding.

If a patient is refractory to general approaches, clinicians may consider non-specific reversal strategies. Several studies of clotting factor concentrates, such as activated and non-activated prothrombin complex concentrates (PCCs) or recombinant Factor VIIa, for DOAC reversal have been reported. This evidence, recently summarized in a systematic review, is of very low quality, as it is limited to in vitro studies, animal models or studies in healthy human volunteers and often shows conflicting results [75]. Additionally, most of these studies evaluated surrogate outcomes, such as normalization of global coagulation assays, instead of relevant clinical outcomes of in vivo hemostasis and mortality. Overall, results suggest that either inactive 4-Factor PCC (KCentra®) 50 U/kg or active PCC (aPCC, FEIBA®) 80 U/kg are reasonable options for reversal of direct Xa inhibitors and direct thrombin inhibitors, respectively [76–85]. These agents contain procoagulant factors II, VII, IX and X. Activated PCC may pose a greater risk of thrombosis, but may be considered if inactive 4-Factor PCC is not available. Recombinant Factor VIIa is not recommended as a first-line reversal agent. Unlike the PCCs, rFVIIa is not formulated with marginal amounts of anticoagulants (e.g. Protein C, Protein S, Antithrombin, heparin) to mitigate thrombotic risk. Meta-analyses suggest that use of rFVIIa results in higher rates of thrombosis than PCCs [86, 87]. Additionally, because both inactive and active PCCs already contain FVII, there is no rationale to employ rFVIIa as a first-line agent for DOAC reversal. Therefore, we suggest rFVIIa only be used in event PCCs have failed to restore hemostasis in a patient with life-threatening bleeding. Clinicians should carefully weigh risk versus benefit of factor concentrate administration as there is no evidence that these agents improve outcomes and the risk of thrombosis is quite significant [86, 87]. Given the low quality of evidence, it is not unreasonable to withhold these strategies, particularly if there is significant underlying thromboembolic risk.

Fresh frozen plasma should not be used for DOAC reversal, as the volume that would be required to overwhelm the inhibition of thrombin or Factor Xa precludes use in urgent or emergent situations and would likely lead to adverse events, such as fluid overload. Desmospressin or platelet transfusion may be considered in DOAC patients recently on concomitant antiplatelet therapy. Antifibrinolytics agents (tranexamic acid, aminocaproic acid) may be considered as adjunctive therapies if the patient is failing to respond.

Until more robust data or specific antidotes are available, clinicians are limited to existing approaches that have been summarized in several recent reviews [75, 88–90].

Several clinical trials of specific antidotes for both DTIs and Xa inhibitors have been completed or are underway [91–104]. Phase II studies and preliminary data from Phase III studies show these agents to be safe and effective in providing complete and sustained DOAC reversal. They have received expedited review from the FDA and are expected to be commercially available within the next few years.

Guidance statement

We suggest hospitals develop evidence-based antithrombotic reversal and bleeding protocols that contain clinical decision support for providers and are easy to access and use in urgent or emergent situations. We suggest that general approaches to bleed management be employed for all patients presenting with severe hemorrhage. For DOAC patients, clinicians should attempt to rapidly determine time of last DOAC ingestion and patient’s renal function to estimate remaining duration of exposure and potential utility of additional interventions. Until specific antidotes are available, we suggest clinicians consider use of non-specific reversal strategies in patient’s refractory to standard therapies. For direct Xa inhibitors, non-activated 4-Factor PCC 50 U/kg may be considered. For direct thrombin inhibitors, either 4-Factor non-activated PCC 50 U/kg or activated PCC 80 U/kg may be considered. However, it is reasonable to withhold these strategies given the associated thrombosis risk and the low quality of evidence that they are beneficial in this setting.

  • 8.

    What is an appropriate care transitions and follow-up strategy for VTE patients on DOAC therapy?

Inadequate care transitions have been implicated in an estimated annual $25–45 billion in wasted healthcare dollars in the US [105]. Thus, the importance of care transitions has been brought to forefront through numerous national quality initiatives that have emerged in recent years. When looking at approaches specific to anticoagulation patients, implementation of pharmacy-directed anticoagulation services (PDAS) has been shown to significantly improve adherence with specified care transition metrics as well as clinical outcomes [106]. Also, PDAS have been shown to improve patient satisfaction with their care, which now has a direct impact on Medicare reimbursement to hospitals [107]. In efforts to further systematize the delivery of anticoagulation care, reduce adverse drug events and improve care transitions in this high-risk population, a recent consensus statement from EHR Task Force of the New York State Anticoagulation Coalition has called for the incorporation of key anticoagulation-related features into existing EHRs or specialized anticoagulation management systems [108].

There are important nuances in the management of DOACs for VTE, and some of these are not well known. Each of the DOACs requires a dose de-escalation or switch from parenteral therapy at a specified time. The importance of this was recently highlighted in an ISMP alert (https://www.ismp.org/newsletters/acutecare/issue.aspx?id=82) in which a patient prescribed rivaroxaban was given both the 15 mg BID and 20 mg once daily prescriptions prior to discharge. The patient erroneously took both the 15 mg tablets and the 20 mg tablets for several days before the error was discovered. This underscores the importance of clinician familiarity with dosing strategies combined with strong infrastructures, educational processes and thorough handoffs that support accurate and timely implementation of these changes to avoid adverse events [109, 110].

Similar to conventional therapies for VTE treatment, clinicians should evaluate patient eligibility for outpatient or early discharge DOAC therapy, as this has been shown to be safe and effective and provides significant cost savings to the healthcare system [111]. The advent of LMWH and fondaparinux significantly enhanced the feasibility of outpatient treatment during transition to warfarin. Outpatient VTE treatment is made even more feasible with the availability of the DOACs. As with conventional therapies, DOAC patients must meet certain clinical, behavioral and social criteria to be considered a viable candidate for outpatient therapy [111]. For stable patients with acute DVT that does not warrant thrombolysis or thrombectomy, outpatient therapy is an option as long as they are deemed likely to be adherent with medications and follow up, have confirmed ability to obtain the anticoagulant(s), have expressed understanding of their condition and what to do in the event of bleeding or clotting, and have a good social support system at home. Clinicians tend to be less comfortable treating patients with a pulmonary embolism in the outpatient setting. However, evidence for this strategy in appropriately selected patients is increasing. There are clinical prediction tools, such as the modified Pulmonary Embolism Severity Index (PESI) score [112] that aid in identifying PE patients with a low risk of adverse outcomes that may be considered for outpatient treatment (Table 17).

Care transitions can also occur within the hospital, such as when patients transfer to or from the ICU. At each transition, a review of the patient’s medication profile and communication of therapeutic plans for each patient issue should be affected between the previous and current multidisciplinary teams. Surgical patients on DOACs warrant particular attention during care transitions within the hospital, as clinicians have far more experience with managing temporary interruptions in warfarin therapy, and staff may not be familiar with management of DOACs in the perioperative period, or even recognize DOACs as anticoagulants. Thus, potential transitions between drug therapies and across care settings (e.g. medical ward to OR and back) require thoughtful consideration and planning.

General Essay Writing Tips


Despite the fact that, as Shakespeare said, "the pen is mightier than the sword," the pen itself is not enough to make an effective writer. In fact, though we may all like to think of ourselves as the next Shakespeare, inspiration alone is not the key to effective essay writing. You see, the conventions of English essays are more formulaic than you might think – and, in many ways, it can be as simple as counting to five.

The Five Paragraph Essay

Though more advanced academic papers are a category all their own, the basic high school or college essay has the following standardized, five paragraph structure:

Paragraph 1: Introduction
Paragraph 2: Body 1
Paragraph 3: Body 2
Paragraph 4: Body 3
Paragraph 5: Conclusion

Though it may seem formulaic – and, well, it is - the idea behind this structure is to make it easier for the reader to navigate the ideas put forth in an essay. You see, if your essay has the same structure as every other one, any reader should be able to quickly and easily find the information most relevant to them.

The Introduction

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The principle purpose of the introduction is to present your position (this is also known as the "thesis" or "argument") on the issue at hand but effective introductory paragraphs are so much more than that. Before you even get to this thesis statement, for example, the essay should begin with a "hook" that grabs the reader’s attention and makes them want to read on. Examples of effective hooks include relevant quotations ("no man is an island") or surprising statistics ("three out of four doctors report that…").

Only then, with the reader’s attention "hooked," should you move on to the thesis. The thesis should be a clear, one-sentence explanation of your position that leaves no doubt in the reader’s mind about which side you are on from the beginning of your essay.

Following the thesis, you should provide a mini-outline which previews the examples you will use to support your thesis in the rest of the essay. Not only does this tell the reader what to expect in the paragraphs to come but it also gives them a clearer understanding of what the essay is about.

Finally, designing the last sentence in this way has the added benefit of seamlessly moving the reader to the first paragraph of the body of the paper. In this way we can see that the basic introduction does not need to be much more than three or four sentences in length. If yours is much longer you might want to consider editing it down a bit!

Here, by way of example, is an introductory paragraph to an essay in response to the following question:

"Do we learn more from finding out that we have made mistakes or from our successful actions?"

"No man is an island" and, as such, he is constantly shaped and influenced by his experiences. People learn by doing and, accordingly, learn considerably more from their mistakes than their success. For proof of this, consider examples from both science and everyday experience.

DO – Pay Attention to Your Introductory Paragraph

Because this is the first paragraph of your essay it is your opportunity to give the reader the best first impression possible. The introductory paragraph not only gives the reader an idea of what you will talk about but also shows them how you will talk about it. Put a disproportionate amount of effort into this – more than the 20% a simple calculation would suggest – and you will be rewarded accordingly.

DO NOT – Use Passive Voice or I/My

Active voice, wherein the subjects direct actions rather than let the actions "happen to" them – "he scored a 97%" instead of "he was given a 97%" – is a much more powerful and attention-grabbing way to write. At the same time, unless it is a personal narrative, avoid personal pronouns like I, My, or Me. Try instead to be more general and you will have your reader hooked.

The Body Paragraphs

The middle paragraphs of the essay are collectively known as the body paragraphs and, as alluded to above, the main purpose of a body paragraph is to spell out in detail the examples that support your thesis.

For the first body paragraph you should use your strongest argument or most significant example unless some other more obvious beginning point (as in the case of chronological explanations) is required. The first sentence of this paragraph should be the topic sentence of the paragraph that directly relates to the examples listed in the mini-outline of introductory paragraph.

A one sentence body paragraph that simply cites the example of "George Washington" or "LeBron James" is not enough, however. No, following this an effective essay will follow up on this topic sentence by explaining to the reader, in detail, who or what an example is and, more importantly, why that example is relevant.

Even the most famous examples need context. For example, George Washington’s life was extremely complex – by using him as an example, do you intend to refer to his honesty, bravery, or maybe even his wooden teeth? The reader needs to know this and it is your job as the writer to paint the appropriate picture for them. To do this, it is a good idea to provide the reader with five or six relevant facts about the life (in general) or event (in particular) you believe most clearly illustrates your point.

Having done that, you then need to explain exactly why this example proves your thesis. The importance of this step cannot be understated (although it clearly can be underlined); this is, after all, the whole reason you are providing the example in the first place. Seal the deal by directly stating why this example is relevant.

Here is an example of a body paragraph to continue the essay begun above:

Take, by way of example, Thomas Edison. The famed American inventor rose to prominence in the late 19th century because of his successes, yes, but even he felt that these successes were the result of his many failures. He did not succeed in his work on one of his most famous inventions, the lightbulb, on his first try nor even on his hundred and first try. In fact, it took him more than 1,000 attempts to make the first incandescent bulb but, along the way, he learned quite a deal. As he himself said, "I did not fail a thousand times but instead succeeded in finding a thousand ways it would not work." Thus Edison demonstrated both in thought and action how instructive mistakes can be.

DO – Tie Things Together

The first sentence – the topic sentence - of your body paragraphs needs to have a lot individual pieces to be truly effective. Not only should it open with a transition that signals the change from one idea to the next but also it should (ideally) also have a common thread which ties all of the body paragraphs together. For example, if you used "first" in the first body paragraph then you should used "secondly" in the second or "on the one hand" and "on the other hand" accordingly.

DO NOT – Be Too General

Examples should be relevant to the thesis and so should the explanatory details you provide for them. It can be hard to summarize the full richness of a given example in just a few lines so make them count. If you are trying to explain why George Washington is a great example of a strong leader, for instance, his childhood adventure with the cherry tree (though interesting in another essay) should probably be skipped over.

A Word on Transitions

You may have noticed that, though the above paragraph aligns pretty closely with the provided outline, there is one large exception: the first few words. These words are example of a transitional phrase – others include "furthermore," "moreover," but also "by contrast" and "on the other hand" – and are the hallmark of good writing.

Transitional phrases are useful for showing the reader where one section ends and another begins. It may be helpful to see them as the written equivalent of the kinds of spoken cues used in formal speeches that signal the end of one set of ideas and the beginning of another. In essence, they lead the reader from one section of the paragraph of another.

To further illustrate this, consider the second body paragraph of our example essay:

In a similar way, we are all like Edison in our own way. Whenever we learn a new skill - be it riding a bike, driving a car, or cooking a cake - we learn from our mistakes. Few, if any, are ready to go from training wheels to a marathon in a single day but these early experiences (these so-called mistakes) can help us improve our performance over time. You cannot make a cake without breaking a few eggs and, likewise, we learn by doing and doing inevitably means making mistakes.

Hopefully this example not only provides another example of an effective body paragraph but also illustrates how transitional phrases can be used to distinguish between them.

The Conclusion

Although the conclusion paragraph comes at the end of your essay it should not be seen as an afterthought. As the final paragraph is represents your last chance to make your case and, as such, should follow an extremely rigid format.

One way to think of the conclusion is, paradoxically, as a second introduction because it does in fact contain many of the same features. While it does not need to be too long – four well-crafted sentence should be enough – it can make or break and essay.

Effective conclusions open with a concluding transition ("in conclusion," "in the end," etc.) and an allusion to the "hook" used in the introductory paragraph. After that you should immediately provide a restatement of your thesis statement.

This should be the fourth or fifth time you have repeated your thesis so while you should use a variety of word choice in the body paragraphs it is a acceptable idea to use some (but not all) of the original language you used in the introduction. This echoing effect not only reinforces your argument but also ties it nicely to the second key element of the conclusion: a brief (two or three words is enough) review of the three main points from the body of the paper.

Having done all of that, the final element – and final sentence in your essay – should be a "global statement" or "call to action" that gives the reader signals that the discussion has come to an end.

In the end, then, one thing is clear: mistakes do far more to help us learn and improve than successes. As examples from both science and everyday experience can attest, if we treat each mistake not as a misstep but as a learning experience the possibilities for self-improvement are limitless.

DO – Be Powerful

The conclusion paragraph can be a difficult paragraph to write effectively but, as it is your last chance to convince or otherwise impress the reader, it is worth investing some time in. Take this opportunity to restate your thesis with confidence; if you present your argument as "obvious" then the reader might just do the same.

DO NOT – Copy the First Paragraph

Although you can reuse the same key words in the conclusion as you did in the introduction, try not to copy whole phrases word for word. Instead, try to use this last paragraph to really show your skills as a writer by being as artful in your rephrasing as possible.

Taken together, then, the overall structure of a five paragraph essay should look something like this:

Introduction Paragraph

  • An attention-grabbing "hook"
  • A thesis statement
  • A preview of the three subtopics you will discuss in the body paragraphs.

First Body Paragraph

  • Topic sentence which states the first subtopic and opens with a transition
  • Supporting details or examples
  • An explanation of how this example proves your thesis

Second Body Paragraph

  • Topic sentence which states the second subtopic and opens with a transition
  • Supporting details or examples
  • An explanation of how this example proves your thesis

Third Body Paragraph

  • Topic sentence which states the third subtopic and opens with a transition
  • Supporting details or examples
  • An explanation of how this example proves your thesis

Concluding Paragraph

  • Concluding Transition, Reverse "hook," and restatement of thesis.
  • Rephrasing main topic and subtopics.
  • Global statement or call to action.

More tips to make your essay shine

Planning Pays

Although it may seem like a waste of time – especially during exams where time is tight – it is almost always better to brainstorm a bit before beginning your essay. This should enable you to find the best supporting ideas – rather than simply the first ones that come to mind – and position them in your essay accordingly.

Your best supporting idea – the one that most strongly makes your case and, simultaneously, about which you have the most knowledge – should go first. Even the best-written essays can fail because of ineffectively placed arguments.

Aim for Variety

Sentences and vocabulary of varying complexity are one of the hallmarks of effective writing. When you are writing, try to avoid using the same words and phrases over and over again. You don’t have to be a walking thesaurus but a little variance can make the same idea sparkle.

If you are asked about "money," you could try "wealth" or "riches." At the same time, avoid beginning sentences the dull pattern of "subject + verb + direct object." Although examples of this are harder to give, consider our writing throughout this article as one big example of sentence structure variety.

Practice! Practice! Practice!

In the end, though, remember that good writing does not happen by accident. Although we have endeavored to explain everything that goes into effective essay writing in as clear and concise a way as possible, it is much easier in theory than it is in practice.

As a result, we recommend that you practice writing sample essays on various topics. Even if they are not masterpieces at first, a bit of regular practice will soon change that – and make you better prepared when it comes to the real thing.

Now that you’ve learned how to write an effective essay, check out our Sample Essays so you can see how they are done in practice.

Essay Writing Center

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