Strokes and Transient Ischemic Attacks Occurrence During Annual Dual Antiplatelet Therapy.

BACKGROUND: The incidence of stroke/TIA during annual dual antiplatelet therapy (ADAPT) for acute coronary syndrome (ACS) remains high. Some evidence suggests that shorter than ADAPT may diminish such risk, still providing adequate vascular protection. However, the precise timing of strokes/TIA occurrences during ADAPT is unclear but may be important for determining optimal preventive treatment duration. STUDY QUESTION: The precise timing of secondary cerebrovascular events over ADAPT. STUDY DESIGN: Access was gained to the FDA-issued Platelet Inhibition and Outcomes (PLATO) trial data set on which post hoc analyses of stroke/TIA timing after ticagrelor and clopidogrel on top of aspirin was explored. MEASURES AND OUTCOMES: Events were counted and plotted over time from day 1 till day 365 after the index ACS event. RESULTS: Among 18,624 enrollees, 252 strokes and 49 TIAs were reported. After the exclusion of entries with missing dates, unclear randomization codes, and events beyond 1-year follow-up, 238 strokes and 45 TIAs were analyzed. Overall, most frequent strokes/TIAs occurred within the first day after qualifying ACS, with the gradual declines after day 7 and day 40 reaching background counts thereafter. The strokes/TIAs patterns did not differ much between P 2 Y12 inhibitors except for twice more events at day 1 and excess exclusions after day 365 in the ticagrelor arm. CONCLUSIONS: Most cerebrovascular events emerged very early after ACS despite ADAPT. This large hypothesis-generating evidence may justify shorter than the ADAPT duration after ACS. Twice more events at day 1 and excess late ticagrelor exclusions in PLATO deserve further scrutiny. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00391872.

Time Course of Death After Acute Coronary Syndrome Treated With Dual Antiplatelet Therapy for 1 Year.

BACKGROUND: Excess mortality remains the cornerstone concern despite dual antiplatelet therapy (DAPT) after acute coronary syndrome. Some data suggest that shorter periods than 12 months of DAPT diminish bleeding risks yet still provide adequate vascular protection and improving survival. However, the precise timing of deaths after acute coronary syndrome has not been mapped in many studies. This knowledge may be critical for defining optimal treatment duration. METHODS: Access was gained to the data set for the Platelet Inhibition and Outcomes (PLATO) trial, which was issued by the Food and Drug Administration, in which post hoc analyses of timing of death events during DAPT (with either aspirin/ticagrelor or aspirin/clopidogrel) were performed. All-cause individual deaths were counted and plotted over time from day 1 to day 365 after the index event. RESULTS: Among 18,624 enrollees, 938 total deaths were reported to the Food and Drug Administration in PLATO. After exclusion of deceased patients with missing dates, randomization errors, and deaths beyond 1 year of follow-up, 913 fatalities (509 after clopidogrel and 404 after ticagrelor) were analyzed. The PLATO records did not indicate where exactly deaths occurred making impossible to triage in the hospital versus outpatient fatalities. Most frequent deaths occurred within the Day 1 (n = 41); Day 2 (n = 48); and Day 3 (n = 33) and overall during the first week (n = 202; 22.1%) after the index acute coronary syndrome, with a gradual decline after Day 10 and Day 60, reaching background counts after Day 220. CONCLUSION: Focusing on mortality reduction, this large data set may support a shorter than 12 months' duration of DAPT.

Impact of the reporting source on Platelet Inhibition and Treatment Outcomes (PLATO) trial deaths.

BACKGROUND: Platelet Inhibition and Clinical Outcomes (PLATO) was a multicenter, randomized double-blind trial assessing efficacy and safety of ticagrelor versus clopidogrel in patients with acute coronary syndrome. The reported mortality benefit of ticagrelor in the PLATO trial has been challenged for over decade, and never confirmed in later trials. OBJECTIVE: To compare if there were any differences when deaths were reported to the FDAby the sponsors or by independent Contract Research Organizations (CRO). METHODS: We obtained the complete PLATO deaths dataset reported to the FDA and revealed that some events were inaccurately reported favoring ticagrelor. The entire FDA list contains precisely detailed 938 PLATO deaths. The CRO reported outcomes from the USA, Russia, Georgia, and most of Ukraine, while sites in 39 other countries were controlled by the trial sponsors. We compared vascular- (code "11"), non-vascular- (code "12"), and unknown (code "97") deaths triaged by the reporting source. RESULTS: Overall, most PLATO deaths were vascular (n=677), less non-vascular (n=159) andunexpectedly many of "other" (n=7) or "unknown" (n=95) origin reported either by sponsors (n=807) or CRO (n=131). The trial sponsors reported more clopidogrel deaths from vascular (313 vs.239), non-vascular (86 vs.58) and unknown (53 vs. 26) causes.In contrast, CRO-monitored sites reported significantly (72 vs. 53; p<0.01) more ticagrelordeaths than after clopidogrel from vascular (51 vs.39), non-vascular (8 vs.7) and unknown (10 vs. 4) causes. CONCLUSION: Deaths were reported differently by sponsors and CRO within the same trial. Since some deaths were misreported by PLATO sponsors, only the CRO data seems mostly reliable. Among all countries, the CRO - reported PLATO-USA outcomes represent the largest and most realistic dataset of realistic evidence suggesting ticagrelor inferiority to clopidogrel for all primary endpoint components including vascular death.

The FDA and PLATO Investigators death lists: Call for a match.

PURPOSE: The FDA-issued PLATO trial dataset revealed that some primary death causes (PDCs) were inaccurately reported favouring ticagrelor. However, the PLATO Investigators operated the shorter death list of uncertain quality. We compared if PDC match when trial fatalities were reported to the FDA and by the PLATO Investigators. METHOD: The FDA list contains precisely detailed 938 PLATO deaths, while shorter investigators dataset consists of 905 deaths. We matched four vascular (sudden, post-MI, heart failure and stroke), and three non-vascular (cancer, sepsis and suicide) PDC between death lists. RESULTS: There were more sudden deaths in the shorter list than in the FDA dataset (161 vs 138; P < .03) and post-AMI (373 vs 178; P < .001) but fewer heart failure deaths (73 vs 109; P = .02). Stroke numbers match well (39 vs 37; P = NS) with only two ticagrelor cases removed. Cancer matched well (32 vs 31; P = NS), and sepsis cases were identical (30 vs 30; P = NS). However, two extra clopidogrel suicides in the shorter list are impossible to comprehend. CONCLUSIONS: The PLATO trial PDCs were mismatched between FDA and investigators sets. We are kindly asking the ticagrelor sponsor or/and concerned PLATO Investigators to clarify the PDC dataset match.

Verifying Death Reports in the Platelet Inhibition and Patient Outcomes (PLATO) Trial.

BACKGROUND: Excess vascular deaths in the PLATO trial comparing ticagrelor to clopidogrel have been repeatedly challenged by the Food and Drug Administration (FDA) reviewers and academia. Based on the Freedom of Information Act, BuzzFeed won a court order and shared with us the complete list of reported deaths for the ticagrelor FDA New Drug Application (NDA) 22-433. This dataset was matched against local patient-level records from PLATO sites monitored by the sponsor. STUDY QUESTION: Whether FDA death data in the PLATO trial matched the local site records. STUDY DESIGN: The NDA spreadsheet contains 938 precisely detailed PLATO deaths. We obtained and validated local evidence for 52 deaths among 861 PLATO patients from 14 enrolling sites in 8 countries and matched those with the official NDA dataset submitted to the FDA. MEASURES AND OUTCOMES: Existence, precise time, and primary cause of deaths in PLATO. RESULTS: Discrepant to the NDA document, sites confirmed 2 extra unreported deaths (Poland and Korea) and failed to confirm 4 deaths (Malaysia). Of the remaining 46 deaths, dates were reported correctly for 42 patients, earlier (2 clopidogrel), or later (2 ticagrelor) than the actual occurrence of death. In 12 clopidogrel patients, cause of death was changed to "vascular," whereas 6 NDA ticagrelor "nonvascular" or "unknown" deaths were site-reported as of "vascular" origin. Sudden death was incorrectly reported in 4 clopidogrel patients, but omitted in 4 ticagrelor patients directly affecting the primary efficacy PLATO endpoint. CONCLUSIONS: Many deaths were inaccurately reported in PLATO favoring ticagrelor. The full extent of mortality misreporting is currently unclear, while especially worrisome is a mismatch in identifying primary death cause. Because all PLATO events are kept in the cloud electronic Medidata Rave capture system, securing the database content, examining the dataset changes or/and repeated entries, identifying potential interference origin, and assessing full magnitude of the problem are warranted.

Does Ivabradine Decrease Cardiovascular Deaths in Heart Failure Patients?

BACKGROUND: Ivabradine, a heart rate-slowing drug used to treat heart failure and (in Europe) angina, had varying impacts upon cardiovascular events in its 3 large outcome trials. Food and Drug Administration (FDA) analyses may explain the reasons for the variability. METHODS: An FDA reviewer analyzed the raw data from the 3 trials using logistic regressions to assess interactions between ivabradine and other drugs and forest plots to display dose responses. RESULTS: Ivabradine in its SHIFT heart failure trial shows a significant interaction with loop diuretics with a beneficial impact upon cardiovascular deaths (odds ratio 0.61; 95% confidence interval, 0.42-0.87, P = .007). This favorable effect is supported by similar interactions in the other 2 trials (BEAUTIFUL, SIGNIFY) and by a dose response for loop diuretics interacting with ivabradine in the SHIFT and BEAUTIFUL trials. The interaction is not related to heart failure severity. CONCLUSION: Ivabradine used concomitantly with a loop diuretic has a beneficial impact upon cardiovascular death.

Should We Use Tegaserod for Irritable Bowel Syndrome?

BACKGROUND: Tegaserod, a serotonin (5-HT4) agonist initially approved for constipation but withdrawn from use in 2007 because of concerns about cardiovascular adverse effects, was resubmitted to the Food and Drug Administration (FDA) in 2018 for use in a restricted population. AREAS OF UNCERTAINTY: Despite an 18-year regulatory history, there remain pharmacology and clinical trial concerns that have not been addressed but are critical for proper assessment of the drug safety and efficacy profile. SOURCES: Original FDA reviews, FDA and developer advisory committee briefing documents, and published literature. RESULTS: The major pharmacology concern is that the fate and effects of half of the molecule, the pentylaminoguanidine moiety, are unknown. There is evidence that pentylaminoguanidine may contribute to both efficacy and safety. There are other metabolites that are poorly characterized, and potential receptor interactions that suggest cardiovascular effects are possible. The major clinical trial concern is that, while the trial data support a low but definite cardiovascular risk, both subject follow-up and cardiovascular event descriptions were incomplete such that an accurate estimate of cardiovascular risk is not possible. CONCLUSIONS: The uncertainties and lack of reliable evidence regarding tegaserod metabolism and cardiovascular risk estimates may discourage clinical use. Signals for cardiovascular toxicity in typical drug development programs are subtle and must be pursued aggressively, with complete case follow-up and cardiovascular event capture in the clinical trials.

Ranolazine, ACE Inhibitors, and Angiotensin Receptor Blockers.

BACKGROUND: Ranolazine is an anti-angina agent with many metabolites creating the potential for off-target effects. The U.S. Food and Drug Administration (FDA) reviews sometimes contain clinically relevant data not found in other sources. METHODS: We reanalyzed data in an FDA review of the placebo-controlled MERLIN trial of ranolazine to display differences in adverse event rates graphically. RESULTS: Rates of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)-related adverse events (eg, angioedema, dry cough, renal impairment, hypotension, anemia, and serum potassium > 5.5 mmol/L) were higher in patients receiving ranolazine and an ACEI or ARB. Rates of adverse events that should be decreased by ACEI/ARBs (eg, hypokalemia, hypertension, and serum potassium < 3.5 mmol/L) were lower in patients receiving ranolazine and an ACEI or ARB compared to rates in patients receiving placebo and an ACEI or ARB. CONCLUSIONS: Ranolazine potentiates the effects of ACEIs and ARBs. Clinicians should monitor for this potentiation when initiating treatment with ranolazine and an ACEI or ARB.

Mortality and adverse events with brand and generic clopidogrel in the US Food and Drug Administration Adverse Event Reporting System.

AIMS: Clopidogrel is commonly used even after expiring patents. The brand clopidogrel (BC) was dealt by single company, while numerous manufacturers produce generic clopidogrel (GC). There are no convincing data to compare the safety of different formulations. Therefore, the data yielded from international, uniform, government-mandated registries may be useful. METHODS AND RESULTS: We assessed primary causative adverse events (PCAE) after BC and GC in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The outcomes were divided into death, cardiac, thrombotic/embolic, haemorrhagic, and rash/dermal complications. These primary endpoints were then examined by proportional reporting ratios (PRR) and chi-square (χ2). Among total FAERS (n = 9 466 679) reports, overall BC (n = 88 863) cases were more common than after GC (n = 36 559). When triaged by PCAE role, BC (n = 18 328) was also more abundant than GC (n = 3987). The reported death rates were more than doubled after BC [18.4% vs. 7.0%; PRR = 0.38; 95% confidence interval (95% CI) 0.32-0.43; χ2=369.7; P<0.0001] for total FAERS, and consistent for late 2010-2017 (17.6% vs. 7.0% PRR = 0.40; 95% CI 0.37-0.45; χ2=286.2; P<0.004) PCAE cases. In contrast, GC trended to co-report more cardiac (14.6% vs. 13.3%; PRR = 1.12; 95% CI 1.0-1.25; χ2=3.5; P<0.06). The haemorrhagic (40.9% vs. 32.3%; PRR = 1.45; 95% CI 1.33-1.57; χ2=75.8; P<0.0001), and rash/dermal (5.4% vs. 4.6%; PRR = 1.20; 95% CI 1.0-1.44; χ2=3.75; P<0.05) events were also more common for GC. Thrombotic/embolic events were reported equally (at 7.0%) after each formulation. CONCLUSION: The PCAE profiles differ with BC and GC in FAERS. While deaths reports were higher, the rates of cardiac, haemorrhagic, and skin complications were less common for BC. Despite expected reporting bias, this may indicate that the manufacturers of GC are reluctant to report deaths to the FDA. However, the overall adverse event profile suggests potentially better safety of BC over GC formulations.

Assessing Cancer Signal during Oral Antiplatelet Therapy in the Food and Drug Administration Adverse Event Reporting System: Mission Impossible.

Whether aggressive prolonged dual antiplatelet therapy (DAPT) promotes solid cancer risks remains a critical unsolved issue. Since the evidence from randomized trials, affiliated U.S. Food and Drug Administration (FDA) reviews, meta-analyses, and national registries is mixed, the search is ongoing. The FDA Adverse Event Reporting System (FAERS) is a global passive surveillance repository requiring mandatory updates for serious events. We assessed the frequencies of co-reporting any cancers with oral antiplatelet agent (OAA) strategies in FAERS. We examined the entire FAERS database ( n = 8,604,889) with regard to monotherapy or DAPT with OAA, suspected causative role, and co-reporting any cancers ( n = 433,111). We extracted cancer cases during monotherapy with aspirin (20,984 out of 462,371 or 4.54%), clopidogrel (2,797 out of 62,791 or 4.45%), prasugrel (119 out of 4,364 or 2.73%), and ticagrelor (144 out of 8.268 or 1.71%). DAPT with clopidogrel reported (2,453 out of 58,101, or 4.22%); prasugrel (162 out of 4,036, or 4.01%); and ticagrelor (195 out of 5,302 or 3.68%) cancer reports all on top of aspirin. We conclude that FAERS is currently unreliable for adequate assessment of cancer risks during DAPT. The retrieved evidence appears random and sporadic, while associated cancers are heavily underreported or/and missed. Without stricter rules, better surveillance, and enforcements, oncology outcome research options in FAERS are challenging.

Filing Sources after Oral P2Y12 Platelet Inhibitors to the Food and Drug Administration Adverse Event Reporting System (FAERS).

BACKGROUND: The US Food and Drug Administration Adverse Event Reporting System (FAERS) is a global passive surveillance database that relies on voluntary reporting by health care professionals and consumers as well as required mandatory reporting by pharmaceutical manufacturers. However, the initial filers and comparative patterns for oral P2Y12 platelet inhibitor reporting are unknown. We assessed who generated original FAERS reports for clopidogrel, prasugrel, and ticagrelor in 2015. METHODS: From the FAERS database we extracted and examined adverse event cases coreported with oral P2Y12 platelet inhibitors. All adverse event filing originating sources were dichotomized into consumers, lawyers, pharmacists, physicians, other health care professionals, and unknown. RESULTS: Overall, 2015 annual adverse events were more commonly coreported with clopidogrel (n = 13,234) with known source filers (n = 12,818, or 96.9%) than with prasugrel (2,896; 98.9% out of 2,927 cases) or ticagrelor (2,163, or 82.3%, out of 2,627 cases, respectively). Overall, most adverse events were filed by consumers (8,336, or 44.4%), followed by physicians (5,290, or 28.2%), other health care professionals (2,997, or 16.0%), pharmacists (1,125, or 6.0%), and finally by lawyers (129, or 0.7%). The origin of 811 (4.7%) initial reports remains unknown. The adverse event filing sources differ among drugs. While adverse events coreported with clopidogrel and prasugrel were commonly originated by patients (40.4 and 84.3%, respectively), most frequently ticagrelor reports (42.5%) were filed by physicians. CONCLUSION: The reporting quality and initial sources differ among oral P2Y12 platelet inhibitors in FAERS. The ticagrelor surveillance in 2015 was inadequate when compared to clopidogrel and prasugrel. Patients filed most adverse events for clopidogrel and prasugrel, while physicians originated most ticagrelor complaints. These differences justify stricter compliance control for ticagrelor manufacturers and may be attributed to the confusion of treating physicians with unexpected fatal, cardiac, and thrombotic adverse events linked to ticagrelor.