Is it possible to conduct clinical trials during a pandemic? The example of a trial of hydroxychloroquine.

OBJECTIVES: to examine the factors that, in the context of the current pandemic, have influenced the conduct of a randomized clinical trial on hydroxychloroquine in Italy. DESIGN: the trend of enrolment in the PROTECT study, "A randomized study with Hydroxychloroquine versus observational support for prevention or early phase treatment of Coronavirus disease (COVID-19)" (Eudract number: 2020-001501-24, NCT04363827), conducted in the period from May to September 2020, was analysed to evaluate the possible association of the enrolment rate with the amount of information published in the national and local press on hydroxychloroquine. SETTING AND PARTICIPANTS: the PROTECT clinical study is an Italian interventional superiority study, open label, with cluster randomization, aimed at evaluating whether treatment with hydroxychloroquine can reduce the percentage of symptomatic subjects compared to observation only in a population of subjects exposed to SARS-CoV-2 virus consisting of cohabitants/contacts of COVID-19 patients and asymptomatic or paucisymptomatic subjects diagnosed with COVID-19. MAIN OUTCOME MEASURES: the number of asymptomatic or paucisymptomatic COVID-19 patients and the number of contacts/cohabitants of COVID-19 patients enrolled in the Protect study from May to September 2020. RESULTS: from May to September 2020, the number of patients diagnosed with COVID-19 enrolled in the PROTECT clinical trial showed a decrease consistent with the number of news on hydroxychloroquine appearing in the national and local press, starting from the time when the first criticisms of the efficacy of hydroxychloroquine were made known; the number of contacts/cohabitants of COVID-19 patients showed a more marked and more timely decrease. CONCLUSIONS: in the context determined by the current COVID-19 pandemic, conducting a controlled clinical trial is strongly influenced by public opinion on scientific issues. Adherence to a clinical study can become highly problematic and invalidate the possibility of answering a scientific question and the validity of a project. In the current pandemic situation, randomized controlled trials may not always be the optimal tool to reach the expected scientific evidence, due to a number of problems. It is preferable to use a sequential or adaptive design. Furthermore, study protocols should implement innovative approaches that also include the involvement of participants in the decision-making process. In any case, the influence of public information on scientific issues is an extremely important factor to consider in the design of clinical trials in exceptional situations such as a pandemic.

Percutaneous coronary interventions in octogenarians: Acute and 12 month results in a large single-centre experience.

OBJECTIVES: To review the results of PCI in patients aged >or=80 years. BACKGROUND: Octogenarians represent a growing proportion of patients treated with PCI; in this subset of high-risk patients, the role of complete revascularization is still controversial. METHODS: We examined in-hospital, 30 days, and 12-month events in 356 patients aged >or=80 years submitted to PCI from 2004 to 2006 and 754 patients aged <80 years treated in 2006. RESULTS: Octogenarians had a higher risk profile. A complete revascularization was obtained in 48% of them and in 65% of younger patients (P < 0.001); glycoprotein IIb/IIIa inhibitors (GPI) use was common in both groups (43 vs. 46.5%). In-hospital mortality was higher in octogenarians (3.9 vs. 1.3%, P = 0.01) as well as vascular complications (2.8 vs. 1%, P = 0.058). Mortality resulted 5.9 vs. 1.2% at 30 days (P < 0.001), and 16.3 vs. 3.9% at 12 months (P <0.001) in the two groups whereas repeat revascularization procedures did not differ (9.3 vs. 8.4%, respectively). In patients aged >or=80, there was no difference in 12 months total events (20 vs. 28%, P = 0.07) and repeat revascularizations (8 vs. 10%, P = 0.498) in completely or uncompletely revascularized subjects. At multivariate analysis age (P = 0.002), diabetes (P = 0.002), three vessel disease (P = 0.020) and procedural success (P = 0.002) were independent predictors of total events at 12 months. CONCLUSIONS: In our experience, frequent GPI use and multivessel PCI in 41% of >or=80 years-old patients resulted in good immediate and mid-term clinical outcomes, irrespective of the completeness of revascularization achieved.

Is electrocardiography a reliable tool for identifying patients with isthmus-dependent atrial flutter?

AIMS: To verify the reliability of the surface ECG to discriminate between cavotricuspid isthmus-dependent atrial flutter (CTI-AFL) and non-CTI-AFL. METHODS AND RESULTS: We reviewed the ECGs of 186 consecutive patients who underwent catheter ablation of AFL between January 2004 and January 2008. The ECG pattern was defined typical for CTI-AFL, if F-waves were: (i) dominantly negative in the inferior leads and positive in V1 (CCW) or (ii) dominantly positive in the inferior leads and negative in V1 (CW). At the electrophysiological study (EPS), 138 patients (74.2%) had a CTI-AFL and 48 patients (25.8%) had a non-CTI-AFL. A CTI-AFL was found not only in 90.5% of patients having a typical ECG, but also in 40% of patients having an atypical ECG. Thus, a typical AFL ECG showed a sensitivity of 0.83 and a specificity of 0.75 to predict a CTI-AFL, with a positive predictive value of 90.5% and a negative predictive value of 60%. CONCLUSION: Typical AFL ECG is a good predictor of CTI-AFL, and in this case, an ablation procedure can be recommended. On the contrary, an atypical AFL ECG does not rule out a CTI-AFL; so, even in this group of patients, an EPS should not be denied when indicated by the clinical circumstances.

Single or multivessel percutaneous coronary intervention in ST-elevation myocardial infarction patients.

OBJECTIVES: To evaluate clinical results of percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI) in patients with multivessel disease (MVD), in relation to single or multivessel (MV)-PCI and to patients with single vessel disease (SVD). METHODS: Patients treated with PCI in the setting of <24 hr STEMI in the years 2004-2007 were considered. RESULTS: Seven hundred forty-five primary PCI, 346 (46%) in patients with SVD and 399 (54%) in patients with MVD were performed. Among MVD patients, 156 (39%) had infarct related artery (IRA)-only treatment and 243 had MV-PCI: 147 (37%) in a single session, 48 (12%) within 24 hr, and 48 (12%) predischarge. Revascularization was complete in 46% of MVD patients. At a median follow-up of 597 days, mortality was 6.3% in SVD and 12% in MVD (P = 0.007), new revascularization 2.9% and 9%, respectively (P < 0.001). Thirty-day mortality was 2.4% in SVD and 6.7% in MVD (P = 0.006). After exclusion of patients with cardiogenic shock or pulmonary oedema, more frequent in the MV-PCI in single session group (P = 0.006), 30-day mortality was SVD 1.3%, IRA-only 6.3%, MV-PCI 2.8% (P = 0.023), without differences if in a single (3.3%) or in staged session (2.2%). By multivariate analysis, female sex, anterior STEMI, cardiogenic shock, MVD, and procedural failure were independent predictors of 30-day mortality. CONCLUSIONS: STEMI patients with MVD have a worse prognosis than those with SVD. MV-PCI in patients without hemodynamic compromise yields good short-term results, even if performed very early, with a 30-day mortality in between that of SVD patients and that of MVD patients with IRA-only treatment.

Left main percutaneous coronary intervention in ACS or stable coronary artery disease: acute and long-term results.

BACKGROUND: The aim of this study was to assess in-hospital and long-term results of the novo unprotected left main (UPLM) percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) or stable coronary artery disease (CAD), in an unselected population admitted to a single high- volume cath-lab without on-site cardiac surgery. METHODS: From 2008 to 2011, among 317 PCI performed in patients with the novo UPLM stenosis, 49 patients presented ST-elevation myocardial infarction (STEMI), 152 non ST-elevation MI/unstable angina (NSTEMI/UA), 116 stable CAD. RESULTS: In-hospital mortality was 20% in STEMI, 5.3% in NSTEMI/UA and 1.7% in stable CAD patients (P<0.001). Two-year total mortality was 24.5%, 25.6% and 6% in the 3 groups, and cardiac death was 20%, 13.8% and 3.4% (P=0.002). Left main target lesion revascularization (TLR) was similar in the 3 groups, as the clinically-driven TLR (10% vs. 11% vs. 7.7%, P=0.642), with neither definite nor probable stent thrombosis. Multivariate analysis showed the following independent predictors of 2-year mortality: bare-metal stent use (OR 4.53, P<0.001), Syntax Score >32 (OR 3.53, P=0.012), ACS as the indication (OR 3.24, P=0.012), peripheral artery disease (OR 2.20, P=0.042), and age >75 years (OR 2.09, P=0.05). CONCLUSIONS: Our experience showed acceptable results of UPLM PCI in STEMI patients, where short-term prognosis was related to hemodynamic conditions, good results in NSTEMI/UA patients where mortality increased in the follow-up due to comorbidities, and very good results in patients with stable CAD.

Administration of eptifibatide during transfer for primary PCI in patients with STEMI: effect on Pre-PCI TIMI flow and its correlation with pain-to-therapy time.

BACKGROUND: Facilitation therapy in ST-elevation myocardial infarction (STEMI) is still controversial and no relationship between timing of treatment and efficacy has been reported to date. METHODS: In order to evaluate the effect of pre-catheterization laboratory (cath lab) administration of eptifibatide on pre-percutaneous coronary intervention (PCI) thrombolysis in myocardial infarction (TIMI) flow and its correlation with ischemia duration, we studied all 438 STEMI patients treated with primary PCI from January 2006 to December 2007: 310 patients were pretreated with eptifibatide (Group P), while 128 patients received either no glycoprotein IIb/IIIa inhibitors or were only given them in the cath lab (Group C). All ischemia times (chest pain onset, diagnostic electrocardiogram, eptifibatide administration, cath lab arrival, first balloon inflation) were recorded. Group P was divided into early (E:159 patients with symptoms duration or= 2 flow on multivariable analysis. Thirtyday mortality was 1.9% in Group P and 9.5% in Group C (p < 0.001). CONCLUSIONS: In our experience, very early (< 90 minutes) eptifibatide therapy prior to primary PCI achieves a higher rate of pre-PCI TIMI flow >or= 2 with respect to late administration.