Delayed Time to Defibrillation after In-Hospital Cardiac Arrest

Further information: The Implantable Cardioverter-Defibrillator from Cardiovascular Medicine, 3rd Edn*

Investigators in this current study used data from the National Registry of Cardiopulmonary Resuscitation (NRCPR), a large registry of US hospitals using standardized Utstein definitions (uniform guidelines developed by international experts) for the assessment of the processes of care and of outcomes during in-hospital cardiac arrests [1]. Cardiac arrest is defined as cessation of cardiac mechanical activity as determined by the absence of a palpable central pulse, apnea, and unresponsiveness.

The current study analyzed data from 369 acute care hospitals that provided data for at least 6 months between January 1, 2000, and July 31, 2005. Patients studied were 18 years old or older with the first identifiable rhythm being ventricular fibrillation or pulseless ventricular tachycardia, and with the cardiac arrests occurring in intensive care units or inpatient beds. Patients in other hospital environments were excluded, and patients with implantable cardioverter defibrillators and patients receiving intravenous infusions of acute cardiac life support medications were excluded as well.

The overall median time to defibrillation was 1 minute (interquartile range, <1 to 3 min). Of 6789 patients in the 369 included hospitals, 2315 patients (34.1%) survived to discharge, and 2045 patients (30.1%) received defibrillation after the recommended 2 min. Hospital factors that were associated with delayed defibrillation included patients of the black race, as well as patients having cardiac arrest in small hospitals (<250 beds), in unmonitored hospital units, after hours or on weekends, or having noncardiac diagnosis upon hospital admission. Delayed defibrillation was associated with lower rate of survival to discharge (22.2% vs. 39.3% when defibrillation was not delayed; adjusted odds ratio, 0.48; 95% confidence interval, 0.42–0.54; P>0.001). This study affirms current recommendations for prompt defibrillation for patients with in-hospital tachyarrhythmic cardiac arrest.

[1] Chan PS, Krumholz HM, Nichol G, et al. Delayed time to defibrillation after in-hospital cardiac arrest. N Engl J Med 2008;358:9-17

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Home Use of Automated External Defibrillators for Sudden Cardiac Death

Further information: The Implantable Cardioverter-Defibrillator from Cardiovascular Medicine, 3rd Edn*

The Home Automated External Defibrillator (HAT) trial [1] was conducted to evaluate whether home access to an automated external defibrillator (AED) could improve survival rates in patients with fairly low risk of sudden cardiac arrest (SCA) by providing immediate, home-based defibrillation. Patients enrolled in the study had previous anterior-wall myocardial infarction (MI), but were not candidates for an implantable cardioverter-defibrillator (ICD), a device that is implanted in patients at high risk of ventricular tachyarrhythmia (VT). The results of having an AED available to use when a SCA is witnessed, such as on an airplane or in an airport, have been encouraging. However, usually SCA occurs in the home and is often unwitnessed; successful resuscitation occurs in only 2% of cases once the emergency medical service (EMS) is called.

Of the 7001 patients randomized by the HAT investigators, 3506 patients received the control response that involved calling EMS to administer cardiopulmonary resuscitation (CRP) and 3495 patients had the use of an AED at home before calling EMS for CRP. The primary outcome was death from any cause. The spouse or companion of the patients randomized to have the use of an AED at home agreed to perform CRP and use the AED, and they were provided complete instructions. Patients’ median age was 62 years, and 17% of the patients were women. The median follow-up time was 37 months. Of the 3506 patients in the control group, 228 (6.5%) died, and of the 3495 patients in the AED group, 222 (6.4%) died (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.81–1.17; P=0.77). Mortality did not differ significantly in major prespecified subgroups, and only 160 deaths (35.6%) had SCD from VT. Of the 160 deaths, 117 occurred at home and 58 were witnessed. AEDs were used in 32 patients, and of those, 14 received an appropriate shock and four survived to hospital discharge. At the median follow-up of 3 years, investigators concluded that there were no significant differences between the two groups in morality.

[1] Bardy GH, Lee KL, Mark DB, et al. Home use of automated external defibrillators for sudden cardiac death. N Engl J Med 2008;358:1793-804.

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Prophylactic Catheter Ablation for the Prevention of Defibrillator Therapy

Further information: Catheter Ablation of Supraventricular and Ventricular Arrhythmias from Cardiovascular Medicine, 3rd Edn*

Substrate Mapping & Ablation in Sinus Rhythm to Halt Ventricular Tachycardia (SMASH VT) was a prospective, unblinded, randomized, controlled, multicenter trial conducted in three centers, two in Boston and one in the Czech Republic, from August 2000 to June 2004, and follow-up was completed in June 2006 [1]. Although implantable cardioverter defibrillators (ICD) are the primary treatment option for patients who have a history of myocardial infarction (MI) and who have experienced an episode of ventricular arrhythmia (VT), defibrillator charges are painful and cause significant and depressing anxiety for the patients who experience them.

The trial in this study was a small, randomized study of post-MI patients who received an implantable cardioverter defibrillator (ICD) after a first arrhythmic event in which substrate-based catheter ablation was performed to reduce the incidence of future ICD therapies. A total of 128 patients were randomized to receive either an ICD implant and radiofrequency substrate ablation or an ICD implant alone. There were 64 patients in each group. Criteria for each patient included a history of MI, a recent ICD implant, or an implant scheduled, and none of the patients took antiarrhythmic drugs. In the substrate procedure, arrhythmogenic tissue is identified and ablated while the heart is in sinus rhythm.

In the group receiving an ICD and the substrate procedure, the mortality rate was zero 30 days after the procedure. There were no significant changes in ventricular function or functional class during the mean (±SD) follow-up period of 22.5±5.5 months. Echo studies were performed at 3 and 12 months. The primary endpoint of the study was appropriate ICD therapy defined as shocks or antitachycardia pacing. Twenty-one patients (33%) receiving implantation alone and eight patients (12%) receiving implantation plus ablation received appropriate ICD therapy (hazard ratio [HR] in the ablation group, 0.35; 95% confidence interval [CI], 0.15–0.78, P=0.007). Among these patients, 20 in the control group (31%) and six in the ablation group (9%) received shocks P=0.003). Mortality was not increased in the ablation group when compared to the control group (9% vs. 17%, P=0.29. The investigators found no evidence that catheter ablation adversely affected ventricular function.

The investigators acknowledged that the study was relatively small, and the findings may not apply to patients who have arrhythmias due to other causes, such as cardiomyopathy, but the study convincingly shows that highly selected patients who underwent ICD implantation had fewer ICD therapies when substrate-based catheter ablation was also used.

[1] Reddy VY, Reynolds MR, Neuzil P, et al. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med 2007;357:2657-65

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Telmisartan and/or Ramipril in Patients at High Risk for Vascular Events

Further information: Endocrine Disorders and the Heart from Cardiovascular Medicine, 3rd Edn*

Investigators from 733 centers in 40 countries conducted the “Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint (ONTARGET)” trial [1], in which 25,620 patients over 55 years of age who had coronary heart disease or diabetes, but had no evidence of heart failure (HF), were enrolled.

The initial phase was a single-blind, run-in phase followed by double-blind randomization of patients into three groups: 8576 received ramipril 10 mg/day, 8542 received telmisartan 80 mg/day, and 8502 received both drugs (combination therapy). The primary aim of the study was to determine the effectiveness of telmisartan 80 mg as compared with ramipril 10 mg/day in reducing mortality or morbidity from cardiovascular causes, and to determine if the combination therapy were more effective than either of the two drugs alone, thus reducing the primary composite outcome of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for HF. Ramipril is an angiotensin-converting-enzyme (ACE) inhibitor that reduces mortality and morbidity in patients with vascular disease or diabetes without HF, but is not well-tolerated by some patients because of cough, hypotension, or angioneurotic edema. Telmisartan is an angiotensin-receptor blocker (ARB), and the effect of ARBs in such patients is unknown, but ARBs may be better tolerated by patients than ACE inhibitors.

Results showed that in the telmisartan group, mean blood pressure was lower than in the ramipril group by 1 mmHg lower systolic pressure, and the combination therapy lowered blood pressure still further (2 mmHg systolic lower). The combination therapy was associated with higher rate of hypotension-related side effects, including syncope, and potassium levels were decreased.

The investigators concluded that telmisartan is a safe and effective alternative to ramipril and has fewer side effects, but the combination therapy of telmisartan and ramipril should not be used.

[1] ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-59

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Comparison of Pioglitazone and Glimepiride on Progression of Coronary Atherosclerosis in Type 2 Diabetes

Further information: Endocrine Disorders and the Heart from Cardiovascular Medicine, 3rd Edn*

The “Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstructive Prospective Evaluation (PERISCOPE)” trial [1] was a prospective, randomized, multicenter, double-blind trial that treated 543 patients with coronary artery disease (CAD) and type 2 diabetes for 18 months at 97 academic centers and community hospitals in America. A primary goal of therapy for diabetics is management of glucose levels, and although the progression of atherosclerosis is especially aggressive in diabetic patients, a diabetic therapy regimen has not been found that reduces the progression of coronary atherosclerosis.

Investigators compared an insulin sensitizer, pioglitazone, with glimepiride, an insulin secretagogue (stimulates insulin release by the pancreas), on the progression of coronary atherosclerosis in patients with type 2 diabetes. At entry, all patients underwent intravascular ultrasonography (IVUS) to measure the amount of plaque volume on the arterial wall, and then were randomized to receive glimepiride, 1–4 mg, or pioglitazone, 15–45 mg, for 18 months and titrated to maximum dosage, if tolerated. At 18 months, a second IVUS examination was performed to determine the amount of change in coronary plaque volume. The primary outcome was the calculation of the change in percent atheroma volume (PAV), an indicator of the progression of coronary plaque buildup.

The principle finding of the study showed no progression of plaque buildup with the use of pioglitazone (–16%) as compared with significant progression of plaque buildup with glimepiride (+0.73%), (P=0.002). Pioglitazone was also more effective in favorably altering levels of high-density lipoprotein (HDL), triglycerides, and C-reactive protein.

After analyzing the data from PERISCOPE, investigators concluded that when compared with glimepiride, the use of pioglitazone resulted in a lower rate in the progression of coronary atherosclerosis.

[1] Nissen SE, Nicholls SJ, Wolski K, et al. Comparison of pioglitazone vs. glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: PERISCOPE. JAMA 2008;299:1561-1573

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Cardiovascular Risk of Celecoxib

Further information: Connective Tissue Diseases and the Heart from Cardiovascular Medicine, 3rd Edn*

The aim of the investigators in this study [1] was to assess the cardiovascular risk of celecoxib (trade name Celebrex), a cyclooxygenase-2 inhibitor (coxib), in three dose regimens and to assess the relationship between baseline cardiovascular risk and the effect of celecoxib on cardiovascular events. Prior analyses had a limited ability to clarify the relationship between the coxib dose or pretreatment cardiovascular status and drug-associated cardiovascular risk. Data to be used in a patient-level pooled analysis were collected from trials according to specific criteria and included trials that were randomized, double-blinded, placebo controlled, and had 3-year follow-up for each participant. Six trials met the criteria, and the study included 7950 patients enrolled in trials that compared celecoxib with placebo for conditions other than arthritis. The dosing regimens were 400 mg QD, 200 mg BID, or 400 mg BID.

For the primary end point of cardiovascular death, myocardial infarction, stroke, heart failure, or thromboembolic events, the overall pooled hazard ratio (HR), including all dose regimens, was 1.6 (95% confidence interval [CI], 1.1–2.3). Individual hazard ratios for each dose regimens were calculated and evaluated as to whether celecoxib-related risks were associated with baseline cardiovascular risks. Risk increased with the dose given (P=0.0005), and was lowest for the 400 mg QD dose (HR, 1.1; 95% CI, 0.6–2.0), intermediate for the 200 mg BID dose (HR, 1.8; 95% CI, 1.1–3.1), and highest for the 400 mg BID dose (HR, 3.1; 95% CI, 1.5–6.1). Patients having the highest baseline risk had a greater risk of celecoxib-related adverse events (P for interaction=0.034).

Investigators concluded that the data showed evidence of differential cardiovascular risk as a function of the celecoxib dose regimen and baseline cardiovascular risk. Twice-daily dosing was shown to have greater risk than once-daily dosing. With the extent of cardiovascular risk in the use of celecoxib clarified, treatment decisions should be clearer for patients who receive clinical benefits from their use of the drug.

[1] Solomon SD, Wittes J, Finn PV, et al. Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation 2008;117:2104-13

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Aprotinin

Further information: Hematologic Disease and Heart Disease from Cardiovascular Medicine, 3rd Edn*

Investigators used a database that maintains records according to charges that are assessed to patients for medications used during their hospital stay to determine which patients were given either aprotinin or aminocaproic acid on the day that CABG was performed [1].

The Premier Perspective Comparative Database showed that in a cohort of 78,199 patients, 33,517 were given aprotinin and 44,682 aminocaproic acid. After performing three types of analyses (multivariable logistic-regression analysis, propensity-score analysis, instrumental-variable analysis), the results showed that 1512 (4.5%) of the 33,517 patients who received aprotinin died, and 1101 (2.5%) of the 44,682 patients who received aminocaproic acid died. After adjustments for patients and hospitals, the estimated risk of death was 64% higher in the aprotinin group of patients than in the aminocaproic acid group (relative risk [RR], 1.64; 95% confidence interval [CI], 1.50–1.78). In the first 7 days following surgery, the adjusted risk (AR) of in-hospital risk in the aprotinin group was 1.78 (95% CI, 1.56–2.02). The RR in a propensity-score analysis showed that the use of Aprotinin was 1.32 (95% CI, 1.08–1.63). In the instrument-variable analysis, the use of aprotinin was associated with an excess risk of death of 1.59 per 100 patients (95% CI, 0.14–3.04). The need for postoperative revascularization and dialysis was also greater in aprotinin patients. Findings support the hypothesis that in aprotinin patients, when compared with those receiving aminocaproic acid, there is increased risk of in-hospital death, and the results cannot be attributed to characteristics of patients, hospitals, or surgeons.

Another study on the use of aprotinin was conducted solely in patients having coronary-artery bypass grafting (CABG) at Duke University Medical Center [2]. Data on 10,275 patients treated with aprotinin between January 1, 1996 and December 31, 2005 were analyzed. 1343 patients (13.2%) received aprotinin, 6776 patients received aminocaproic acid, and 2029 (20%) received no antifibrinolytic therapy. Follow-up continued up to 10 years. All patients had CABG, and 1181 patients (11.5%) had combined CABG and valve surgery. In the risk adjusted (RA) model, survival was worse among patients treated with aprotinin, with main-effects hazard ratio (HR) for death of 1.32 (95% CI, 1.12–1.55) for the comparison with patients receiving no antifibrinolytic therapy (P=0.003) and 1.27 (95% CI, 1.10–1.46) for the comparison with patients receiving aminocaproic acid (P=0.004). In comparing the use of either aminocaproic acid or no antifibrinolytic agent, the use of aprotinin was also associated with larger RA increase in the serum creatinine level (P<0.001), but not with greater RA incidence of dialysis (P=0.56). The findings of this study show an association between aprotinin use and reduced survival at 30 days, 1 year, and beyond, and show an association between aprotinin use and decline in renal function.

The use of aprotinin during cardiac surgery is acknowledged for its blood-saving effects. However, use of the drug has come under scrutiny because of its association with increased renal dysfunction and mortality. The investigators of final study [3] focused on the use of aprotinin during on-pump vs. off-pump surgical procedures. According to Royston et al in a 1987 publication of The Lancet [4], aprotinin is a serine protease inhibitor with anti-inflammatory, antifibrinolytic, and platelet-sparing effects. However, there are a number of risk factors that are associated with renal dysfunction after cardiac surgery that are not modifiable, and they include illnesses that often accompany advanced age. There are also modifiable risk factors, such as surgical technique (on-pump or off-pump CABG) and drug use (aprotinin and angiotensin-converting enzyme [ACE] inhibitors). A total of 5434 patients in the study underwent on-pump cardiac surgery, and the odds ratio (OR) between aprotinin and an increased risk of renal dysfunction without ACE inhibitor was 1.81 (95% CI, 0.79–4.13, P=0.162) and with ACE inhibitor, 1.73 (0.56–5.32, P=0.342). In the 848 patients taking ACE inhibitors and having off-pump cardiac surgery, aprotinin was associated with a greater than two-fold increase in the risk in the risk of renal dysfunction (OR 2.87 [1.25–6.58], P=0.013). The study shows that in patients taking ACE inhibitors and having CABG, the use of aprotinin is associated with postoperative renal dysfunction. However, the investigators found little association between the occurrence of renal dysfunction and the use of aprotinin in patients having on-pump surgery.

[1] Schneeweiss S, Seeger JD, Landon J, et al. Aprotinin during coronary-artery bypass grafting (CABG) and risk of death. N Engl J Med 2008;358:771-83

[2] Shaw AD, Stafford-Smith M, White WD, et al. The effect of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med 2008;358:784-93

[3] Mouton R; Finch D, Davies, I, Binks A, Zacharowski K. Effect of Aprotinin on renal dysfunction in patients undergoing on-pump and off-pump cardiac surgery: a retrospective observational study. Lancet 2008;371:475-82

[4] Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987;2:1289-91

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