Download this article's Factoid (PDF & PPT for Gold Subscribers)

Electrocardiographic (ECG) assessment of patients with acute coronary syndromes (ACS) in the PLATO trial confirms that those receiving ticagrelor are more likely to experience ventricular pauses than those treated with clopidogrel. However, the arrhythmias typically do not result in adverse clinical events, according to a substudy published in the May 10, 2011, issue of the Journal of the American College of Cardiology.

In the main PLATO (Platelet Inhibition and Patient Outcomes) trial, 18,624 ACS patients with or without ST-segment elevation were randomized to the oral reversible P2Y12 antagonist ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300-600–mg loading dose, 75 mg daily thereafter). At 12 months, ticagrelor significantly reduced the primary endpoint, a composite of cardiovascular death, MI, or stroke (9.8% vs. 11.7% for the clopidogrel group; P < 0.001).

Because an ad hoc analysis from an earlier phase 2 dose-ranging study (DISPERSE-2) had uncovered an increase in ventricular pauses in patients receiving ticagrelor, the PLATO study built in prospective assessment of a group of patients who would undergo continuous ECG (Holter) monitoring.

Ventricular Pauses Mostly Early 

For the PLATO substudy, investigators led by Benjamin M. Scirica, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), analyzed 2,908 patients: 2,866 underwent baseline Holter monitoring for about 1 week (median 6.2 days) starting at randomization, 1,991 completed another week (median 6.8 days) of monitoring at 1 month, and 1,949 completed both rounds of ECG recordings.

There were no important differences between the ticagrelor and clopidogrel groups in baseline characteristics, index diagnosis, planned invasive therapy, or concomitant use of drugs that might adversely affect sinoatrial (SA) or atrioventricular (AV) node function.

During the first week after randomization, ventricular pauses of at least 3 seconds, the principal safety endpoint, occurred more frequently in the ticagrelor group than the clopidogrel group. This was due mainly to an excess of SA node pauses, as there was no difference in the incidence of AV node pauses. A similar pattern was seen for pauses lasting 5 seconds or longer, although in the longer duration only AV node pauses reached statistical significance (table 1).

Table 1. Arrhythmias During Week 1

Ventricular pauses lasting at least 3 seconds were most common in the first 48 hours for both drugs. During each 2-day interval evaluated over week 1, ticagrelor was associated with a greater numerical risk vs. clopidogrel.

In the 1-month assessment, the absolute rate of ventricular pauses was less than half that at week 1. Pauses of at least 3 and 5 seconds remained more common in the ticagrelor group than the clopidogrel group, but the differences were small and not significant.

Analysis of the cohort that completed both week 1 and 1-month monitoring showed that 28% of ticagrelor patients who had asymptomatic ventricular pauses lasting at least 3 seconds within the first week after randomization also experienced such pauses at 1 month, compared to 18% of clopidogrel patients who had week-1 pauses, although the difference was not significant (RR 1.56; 95% CI 0.63-5.06; P = 0.28). On the other hand, the risk of ventricular pauses of at least 3 seconds at 1 month in patients who experienced no pauses during week 1 was very low and similar for both treatment groups (0.6% for ticagrelor and 1.1% for clopidogrel; P = 0.28).

Interestingly, the largest relative excess of ventricular pauses in ticagrelor vs. clopidogrel patients was seen in those who experienced multiple pauses at both time points (1.4% vs. 0.4% at week 1 and 1.1% vs. 0.6% at 1 month). In addition, ventricular pauses tended to be more common at night, with a nocturnal peak more evident among patients receiving ticagrelor.

Pauses Without Consequences

Importantly, clinical bradycardic events were far less common than ventricular pauses. For example, during both ECG monitoring periods, syncope occurred in only 5 patients in the ticagrelor group and 2 in the clopidogrel group, while heart block was experienced by 6 ticagrelor patients and 15 clopidogrel patients.

Patients with at least 1 ventricular pause were more likely to experience a clinical arrhythmic event. But during the ECG monitoring periods, there was no difference in the incidence of adverse events of interest between the ticagrelor and clopidogrel groups (10.1% vs. 8.8% overall regardless of pauses; an identical 25.8% for those with a pause of 3 seconds or longer; and 31.3% vs. 40.0% for those with a pause of 5 seconds or longer).

To home in on any relationship between ventricular pauses and clinical events, the investigators also analyzed their timing, to see how frequently the electrical and clinical events occurred on the same day. The proportion of overlapping instances was similar for the ticagrelor and clopidogrel groups at 19.1% and 22.6%, respectively.

In addition, at week 1 there was no increased risk from use of ticagrelor vs. clopidogrel for either supraventricular tachyarrythmia (58.2% vs. 55.2%; RR 1.05; 95% CI 0.99-1.12) or ventricular tachyarrhythmia (36.0% vs. 35.5%; RR 1.01; 95% CI 0.92-1.12). Moreover, just as in the main study population, the substudy found that mortality was lower in the ticagrelor group compared with the clopidogrel group over the duration of the PLATO trial (2.4% vs. 3.9%; RR 0.63; 95% CI 0.41-0.94).

The Adenosine Angle

The authors suggest several potential mechanisms that might explain the link between ticagrelor and ventricular pauses. The most promising hypothesis, they say, centers on a so-called ‘off-target’ effect—one that is independent of platelet inhibition. Ticagrelor has been shown to interfere with adenosine reuptake, thereby increasing its concentration. Higher tissue levels of adenosine at the SA and AV nodes might promote bradycardic events, they write. Interestingly, adenosine has also been proposed to be cardioprotective during ischemia and may be responsible for some of ticagrelor’s overall benefit, the investigators observe.

In a telephone interview with TCTMD, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), said that the substudy “adds further important data to the ticagrelor story.”

Even though in PLATO ticagrelor was seen to reduce mortality, earlier phase 2 research had raised safety concerns regarding dyspnea and ventricular pauses, Dr. Bhatt noted, adding that “if there is a [potentially] bad side effect, you want to characterize it, and better to characterize it in a large, phase 3 trial.” Fortunately, with the current analysis “what might have been a really troublesome side effect turns out, with proper study, not to be a major issue,” he said.

Reassurance—But with Some Caveats

Like the authors, however, Dr. Bhatt cautioned against “extrapolating this documentation of safety beyond the type of patients who were enrolled in PLATO,” noting that those at increased risk for symptomatic bradycardia—for example, patients with sick sinus syndrome or high-grade AV conduction block—were excluded from the trial. “It would not be a good idea to use ticagrelor in those patients,” he said. “Going with clopidogrel or, depending on the situation, prasugrel, would be appropriate.

“If someone didn’t have a predisposition to bradycardia, and I noticed some occasional pauses after starting ticagrelor, the current data would reassure me,” Dr. Bhatt continued. “But even then I likely would have to do something further, because how do I know those pauses are due to ticagrelor and not some intrinsic conduction disease that the patient developed now that they’re 75, or now that they have just had a heart attack? So in practice this could be a little trickier than it was in a clinical trial.”

Dr. Bhatt said he believed that the ventricular pauses are “almost certainly due to adenosine-related mechanisms.” As for the opposite side of the coin, the issue of whether ticagrelor’s mortality benefit is attributable to more potent platelet inhibition or its effect on adenosine, or both, is “a huge scientific question,” he noted.

“If it’s [the adenosine effect] and we could capitalize on it to develop drugs that work specifically via that mechanism, that could be a major breakthrough,” Dr. Bhatt said. “But I don’t think we’ll be able to understand that just from the PLATO dataset.”

Finally, Dr. Bhatt commented that the substudy sets a good example for clinical trialists. “It shows that a careful ECG study can be successfully executed in the context of a large, phase 3 trial. A lot of people thought that would be logistically impossible.” When a new drug raises concerns about cardiovascular safety, incorporating Holter monitoring into a clinical trial can be very useful, he explained.

 

---

Source:
Scirica BM, Cannon CP, Emanuelsson H, et al. The incidence of bradyarrhythmias and clinical bradyarrhythmic events in patients with acute coronary syndromes treated with ticagrelor or clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) trial: Results of the Continuous Electrocardiographic Assessment substudy. J Am Coll Cardiol. 2011;57:1908-1916.

 

• Dr. Scirica reports receiving research grants from multiple pharmaceutical companies via the TIMI Study Group and Brigham and Women’s Hospital and serving as a consultant for AstraZeneca, Cogentus, CV Therapeutics, Gilead Sciences, Merck/Schering-Plough, Novartis Pharmaceuticals, and Shionogi.
• Dr. Bhatt reports receiving research grants from AstraZeneca, Bristol-Myers Squibb, Eisai, Sanofi-Aventis, and The Medicines Company.

 

Related Stories:

• Ticagrelor Shows More Rapid, Powerful Platelet Inhibition Than Clopidogrel
• Ticagrelor: Despite Dyspnea Risk, No Evidence of Cardiopulmonary Dysfunction
• PLATO Analysis: Ticagrelor Superior to Clopidogrel in STE ACS Patients