Progression of Atrial Fibrillation after Cryoablation or Drug Therapy.

BACKGROUND: Atrial fibrillation is a chronic, progressive disorder, and persistent forms of atrial fibrillation are associated with increased risks of thromboembolism and heart failure. Catheter ablation as initial therapy may modify the pathogenic mechanism of atrial fibrillation and alter progression to persistent atrial fibrillation. METHODS: We report the 3-year follow-up of patients with paroxysmal, untreated atrial fibrillation who were enrolled in a trial in which they had been randomly assigned to undergo initial rhythm-control therapy with cryoballoon ablation or to receive antiarrhythmic drug therapy. All the patients had implantable loop recorders placed at the time of trial entry, and evaluation was conducted by means of downloaded daily recordings and in-person visits every 6 months. Data regarding the first episode of persistent atrial fibrillation (lasting ≥7 days or lasting 48 hours to 7 days but requiring cardioversion for termination), recurrent atrial tachyarrhythmia (defined as atrial fibrillation, flutter, or tachycardia lasting ≥30 seconds), the burden of atrial fibrillation (percentage of time in atrial fibrillation), quality-of-life metrics, health care utilization, and safety were collected. RESULTS: A total of 303 patients were enrolled, with 154 patients assigned to undergo initial rhythm-control therapy with cryoballoon ablation and 149 assigned to receive antiarrhythmic drug therapy. Over 36 months of follow-up, 3 patients (1.9%) in the ablation group had an episode of persistent atrial fibrillation, as compared with 11 patients (7.4%) in the antiarrhythmic drug group (hazard ratio, 0.25; 95% confidence interval [CI], 0.09 to 0.70). Recurrent atrial tachyarrhythmia occurred in 87 patients in the ablation group (56.5%) and in 115 in the antiarrhythmic drug group (77.2%) (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). The median percentage of time in atrial fibrillation was 0.00% (interquartile range, 0.00 to 0.12) in the ablation group and 0.24% (interquartile range, 0.01 to 0.94) in the antiarrhythmic drug group. At 3 years, 8 patients (5.2%) in the ablation group and 25 (16.8%) in the antiarrhythmic drug group had been hospitalized (relative risk, 0.31; 95% CI, 0.14 to 0.66). Serious adverse events occurred in 7 patients (4.5%) in the ablation group and in 15 (10.1%) in the antiarrhythmic drug group. CONCLUSIONS: Initial treatment of paroxysmal atrial fibrillation with catheter cryoballoon ablation was associated with a lower incidence of persistent atrial fibrillation or recurrent atrial tachyarrhythmia over 3 years of follow-up than initial use of antiarrhythmic drugs. (Funded by the Cardiac Arrhythmia Network of Canada and others; EARLY-AF ClinicalTrials.gov number, NCT02825979.).

Cryoablation or Drug Therapy for Initial Treatment of Atrial Fibrillation.

BACKGROUND: Guidelines recommend a trial of one or more antiarrhythmic drugs before catheter ablation is considered in patients with atrial fibrillation. However, first-line ablation may be more effective in maintaining sinus rhythm. METHODS: We randomly assigned 303 patients with symptomatic, paroxysmal, untreated atrial fibrillation to undergo catheter ablation with a cryothermy balloon or to receive antiarrhythmic drug therapy for initial rhythm control. All the patients received an implantable cardiac monitoring device to detect atrial tachyarrhythmia. The follow-up period was 12 months. The primary end point was the first documented recurrence of any atrial tachyarrhythmia (atrial fibrillation, atrial flutter, or atrial tachycardia) between 91 and 365 days after catheter ablation or the initiation of an antiarrhythmic drug. The secondary end points included freedom from symptomatic arrhythmia, the atrial fibrillation burden, and quality of life. RESULTS: At 1 year, a recurrence of atrial tachyarrhythmia had occurred in 66 of 154 patients (42.9%) assigned to undergo ablation and in 101 of 149 patients (67.8%) assigned to receive antiarrhythmic drugs (hazard ratio, 0.48; 95% confidence interval [CI], 0.35 to 0.66; P<0.001). Symptomatic atrial tachyarrhythmia had recurred in 11.0% of the patients who underwent ablation and in 26.2% of those who received antiarrhythmic drugs (hazard ratio, 0.39; 95% CI, 0.22 to 0.68). The median percentage of time in atrial fibrillation was 0% (interquartile range, 0 to 0.08) with ablation and 0.13% (interquartile range, 0 to 1.60) with antiarrhythmic drugs. Serious adverse events occurred in 5 patients (3.2%) who underwent ablation and in 6 patients (4.0%) who received antiarrhythmic drugs. CONCLUSIONS: Among patients receiving initial treatment for symptomatic, paroxysmal atrial fibrillation, there was a significantly lower rate of atrial fibrillation recurrence with catheter cryoballoon ablation than with antiarrhythmic drug therapy, as assessed by continuous cardiac rhythm monitoring. (Funded by the Cardiac Arrhythmia Network of Canada and others; EARLY-AF ClinicalTrials.gov number, NCT02825979.).

Assessment of Antitachycardia Pacing in Primary Prevention Patients: The APPRAISE ATP Randomized Clinical Trial.

Importance: The emergence of novel programming guidelines that reduce premature and inappropriate therapies along with the availability of new implantable cardioverter-defibrillator (ICD) technologies lacking traditional endocardial antitachycardia pacing (ATP) capabilities requires the reevaluation of ATP as a first strategy in terminating fast ventricular tachycardias (VTs) in primary prevention ICD recipients. Objective: To assess the role of ATP in terminating fast VTs in primary prevention ICD recipients with contemporary programming. Design, Setting, and Participants: This global, prospective, double-blind, randomized clinical trial had an equivalence design with a relative margin of 35%. Superiority tests were performed at interim analyses and the final analysis if equivalence was not proven. Patients were enrolled between September 2016 and April 2021 at 134 sites in 8 countries, with the last date of follow-up on July 6, 2023. Patients were required to have an indication for a primary prevention ICD, including left ventricular ejection fraction less than or equal to 35%. Interventions: Patients were randomized in a 1:1 ratio to receive ATP plus shock vs shock only. Main Outcomes and Measures: The primary end point was time to first all-cause shock. Secondary end points included time to first appropriate shock, time to first inappropriate shock, all-cause mortality, and the composite of time to first all-cause shock plus all-cause mortality. Results: A total of 2595 patients were randomized (mean age, 63.9 years; 22.4% were females). At a mean follow-up of 38 months, first all-cause shock occurred in 129 participants in the ATP plus shock group and 178 participants in the shock only group. The hazard ratio (HR) for the primary end point was 0.72 (95.9% CI, 0.57-0.92), with P = .005 for superiority of the ATP plus shock group over the shock only group. During follow-up in an intention-to-treat analysis, the total shock burden per 100 patient-years was not statistically different, at 12.3 and 14.9, respectively (P = .70). Conclusions and Relevance: The use of a single burst of ATP prior to shock in primary prevention ICD recipients with modern ICD detection programming prolonged the time to first all-cause ICD shock. Trial Registration: ClinicalTrials.gov Identifier: NCT02923726.

Post-operative pain following cardiac implantable electronic device implantation: insights from the BRUISE CONTROL trials.

AIMS: Post-operative pain following cardiac implantable electronic device (CIED) insertion is associated with patient dissatisfaction, emotional distress, and emergency department visits. We sought to identify factors associated with post-operative pain and develop a prediction score for post-operative pain. METHODS AND RESULTS: All patients from the BRUISE CONTROL-1 and 2 trials were included in this analysis. A validated Visual Analogue Scale (VAS) was used to assess the severity of pain related to CIED implant procedures. Patients were asked to grade the most severe post-operative pain, average post-operative pain, and pain on the day of the first post-operative clinic. Multivariable regression analyses were performed to identify predictors of significant post-operative pain and to develop a pain-prediction score. A total of 1308 patients were included. Multivariable regression analysis found that the presence of post-operative clinically significant haematoma {CSH; P value < 0.001; odds ratio (OR) 3.82 [95% confidence interval (CI): 2.37-6.16]}, de novo CIED implantation [P value < 0.001; OR 1.90 (95% CI: 1.47-2.46)], female sex [P value < 0.001; OR 1.61 (95% CI: 1.22-2.12)], younger age [<65 years; P value < 0.001; OR 1.54 (95% CI: 1.14-2.10)], and lower body mass index [<20 kg/m2; P value < 0.05; OR 2.05 (95% CI: 0.98-4.28)] demonstrated strong and independent associations with increased post-operative pain. An 11-point post-operative pain prediction score was developed using the data. CONCLUSION: Our study has identified multiple predictors of post-operative pain after CIED insertion. We have developed a prediction score for post-operative pain that can be used to identify individuals at risk of experiencing significant post-operative pain.

Survival after implantable cardioverter-defibrillator implantation in the elderly.

BACKGROUND: The benefit of implantable cardioverter-defibrillators (ICDs) among elderly patients is controversial and may be attenuated by nonarrhythmic death. We examined the impact of age on device-delivered therapies and outcomes after primary or secondary prevention ICD. METHODS AND RESULTS: In a prospective, inclusive registry of 5399 ICD recipients in Ontario, Canada (February 2007 to September 2010), device-delivered therapies and complications were determined at routine clinic visits. Among primary prevention ICD recipients aged 18 to 49 (n=317), 50 to 59 (n=769), 60 to 69 (n=1336), 70 to 79 (n=1242), and ≥80 (n=275) years, mortality increased with age, as follows: 2.1, 3.0, 5.4, 6.9, and 10.2 deaths per 100 person-years, respectively (P<0.001). Secondary prevention ICD recipients aged 18 to 49 (n=114), 50 to 59 (n=244), 60 to 69 (n=481), 70 to 79 (n=462), and ≥80 (n=159) years also exhibited increasing mortality, as follows: 2.2, 3.8, 6.1, 8.7, and 15.5 deaths per 100 person-years, respectively (P<0.001). However, rates of appropriate shock were similar across age groups: from 6.7 (18-49 years) to 4.2 (≥80 years) per 100 person-years after primary prevention ICDs (P=0.139) and from 11.4 (18-49 years) to 11.9 (≥80 years) per 100 person-years after secondary prevention ICDs (P=0.993). Covariate-adjusted competing risk analysis demonstrated higher risk of death (Ptrend<0.001 for both primary and secondary prevention) but no significant decline in appropriate shocks with older age after primary (P=0.130) or secondary (P=0.810) prevention ICD implantation. CONCLUSIONS: Whereas elderly patients exhibited increased mortality after ICD implantation, rates of appropriate device shocks were similar across age groups. Decisions regarding ICD candidacy should not be based on age alone but should consider factors that predispose to mortality despite defibrillator implantation.

Myocardial injury secondary to ICD shocks: insights from patients with lead fracture.

BACKGROUND: Patients who receive appropriate implantable cardioverter defibrillator (ICD) shocks have a subsequent adverse prognosis. Most data suggest that patients with inappropriate ICD shocks also have a subsequent adverse prognosis, although this is more controversial. The shocks may be an epiphenomenon, that is, a marker of underlying disease progression; however, it cannot be excluded that shocks cause direct myocardial damage. This latter question is difficult to clarify as the arrhythmia provoking the shock can also cause troponin release. Inappropriate shocks secondary to lead fracture are an ideal situation to examine this question; any troponin release in an otherwise well and hemodynamically stable patient, is likely due directly to the shocks. METHODS: All patients with Fidelis lead fracture admitted to our institution with inappropriate shocks were included in this study. Troponin (I or T) was considered positive if the level was above the 99th percentile reference cutoff. RESULTS: Elevated troponin levels were recorded in 16 of 22 patients (73%). Patients with elevated troponin received a higher number of shocks (20.3 ± 30.1 vs 5.3 ± 4.8, P = 0.07) compared with patients with normal troponin. Very elevated troponin levels (>0.8 mcg/L) were seen in five of 22 (22%) patients. The mean peak troponin level for these five patients was 7.06 ± 8.56 mcg/L; two patients had troponin levels that would be expected from a medium-sized myocardial infarction or severe myocarditis. CONCLUSION: Troponin elevation occurred in the majority of our patients after inappropriate ICD discharges secondary to lead fracture. This indicates that ICD shocks can cause myocardial injury.

Antithrombotic therapies in Canadian atrial fibrillation patients with concomitant coronary artery disease: Insights from the CONNECT AF + PCI-II program.

BACKGROUND: Selecting the appropriate antithrombotic regimen for patients with atrial fibrillation (AF) who have undergone percutaneous coronary intervention (PCI) or have had medically managed acute coronary syndrome (ACS) remains complex. This multi-centre observational study evaluated patterns of antithrombotic therapies utilized among Canadian patients with AF post-PCI or ACS. METHODS AND RESULTS: By retrospective chart audit, 611 non-valvular AF patients [median (interquartile range) age 76 (69-83) years, CHADS2 score 2 (1-3)] who underwent PCI or had medically managed ACS between August 2018 and December 2020 were identified by 68 cardiologists across eight provinces in Canada. Overall, triple antithrombotic therapy [TAT: combined oral anticoagulation (OAC) and dual antiplatelet therapy (DAPT)] was the most common initial antithrombotic strategy, with use in 53.8 % of patients, followed by dual pathway therapy (32.7 % received OAC and a P2Y12 inhibitor, and 4.1 % received OAC and aspirin) and DAPT (9.3 %). Median duration of TAT was 30 (7, 30) days. Compared to the previous CONNECT AF + PCI-I program, there was an increased use of dual pathway therapy relative to TAT over time (P-value <.0001). DOACs (direct oral anticoagulants) represented 90.3 % of all OACs used overall, with apixaban being the most utilized (50.5 %). Proton pump inhibitors were used in 57.0 % of all patients, and 70.1 % of patients on ASA. Planned antithrombotic therapies at 1 year were: 76.2 % OAC monotherapy, 8.3 % OAC + ASA, 7.9 % OAC + P2Y12 inhibitor, 4.3 % DAPT, 1.3 % ASA alone, and <1 % triple therapy. CONCLUSION: In accordance with recent Canadian Cardiovascular Society guideline recommendations, we observed an increased use of dual pathway therapy relative to TAT over time in both AF patients post-PCI (elective and emergent) and in those with medically managed ACS. Additionally, DOACs have become the prevailing form of anticoagulation across all antithrombotic regimens. Our findings suggest that Canadian physicians are integrating evidence-based approaches to optimally manage the bleeding and thrombotic risks of AF patients post-PCI and/or ACS.

Adherence to guidelines for surveillance colonoscopy in patients with ulcerative colitis at a Canadian quaternary care hospital.

BACKGROUND: Patients with ulcerative colitis (UC) are at high risk of colonic dysplasia. Therefore, surveillance colonoscopy to detect early dysplasia has been endorsed by many professional organizations. OBJECTIVES: To determine whether gastroenterologists at Hamilton Health Sciences (Hamilton, Ontario) adhere to recommendations for UC surveillance issued by the Canadian Association of Gastroenterology and to retrospectively assess the incidence and type of dysplasia found and the subsequent outcome of patients with dysplasia (ie, colorectal cancer [CRC], colectomy, dysplasia recurrence). METHODS: A retrospective chart review of all patients with UC undergoing colonoscopy screening at Hamilton Health Sciences from January 1980 to January 2005, was performed. Patients were classified by the extent of colonic disease: limited left-sided colitis (LSC), pancolitis and any disease extent with concurrent primary sclerosing cholangitis. RESULTS: A total of 141 patients fulfilled eligibility criteria. They underwent 921 endoscopies, including 453 for surveillance, which were performed by 20 endoscopists. Overall, screening was performed on 90% of patients, and surveillance at the appropriate time in 74%. There was a statistically significant increase in the mean number of biopsies per colonoscopy after the guidelines were published (P<0.01 for all categories). Colonic dysplasia was detected in 24 of 141 patients (17.0%), with 17 of 24 (70.8%) found at surveillance. Two patients (8.3%) had CRC successfully treated. The average age of patients with dysplasia was 56.1 years, with a mean disease duration of 10.9 years in LSC versus 11.8 years in pancolitis (P not significant). Colectomy was not recommended for any patient with flat dysplasia. No patients progressed to high-grade dysplasia or CRC. Patients with pancolitis had a higher incidence of neoplasia (21% [18 of 86]) than patients with LSC (12% [6 of 49]; P=0.24). Forty-one patients (29.5%) had at least one hyperplastic or inflammatory polyp. CONCLUSIONS: For the majority of patients who underwent surveillance colonoscopies, their procedures were performed within the recommended time intervals, and biopsy compliance has improved. Dysplasia tended to arise after approximately 10 years of disease duration and in middle age, with flat dysplasia being rare. Interventions resulted in no dysplasia progressing to CRC, implying successful prevention.

Effect of Direct Oral Anticoagulants, Warfarin, and Antiplatelet Agents on Risk of Device Pocket Hematoma: Combined Analysis of BRUISE CONTROL 1 and 2.

BACKGROUND: Oral anticoagulant use is common among patients undergoing pacemaker or defibrillator surgery. BRUISE CONTROL (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial; NCT00800137) demonstrated that perioperative warfarin continuation reduced clinically significant hematomas (CSH) by 80% compared with heparin bridging (3.5% versus 16%). BRUISE-CONTROL-2 (NCT01675076) observed a similarly low risk of CSH when comparing continued versus interrupted direct oral anticoagulant (2.1% in both groups). Using patient level data from both trials, the current study aims to: (1) evaluate the effect of concomitant antiplatelet therapy on CSH, and (2) understand the relative risk of CSH in patients treated with direct oral anticoagulant versus continued warfarin. METHODS: We analyzed 1343 patients included in BRUISE-CONTROL-1 and BRUISE-CONTROL-2. The primary outcome for both trials was CSH. There were 408 patients identified as having continued either a single or dual antiplatelet agent at the time of device surgery. RESULTS: Antiplatelet use (versus nonuse) was associated with CSH in 9.8% versus 4.3% of patients (P<0.001), and remained a strong independent predictor after multivariable adjustment (odds ratio, 1.965; 95% CI, 1.202-3.213; P=0.0071). In multivariable analysis, adjusting for antiplatelet use, there was no significant difference in CSH observed between direct oral anticoagulant use compared with continued warfarin (odds ratio, 0.858; 95% CI, 0.375-1.963; P=0.717). CONCLUSIONS: Concomitant antiplatelet therapy doubled the risk of CSH during device surgery. No difference in CSH was found between direct oral anticoagulant versus continued warfarin. In anticoagulated patients undergoing elective or semi-urgent device surgery, the patient specific benefit/risk of holding an antiplatelet should be carefully considered. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00800137, NCT01675076.

Corticosteroid therapy for cardiac sarcoidosis: a systematic review.

BACKGROUND: There are no published clinical consensus guidelines or systematic evaluation supporting the use of corticosteroids for the treatment of cardiac sarcoidosis. The purpose of this study was to systematically review the published data on corticosteroid treatment of cardiac sarcoidosis. METHODS: Studies were identified from MEDLINE, EMBASE, Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and National Institutes of Health Clinical Trials.gov database. The quality of included articles was rated using Scottish Intercollegiate Guidelines Network 50. Outcomes examined were atrioventricular (AV) conduction, left ventricular function, ventricular arrhythmias, and mortality. RESULTS: A total of 1491 references were retrieved and 10 publications met the inclusion criteria. There were no randomized trials and all publications were of poor to fair quality. In the 10 reports, 257 patients received corticosteroids and 42 patients did not. There were 57 patients with AV conduction disease treated with corticosteroids, with 27/57 (47.4%) improving. In contrast, 16 patients were not treated with corticosteroids and 0/16 improved. Four publications reported on left ventricular function recovery, 2 reported on ventricular arrhythmia burden, and 9 reported on mortality. However, the data quality were too limited to draw conclusions for any of these outcomes. CONCLUSIONS: Our systematic review identified 10 publications reporting outcomes after corticosteroid therapy. The best data relates to AV conduction recovery and corticosteroids appeared to be beneficial. It is not possible to draw clear conclusions about the utility of corticosteroids for the other outcomes. There is a clear need for large multicentre prospective registries and trials in this patient population.

Reinitiation of anticoagulation after warfarin-associated intracranial hemorrhage and mortality risk: the Best Practice for Reinitiating Anticoagulation Therapy After Intracranial Bleeding (BRAIN) study.

BACKGROUND: While warfarin-related intracranial hemorrhage (ICH) occurs in 0.25%-1.1% patients per year, little is known about the practice and outcomes of anticoagulant reinitiation. METHODS: We studied a cohort of consecutive patients with warfarin-related ICH (intracerebral or subarachnoid) admitted to 13 stroke centres in the Registry of the Canadian Stroke Network between July 2003 and March 2008. We examined patterns of warfarin reinitiation and variables associated with 30-day and 1-year outcomes. RESULTS: Among the 284 patients studied (mean age 74 ± 12 years), warfarin was restarted in-hospital in 91 patients (32%). Factors associated with restarting warfarin were lower stroke severity (adjusted odds ratio [aOR] 2.07, 95% confidence interval [CI]; 1.20-3.57, P = 0.009) or presence of valve prosthesis (aOR 3.07, 95% CI; 1.29-7.27, P = 0.011). Mortality rates were not higher in those who restarted warfarin in-hospital: 31.9% vs 54.4% (30-day, P < 0.001) and 48% vs 61% (1-year, P = 0.04), and bleeding was not increased. Multivariable predictors of mortality included initial international normalized ratio > 3.0 (aOR, 3.28 [30-day, P < 0.001] and 3.32 [1-year, P = 0.003]), greater stroke severity (aOR, 6.04 [30-day] and 4.22 [1-year]; both P < 0.001), and intraventricular hemorrhage (aOR, 2.19 [30-day; P = 0.03] and 2.04 [1-year; P = 0.04]). In selected patients who reinitiated warfarin, there was no increase in 30-day (aOR, 0.49; P = 0.03) or 1-year mortality (aOR, 0.79; P = 0.43). CONCLUSIONS: In selected patients at high thrombosis risk, reinitiation of warfarin after ICH did not confer increased mortality or bleeding events.

Antimicrobials for right-sided endocarditis in intravenous drug users: a systematic review.

BACKGROUND: Right-sided endocarditis (RSE) is a serious complication of intravenous drug use. We sought to systematically review the evidence for obtaining clinical cure with antimicrobials in intravenous drug users (IVDUs) with isolated native valve RSE. SEARCH STRATEGY: We applied broad search strategies in the following databases: MEDLINE (1966-2006), EMBASE (1980-2006) and Cochrane CENTRAL Register (2006, Issue 3). Hand searching was performed on selected peer-reviewed journals and relevant citation lists were screened. No restrictions were set on language and type of publication. SELECTION CRITERIA: We included randomized controlled trials that evaluated clinical and microbiological cure using single or combination antibiotic regimens for the treatment of isolated native valve bacterial RSE. Clinical and microbiological cure and failure outcomes were evaluated between 2 weeks and 6 months after completion of therapy. Quality assessment of relevant studies was performed using an objective scoring scale. RESULTS: We identified seven randomized controlled trials, one comparing single antimicrobial therapies, four comparing combination with single therapy and two studies comparing combination therapies. Short-course therapy was present in at least one arm in three studies, but only one study compared short- and long-course therapy. No statistically significant benefit was demonstrated between any antimicrobial therapy and all studies were scored as having a moderate to severe risk of bias. CONCLUSIONS: Randomized trial evidence does not support one antimicrobial regimen over another in the treatment of RSE in IVDUs.

Organization of ipsilateral excitatory and inhibitory pathways in the human motor cortex.

Motor cortex stimulation has both excitatory and inhibitory effects on ipsilateral muscles. Excitatory effects can be assessed by ipsilateral motor-evoked potentials (iMEPs). Inhibitory effects include an interruption of ipsilateral voluntary muscle activity known as the silent period (iSP) and a reduction in corticospinal excitability evoked by conditioning stimulation of the contralateral motor cortex (interhemispheric inhibition, IHI). Both iSP and IHI may be mediated by transcallosal pathways. Their relationship to the contralateral corticospinal projection and whether iSP and IHI represent the same phenomenon remain unclear. The neuronal population activated by transcranial magnetic stimulation (TMS) is highly dependent on the direction of the induced current in the brain. We examined the relationship among iMEP, iSP, IHI, and the contralateral corticospinal system by examining the effects of different stimulus intensities and current directions. Surface electromyography (EMG) was recorded from both first dorsal interosseous (FDI) muscles. The iSP in the right FDI muscle was obtained by right motor cortex stimulation during voluntary muscle contraction. IHI was examined by conditioning stimulation of the right motor cortex followed by test stimulation of the left motor cortex at interstimulus intervals (ISIs) of 2-80 ms. The induced current directions tested in the right motor cortex were anterior medial (AM), posterior medial (PM), posterior lateral, and anterior lateral (AL). Contralateral MEPs (cMEPs) had the lowest threshold with the AM direction and the shortest latency with the PM direction. iMEPs were present in 8 of 10 subjects. Both iMEP and IHI did not show significant directional preference. iSP was observed in all subjects with the highest threshold for the AL direction and the longest duration for the AM direction. cMEP, iSP, and IHI all increased with stimulus intensity up to approximately 75% stimulator output. Target muscle activation decreased IHI at 8-ms ISI but had little effect on IHI at 40-ms ISI. iSP and IHI at 8-ms ISI did not correlate at any stimulus intensities and current directions tested, and factor analysis showed that they are explained by different factors. However, active IHI at 40-ms ISI was explained by the same factor as iSP. The different directional preference for cMEP compared with iMEP and IHI suggests that these ipsilateral effects are mediated by populations of cortical neurons that are different from those activating the corticospinal neurons. iSP and IHI do not represent the same phenomenon and should be considered complementary measures of ipsilateral inhibition.