Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction. High-dose intracoronary adenosine for myocardial salvage in patients with acute ST-segment elevation myocardial infarction. Beneficial effect of intracoronary verapamil on microvascular and myocardial salvage in patients with acute myocardial infarction. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. Prevention of atrial fibrillation after cardioversion: results of the PAFAC trial. Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) II-B Study. The effect of verapamil on left ventricular remodelling and diastolic function after acute myocardial infarction (the Verapamil Infarction Study on Remodelling and Relaxation--VISOR). High dose adenosine for suboptimal myocardial reperfusion after primary PCI: A randomized placebo-controlled pilot study.
The benefits of vessel recanalization in acute myocardial infarction (AMI) are limited by reperfusion damage. In animal models, adenosine limits reperfusion injury, reducing infarct size and improving ventricular function. The aim of this study was to evaluate the safety and feasibility of adenosine adjunct to primary PTCA in AMI.
                Fifty-four AMI patients undergoing primary PTCA were randomized to intracoronary adenosine or saline. The 2 groups were similar for age, sex, and infarct location. Adenosine administration was feasible and well tolerated. PTCA was successful in all patients and resulted in TIMI 3 flow in all patients given adenosine and in 19 given saline (P<0.05). The no-reflow phenomenon occurred in 1 adenosine patient and in 7 saline patients (P=0.02). Creatine kinase was lower in the adenosine group, and a Q-wave MI developed in 16 adenosine patients and in 23 saline patients (P=0.04). Sixty-four percent of dyssynergic segments improved in the adenosine group and 36% in the saline group (P=0. 001). Function worsened in 2% of dysynergic segments in the adenosine group and in 20% in the saline group (P=0.0001). Adverse cardiac events occurred in 5 patients in the adenosine group and in 13 patients in the saline group (P=0.03).
                Intracoronary adenosine administration is feasible and well tolerated in AMI. Adenosine adjunct to primary PTCA ameliorates flow, prevents the no-reflow phenomenon, improves ventricular function, and is associated with a more favorable clinical course. Previous studies have suggested that intravenous administration of adenosine improves myocardial reperfusion and reduces infarct size in ST-elevation myocardial infarction (STEMI) patients. Intracoronary administration of adenosine has shown conflicting results.
                In a prospective, single-centre, double-blind, placebo-controlled clinical study, we assessed whether selective intracoronary administration of adenosine distal to the occlusion site immediately before initial balloon inflation results in myocardial salvage and decreased microvascular obstruction (MVO) as assessed with cardiac magnetic resonance imaging (MRI). Using a combination of T(2)-weighted and contrast-enhanced sequences, myocardial salvage index (MSI) was defined as the percentage of the area at risk that did not become necrotic. We randomized 112 patients presenting with STEMI within 12 h from symptom onset to selective intracoronary administration of adenosine 4 mg or matching placebo. In 100/110 (91%) patients receiving study drug, MRI was performed on Days 2-3. No significant difference in MSI was found between adenosine- and placebo-treated patients: 41.3% (20.8, 66.7) vs. 47.8% (39.8, 60.9) [median (Q1, Q3)] (P = 0.52). The extent of MVO was comparable in both groups, with a trend favouring the placebo group: 2.4 g (0.0, 6.8) vs. 5.9 g (0.0, 12.8) after adenosine (P = 0.07). TIMI flow grade, TIMI frame count, myocardial blush grade, and ST-segment resolution after primary percutaneous coronary intervention were similar between groups. After 4 months, infarct size was similar in both treatment groups.
                We found no evidence that selective high-dose intracoronary administration of adenosine distal to the occlusion site of the culprit lesion in STEMI patients results in incremental myocardial salvage or a decrease in microvascular obstruction. We assessed the acute effect of intracoronary injection of verapamil on microvascular function after primary percutaneous translumanal coronary angioplasty (PTCA) for acute myocardial infarction (AMI) with myocardial contrast echocardiography (MCE) in relation to functional outcomes.
                Recent clinical studies have documented the potential of verapamil for possible increase in coronary blood flow after primary PTCA.
                Forty patients with a first AMI were randomly assigned to the verapamil group (n = 20) or the control group (n = 20). In the verapamil group, verapamil (0.5 mg) was injected into the infarct-related artery shortly after PTCA, followed by the oral administration. We performed MCE with an intracoronary injection of sonicated microbubbles before and after verapamil. To assess microvascular integrity, we determined the baseline-subtracted peak intensity in the risk area and the ratio of the no reflow zone plus the low reflow zone to the risk area (low reflow ratio). We determined the average wall motion score (dyskinesia/akinesia = 3; normal = 0) in the risk area on the day of AMI and a mean of 24 days later.
                The low reflow zone was observed shortly after PTCA in 14 verapamil group patients, and the low reflow ratio decreased after verapamil (0.39 +/- 0.23 vs. 0.29 +/- 0.17 [mean +/- SD], p < 0.05). Peak intensity significantly (p < 0.05) increased from 6 +/- 5 to 12 +/- 6 after verapamil. The reduction in wall motion score from the acute (day -1) to the late stage (day -24) was significantly greater in the verapamil group than in the control group (0.7 +/- 0.8 vs. 0.2 +/- 1.3, respectively, p < 0.05).
                Intracoronary administration of verapamil after primary PTCA can attenuate microvascular dysfunction and thereby augment myocardial blood flow in patients with AMI, leading to better functional outcome than with PTCA alone. Hypertensive patients are often given a calcium antagonist to reduce cardiovascular disease risk, but the benefit compared with other drug classes is controversial.
                To determine whether initial therapy with controlled-onset extended-release (COER) verapamil is equivalent to a physician's choice of atenolol or hydrochlorothiazide in preventing cardiovascular disease.
                Double-blind, randomized clinical trial conducted at 661 centers in 15 countries. A total of 16 602 participants diagnosed as having hypertension and who had 1 or more additional risk factors for cardiovascular disease were enrolled between September 1996 and December 1998 and followed up until December 31, 2000. After a mean of 3 years of follow-up, the sponsor closed the study before unblinding the results.
                Initially, 8241 participants received 180 mg of COER verapamil and 8361 received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide. Other drugs (eg, diuretic, beta-blocker, or an angiotensin-converting enzyme inhibitor) could be added in specified sequence if needed.
                First occurrence of stroke, myocardial infarction, or cardiovascular disease-related death.
                Systolic and diastolic blood pressure were reduced by 13.6 mm Hg and 7.8 mm Hg for participants assigned to the COER verapamil group and by 13.5 and 7.1 mm Hg for partcipants assigned to the atenolol or hydrochlorothiazide group. There were 364 primary cardiovascular disease-related events that occurred in the COER verapamil group vs 365 in atenolol or hydrochlorothiazide group (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.88-1.18; P =.77). For fatal or nonfatal stroke, the HR was 1.15 (95% CI, 0.90-1.48); for fatal or nonfatal myocardial infarction, 0.82 (95% CI, 0.65-1.03); and for cardiovascular disease-related death, 1.09 (95% CI, 0.87-1.37). The HR was 1.05 (95% CI, 0.95-1.16) for any prespecified cardiovascular disease-related event and 1.08 (95% CI, 0.93-1.26) for all-cause mortality. Nonstroke hemorrhage was more common with participants in the COER-verapamil group (n = 118) compared with the atenolol or hydrochlorothiazide group (n = 79) (HR, 1.54 [95% CI, 1.16-2.04]; P =.003). More cardiovascular disease-related events occurred between 6 AM and noon in both the COER verapamil (99/277) and atenolol or hydrochlorothiazide (88/274) groups; HR, 1.15 (95% CI, 0.86-1.53).
                The CONVINCE trial did not demonstrate equivalence of a COER verapamil-based antihypertensive regimen compared with a regimen beginning with a diuretic or beta-blocker. When considered in the context of other trials of calcium antagonists, these data indicate that the effectiveness of calcium-channel therapy in reducing cardiovascular disease is similar but not better than diuretic or beta-blocker treatment. In patients with persistent atrial fibrillation (AF), the efficacy and safety of two anti-arrhythmic drugs in preventing the recurrence of AF after successful direct current (DC) cardioversion was prospectively assessed in a multi-centre double-blind, placebo-controlled, randomised trial using daily trans-telephonic monitoring.
                1182 patients with persistent AF were prospectively enrolled, 848 patients were successfully cardioverted and then randomised to either sotalol (383 patients), quinidine plus verapamil (377 patients) or placebo (88 patients). The primary outcome parameter was AF recurrence or death. All patients received an event recorder (Tele-ECG) and had to record and transmit via telephone at least one ECG per day during follow-up. The mean follow-up period was 266 days. A total of 191,103 Tele-ECGs were recorded and transmitted. The primary outcome parameter (AF recurrence of any kind or death) was observed in 572 patients (67%) in whom at least one episode of AF recurrence was documented during follow-up, in 348 patients (41%) AF recurrence was persistent. The recurrence rates after one year for any AF were 83% for placebo, 67% for sotalol and 65% for quinidine plus verapamil, the latter being statistically superior to placebo but not different from sotalol. The recurrence rates for the secondary outcome parameter persistent AF were 77%, 49% and 38%, respectively. Quinidine plus verapamil was significantly superior to placebo and to sotalol. About 95% of all AF recurrences were initially detected in the daily Tele-ECG, about 70% of all AF recurrences occurred completely asymptomatic. Adverse events on sotalol and quinidine plus verapamil were comparable with the exception that all torsade de pointes tachycardias occurred on sotalol.
                Anti-arrhythmic treatment after DC cardioversion of persistent AF significantly decreases the recurrence rates of persistent AF compared to placebo with superiority of quinidine plus verapamil compared to sotalol. Symptoms were not reliable as clinical surrogates to detect episodes of AF. In the Thrombolysis in Myocardial Infarction (TIMI) Phase II trial, patients received intravenous recombinant tissue-type plasminogen activator (rt-PA) and were randomized to either a conservative or an invasive strategy. Within this study, the effects of immediate versus deferred beta-blocker therapy were also assessed in patients eligible for beta-blocker therapy, a group of 1,434 patients of which 720 were randomized to the immediate intravenous group and 714 to the deferred group. In the immediate intravenous group, within 2 hours of initiating rt-PA metoprolol was given (5 mg intravenously at 2-minute intervals over 6 minutes, for a total intravenous dose of 15 mg, followed by 50 mg orally every 12 hours in the first 24 hours and 100 mg orally every 12 hours thereafter). The patients assigned to the deferred group received metoprolol, 50 mg orally twice on day 6, followed by 100 mg orally twice a day thereafter. The therapy was tolerated well in both groups and the primary end point, resting global ejection fraction at hospital discharge, averaged 50.5% and was virtually identical in the two groups. The regional ventricular function was also similar in the two groups. Overall, there was no difference in mortality between the immediate intravenous and deferred groups, but in the subgroup defined as low risk there were no deaths at 6 weeks among those receiving immediate beta-blocker therapy in contrast to seven deaths among those in whom beta-blocker therapy was deferred. These findings for a secondary end point in a subgroup were not considered sufficient to warrant a recommendation regarding clinical use. There was a lower incidence of reinfarction (2.7% versus 5.1%, p = 0.02) and recurrent chest pain (18.8% versus 24.1%, p less than 0.02) at 6 days in the immediate intravenous group. Thus, in appropriate postinfarction patients, beta-blockers are safe when given early after thrombolytic therapy and are associated with decreased myocardial ischemia and reinfarction in the first week but offer no benefit over late administration in improving ventricular function or reducing mortality. The VISOR is a double blind, randomized, placebo-controlled study aimed to assess the effects of early and prolonged administration of verapamil on the left ventricular geometry and diastolic function in patients with anterior acute myocardial infarction treated with thrombolysis. Patients with heart failure or ejection fraction < 45% were excluded. Within 12 hours from starting thrombolysis, 70 patients were given verapamil (5 mg/hour intravenously for the first 24 hours, followed by 120 mg t.i.d. perorally for 6 months) or equivalent placebo. Echocardiograms were performed on admittance, before discharge, after 3 months and 6 months. The following parameters were calculated: left ventricular volumes, ejection fraction, sphericity index, early (E) and late (A) transmitral peak flow velocities and time-velocity integrals with their ratios, deceleration time and half-time of E, isovolumic relaxation time (IVRT), and non-invasive time constant of ventricular relaxation (tau). The basal and the last available parameters were considered for statistical analysis. The effects of the treatment on the left ventricular volumes, ejection fraction, and sphericity index were not statistically relevant. Conversely, a reduction of E/A ratio (P < .05) and increases of A integral (P < .01), deceleration time and half-time of E, IVRT and tau (P < .05) were found in the placebo group and not in the verapamil group. No significant changes in the blood pressure, heart rate, PQ interval, and biochemical parameters were observed in the two groups. In conclusion, in patients with a thrombolysed anterior acute myocardial infarction and preserved systolic function, verapamil can prevent alterations of the diastolic function in absence of effect on ventricular remodelling, and has a good safety profile. This study was designed to investigate the influence of high dose intracoronary adenosine on persistent ST-segment elevation after primary percutaneous coronary intervention (PCI).
                After successful PCI for acute myocardial infarction 40-50% of patients show persistent ST-segment elevation indicating suboptimal myocardial reperfusion. Adenosine has been studied to ameliorate reperfusion and is frequently used in a variety of doses, but there are no prospective studies to support its use for treatment of suboptimal reperfusion.
                We conducted a blinded, randomized, and placebo-controlled study with high dose intracoronary adenosine in 51 patients with <70% ST-segment resolution (STRes) after successful primary PCI. All patients were treated with stents and abciximab.
                Immediately after adenosine, significantly more patients showed optimal (>70%) STRes compared with placebo (33% versus 9%, P < 0.05). Mean STRes was higher after adenosine (35.4% versus 23.0%, P < 0.05). In addition, TIMI frame count was significant lower (15.7 versus 30.2, P < 0.005), Myocardial Blush Grade was higher (2.7 versus 2.0, P < 0.05) and resistance index was lower in the adenosine group (0.70 versus 1.31 mm Hg per ml/min, P < 0.005).
                Intracoronary adenosine accelerates recovery of microvascular perfusion in case of persistent ST segment elevation after primary PCI.
We found no evidence that adenosine and verapamil as treatments for no-reflow during PPCI can reduce all-cause mortality, non-fatal myocardial infarction or the incidence of angiographic no-reflow (TIMI flow grade < 3 and MBG 0 to1), but there was some evidence of increased adverse events. Further clinical research into adenosine and verapamil is needed because of the limited numbers of included trials and participants.