Reduction of cyclosporine following the introduction of everolimus in maintenance heart transplant recipients: a pilot study.

Data are scarce concerning the calcineurin inhibitor dose reduction required following introduction of everolimus in maintenance heart transplant recipients to maintain stable renal function. In a 48-week, multicenter, single-arm pilot study in heart transplant patients >12 months post-transplant, everolimus was started at 1.5 mg/day (subsequently adjusted to target C(0) 5-10 ng/ml). Mycophenolate mofetil or azathioprine was discontinued on the same day and cyclosporine (CsA) dose was reduced by 25%, with a further 25% reduction each time calculated glomerular filtration rate (cGFR) decreased to <75% of baseline. Of 36 patients enrolled, 25 were receiving everolimus at week 48. From baseline to week 48, there was a mean decrease of 44.5%, 50.9% and 44.6% in CsA dose, C(0) and C(2), respectively. Mean cGFR was 68.9 +/- 14.5 ml/min at baseline and 61.6 +/- 11.5 ml/min at week 48 (P = 0.018). The prespecified criterion for stable renal function was met, i.e. a mean decrease

VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary disease: results of the NORTHERN trial.

Despite the promise of proangiogenic gene therapy most clinical trials have failed to show benefit for the primary end point analysis. The NOGA angiogenesis Revascularization Therapy: assessment by RadioNuclide imaging (NORTHERN) trial was a double-blind, placebo-controlled study of intramyocardial vascular endothelial growth factor (VEGF165) gene therapy versus placebo, involving seven sites across Canada, designed to overcome major limitations of previous proangiogenic gene therapy trials. A total of 93 patients with refractory Canadian Cardiovascular Society (CCS) class 3 or 4 anginal symptoms were randomized to receive 2,000 microg of VEGF plasmid DNA or placebo (buffered saline) delivered via the endocardial route using an electroanatomical NOGA guidance catheter. There was no difference between the VEGF-treated and the placebo groups in the primary end point of change in myocardial perfusion from baseline to 3 or 6 months, assessed by single photon emission tomography (SPECT) imaging, although a significant reduction in the ischemic area was seen in both groups. Also, similar improvements in exercise treadmill time and anginal symptoms were seen in the VEGF and the placebo groups at 3 and 6 months, although again there were no differences between these groups. Despite the intramyocardial administration of a high "dose" of plasmid DNA using a percutaneous guidance catheter system, there was no benefit of VEGF gene therapy at 3 or 6 months for any of the end points studied.

Cyclosporine reduction in the presence of everolimus: 3-month data from a Canadian pilot study of maintenance cardiac allograft recipients.

BACKGROUND: Concentration-controlled everolimus with concomitant cyclosporine (CsA) dose reduction in renal transplantation permits preservation of kidney function without loss of efficacy. Data are lacking regarding everolimus with reduced-dose CsA in maintenance cardiac transplant patients. METHODS: In a multicenter, open-label, single-arm pilot study, concentration-controlled everolimus was initiated in patients receiving CsA microemulsion (Neoral) with/without mycophenolate mofetil (MMF) or azathioprine, and with/without corticosteroids. On the day of everolimus initiation, MMF/azathioprine was discontinued and CsA dose was reduced by 25% with further reductions as required in response to decreasing calculated glomerular filtration rate (cGFR). RESULTS: Of the 36 patients enrolled (intent-to-treat [ITT]), 27 underwent CsA dose reduction as planned (per protocol [PP]). During Week 1, the CsA dose was reduced by 23.3 +/- 7.3% in the ITT population (p < 0.0001) and 26.9 +/- 2.9% in the PP population (p < 0.0001). Mean cGFR (Nankivell) was 68.9 +/- 14.5 ml/min at baseline and 64.4 +/- 14.3 ml/min at Week 12 in the ITT population (p = 0.021), and 69.5 +/- 14.4 ml/min and 66.6 +/- 8.6 ml/min in the PP cohort (p = 0.132). cGFR at Week 12 met the criterion for non-inferiority vs baseline. One case of acute rejection of Grade >or=3A occurred (2.7%). There was no graft loss or death. Hemoglobin and hematocrit levels decreased significantly, whereas cholesterol and triglyceride levels increased (all p < 0.0001). CONCLUSIONS: This pilot study suggests that initiation of concentration-controlled everolimus with a concomitant 25% reduction in CsA dose in maintenance heart transplant patients is associated with no significant decline in renal function, and no indication of increased rejection to Month 3 post-conversion. Evaluation of more substantial CsA dose reductions is required.

Clopidogrel-precipitated rhabdomyolysis in a stable heart transplant patient.

OBJECTIVE: To report the case of an orthotopic heart transplant recipient who developed rhabdomyolysis precipitated by the addition of clopidogrel to the existing regimen of cyclosporine and atorvastatin, which had been tolerated for more than 3 years without adverse effects or laboratory evidence of myositis. CASE SUMMARY: Fourteen years after cardiac transplantation, a 58-year-old woman began a planned 4 week course of clopidogrel 75 mg/day following coronary angioplasty and placement of a stent in the left circumflex coronary artery. Almost 4 weeks later, she presented with severe muscle pain and weakness and laboratory evidence of rhabdomyolysis, with marked elevations of plasma creatine kinase (96,000 U/L) and urine myoglobin (332,872 microg/L) as well as early acute renal failure (serum creatinine 2.9 mg/dL). Symptoms and laboratory abnormalities resolved with cessation of cyclosporine, atorvastatin, and clopidogrel. Clopidogrel was not restarted, while atorvastatin and cyclosporine were; the patient had no recurrence of symptoms up to 15 months later. DISCUSSION: Both atorvastatin and cyclosporine, as well as clopidogrel's active thiol derivative, are metabolized by the cytochrome P450 3A4 isoenzyme. Cyclosporine is also a moderate inhibitor of this isoenzyme. We postulate that competition between atorvastatin and clopidogrel for CYP3A4 receptors, already partially inhibited by cyclosporine, led to increased atorvastatin concentrations, resulting in the acute onset of rhabdomyolysis. This theory is further supported by the patient's continued ability to tolerate the combination of atorvastatin and cyclosporine, without clopidogrel, on rechallenge. Use of the Naranjo probability scale revealed that rhabdomyolysis was probably precipitated by the addition of clopidogrel to the stable baseline regimen of cyclosporine and atorvastatin. CONCLUSIONS: Practitioners must be conscious of the potential for adverse effects when prescribing clopidogrel to heart transplant patients who are concomitantly receiving cyclosporine and a statin. If concomitant administration is required, careful clinical and laboratory monitoring of the patient is necessary.

What is the frequency and functional and clinical significance of complex lesions in non-infarct-related arteries after fibrinolysis for acute ST-elevation myocardial infarction?

BACKGROUND: Observational data suggest that the diffuse inflammatory nature of coronary disease may be expressed by the presence of unstable coronary lesions in multiple vessels in patients with acute myocardial infarction. The aim of our study was to investigate the existence of complex lesions in nonculprit vessels in patients with ST-elevation myocardial infarction and to assess their clinical and functional significance. METHODS: We evaluated 974 non-infarct-related arteries (nIRAs) in 439 patients presenting within 6 hours of acute ST-elevation myocardial infarction. Coronary angiograms and electrocardiograms (ECGs) were obtained 60 minutes after fibrinolysis and systematically analyzed in core angiographic and ECG laboratories. Complex lesions in nIRA were identified according to prior criteria, that is, stenosis > 50% with one of the following: overhanging edges, markedly irregular borders, ulceration, or thrombus. RESULTS: Complex lesions were identified in 85 (8.7%) of 974 nIRAs. Seventy-three (16.7%) of 439 patients had at least 1 complex lesion in a nIRA, with 10 of the 73 patients having > 1 nIRA affected. There were no differences in baseline total ST deviation on the qualifying ECG between patients with or without nIRA complex lesions. TIMI 3 flow in nIRAs occurred less frequently in vessels with complex lesions (50.8% vs 81.5%, P < .001), a difference maintained when nIRAs with stenosis between 50% and 99% were analyzed (P < .006). Patients with nIRA complex lesions had a higher inhospital incidence of congestive heart failure (16.4% vs 6.3%, P = .007) and a trend toward more recurrent ischemia (13.7% vs 7.4%, P = .102). CONCLUSION: These findings provide new evidence supportive of the concept that active coronary lesions occur simultaneously in > 1 vessel, while also attesting to their functional and clinical significance.

Can symptom presentation predict unstable angina/non-ST-segment elevation myocardial infarction in a moderate-risk cohort?

BACKGROUND: Accurate recognition of acute coronary syndromes (ACS) on initial presentation is key to minimizing morbidity and mortality. The wide spectrum of symptom presentation in ACS complicates recognition. Unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI) may be particularly difficult to diagnose as patients often do not exhibit initial high-risk features, leaving the clinician with symptom presentation alone, on which to base decisions regarding further investigation and treatment. PURPOSE: The aim of this study was to compare typical symptom presentation (classic description of angina) and atypical presentation in a cohort presenting with symptoms suggestive of UA/NSTEMI. METHOD: A prospective cohort design was used to evaluate 100 patients enrolled in an Emergency Department Chest Pain Program. RESULTS: Although patients with typical presentation were more likely to have UA/NSTEMI, atypical presentation did not rule out this diagnosis. Of the 31 patients with UA/NSTEMI, most (n=23, 74.2%) had atypical symptoms. Male gender, symptom location, and history of ischemic heart disease were significantly associated with UA/NSTEMI. Of those with a final diagnosis of UA/NSTEMI, there was no difference in symptom presentation based on age or gender. CONCLUSION: Clinicians should not rely on classic descriptions of angina when evaluating patients suspected of UA/NSTEMI.

Compromised atrial coronary anatomy is associated with atrial arrhythmias and atrioventricular block complicating acute myocardial infarction.

BACKGROUND: The relevance of the atrial coronary anatomy in the pathogenesis of atrial arrhythmias and atrioventricular (AV) block complicating acute myocardial infarction (AMI) remains unclear. OBJECTIVES: We evaluated the location of the infarct-related coronary lesion relative to the principal atrial branches (ie, sinoatrial nodal, AV nodal, left atrial circumflex) in 454 patients with ST-elevation AMI in the CAPTORS II trial. METHODS: Patients underwent systematic 60-minute postfibrinolytic angiograms, and coronary anatomy was correlated with evidence of atrial arrhythmias and AV block on sequential electrocardiograms. RESULTS: Patients with either sinoatrial nodal or left atrial circumflex compromise (n = 34) had a higher incidence of "early" (ie, up to 90 minutes postfibrinolysis) atrial arrhythmias vs those without (23.5% vs 7.1%; P = .004). Patients with AV nodal compromise (n = 207) had a higher incidence of "early" AV block vs those without (12.1% vs 3.6%; P = .001). CONCLUSION: These findings support the etiological role of acute atrial ischemia in the development of early atrial arrhythmias and AV block complicating AMI.

Effect of bare metal stenting on angiographic and clinical outcomes in diabetic and nondiabetic patients undergoing percutaneous coronary intervention of nonacute occluded coronary arteries: a report from the Total Occlusion Study of Canada (TOSCA).

The outcome after PTCA and coronary stenting of nonacute total coronary occlusions in the diabetic population is unknown. The main objective of the present report was to compare the angiographic and 1-year clinical outcomes in the diabetic and nondiabetic patients who were enrolled in the Total Occlusion Study of Canada (TOSCA), a prospective randomized controlled multicenter trial of primary stenting versus PTCA alone in nonacute native coronary artery occlusions. Of the 410 patients enrolled, 68 (16.5%) were diabetics. At 6-month follow-up, stenting resulted in significant improvement in angiographic outcome compared to PTCA alone in both diabetic and nondiabetic populations. Angiographic restenosis was significantly reduced by stenting in the nondiabetic population (69.3% vs. 55.2%; P = 0.009). A reduction in restenosis of a similar magnitude was observed with stenting in the diabetic population (71.1% vs. 59.3%; P = NS). At 1-year clinical follow-up, composite adverse cardiac event rates were similar for both strategies regardless of diabetic status. Target vessel revascularization was reduced by stenting compared to PTCA in diabetics (20% vs. 31.6%) and nondiabetics (21.5% vs. 30%). A significant reduction for any vessel revascularization following stenting compared to PTCA was observed in the nondiabetic population (28.5% vs. 38.8%; P = 0.05) but not in the diabetic subgroup (36.7% vs. 42%; P = NS). In conclusion, stenting appeared to be superior to PTCA alone, resulting in similar magnitude of reduction in angiographic restenosis and target vessel revascularization rates in diabetics and nondiabetics. Restenosis rates in all groups remain high. This analysis forms an important background for future studies that are needed to examine the effect of stenting with drug-eluting stents in diabetics as well as nondiabetics with nonacute coronary occlusions.

Effects of long term cholesterol lowering on coronary atherosclerosis in patient risk factor subgroups: the Simvastatin/enalapril Coronary Atherosclerosis Trial (SCAT).

This study examined the effects of long term cholesterol lowering therapy with simvastatin on progression and regression of coronary atherosclerosis, as determined by quantitative angiographic end points, in subgroups of patients with known coronary risk factors. In this randomized, placebo controlled clinical trial, the effect of simvastatin on coronary atherosclerosis was compared with that of placebo in 394 patients who had paired coronary angiograms taken an average of four years apart. The effects of treatment on the following prespecified subgroups were examined: sex, age (less than 65 years versus at least 65 years), smoking status (current or previous/never), history of diabetes mellitus or hypertension, and severity of coronary artery lesions (diameter at least 50% versus less than 50%). There were significantly smaller decreases in the average minimum diameters, between closeout and baseline angiograms, in all simvastatin-treated subgroups, compared with placebo. Trends toward or significantly smaller decreases in the average of the mean diameters, and similar smaller increases in percentage diameter stenosis were also seen in all subgroups. The slowing of angiographically demonstrable coronary atherosclerotic narrowing supports the contention that this treatment effect is causally related to the reduction of coronary events repeatedly seen in large outcome clinical trials of lipid lowering therapy. Also, this treatment effect occurs in the presence or absence of the traditional coronary risk factors.

Who should receive HMG CoA reductase inhibitors?

During the last decade, the development of the HMG CoA reductase inhibitors, commonly referred to as 'statins', has contributed greatly to cholesterol lowering therapy and cardiovascular risk reduction. These agents are well tolerated and efficacious. Data on nearly 30,000 patients from five long-term randomised, placebo-controlled trials of statins have clearly demonstrated that a broad range of individuals can benefit from such therapy. These include men or women, younger or older individuals, those with elevated or normal cholesterol levels, with or without myocardial infarction or symptomatic coronary heart disease, with or without hypertension or diabetes mellitus, and those who are smokers or non-smokers. Benefits include reductions in the risks for myocardial infarction, and coronary, cardiovascular and all-cause mortality, stroke and the need for coronary revascularisation. Results of the recently completed Heart Protection Trial have clearly confirmed the results of the earlier trials and support the use of statin therapy in secondary prevention. The role of statins in acute coronary syndromes is being actively evaluated and appears promising. In primary prevention, the data are not as convincing and generalisations cannot be made as to whether, and in which subgroup, drug therapy to lower low density lipoprotein (LDL) cholesterol should be initiated. There are important cost implications to consider and the use of statin therapy has to be judged on an individual basis, particularly in those with high or very high LDL cholesterol levels and/or with multiple risk factors rendering them at high short- and long-term risk of coronary heart disease. There is evidence of a 'care gap' in translating trial data into practice, even in secondary prevention, and this needs closing in order to improve patient outcomes.