Inhibition of Platelet Aggregation After Coronary Stenting in Patients Receiving Oral Anticoagulation

Abstract

Background

Approximately 18% of patients with atrial fibrillation undergo a percutaneous coronary intervention (PCI) to treat coronary heart disease. Pharmacological anticoagulation in patients with atrial fibrillation and PCI involves a trade-off of potential ischemic and hemorrhagic complications.

Methods

This review is based on pertinent publications that were retrieved by a selective literature search, including current guidelines and recommendations.

Results

Dual antiplatelet therapy (DAPT) with acetylsalicylic acid (ASA) and a P2Y12 inhibitor protects against stent thrombosis, but not against thromboembolic stroke. In contrast, oral anticoagulation does provide effective prevention against stroke during atrial fibrillation. Combining DAPT with oral anticoagulation (triple therapy) over the long term, as has been recommended to date, carries an elevated risk of hemorrhage. In a randomized controlled trial, 44% of patients with atrial fibrillation receiving triple therapy sustained a hemorrhagic event, compared to 19.4% of patients receiving dual therapy. A meta-analysis has shown that clinically relevant hemorrhage is less common under combined treatment with one of the new oral anticoagulants (NOAC) and a single antiplatelet drug than under triple therapy including a vitamin K antagonist (hazard ratio, 0.56; 95% confidence interval 0.39; 0.80]), but no significant difference was found with respect to stent thrombosis, myocardial infarction, or overall mortality.

Conclusion

After coronary stent implantation, dual therapy with a NOAC and a P2Y12 inhibitor is recommended, subsequent to triple therapy given only during the peri-interventional period

Incidence.

Atrial fibrillation is the most common supraventricular arrhythmia. Approximately 18% of patients with atrial fibrillation have a coronary stent implanted.

Oral anticoagulants (OACs) are commonly prescribed drugs. In patients with atrial fibrillation they are used to prevent thromboembolic events.

Dual antiplatelet therapy (DAPT), consisting of acetylsalicylic acid (ASA) and a P2Y₁₂ inhibitor, is the basic short-term adjunctive drug therapy after implantation of a coronary stent to prevent the occurrence of stent thrombosis or myocardial (re)infarction. Approximately 34% of patients with atrial fibrillation have concomitant coronary artery disease, and 18% undergo percutaneous coronary intervention/coronary stent implantation (1). Combining these two therapeutic approaches, however—a practice known as triple therapy, and usually recommended in treatment guidelines until now—is associated with a significantly increased risk of bleeding. In one randomized controlled trial, 44.4% of patients on triple therapy had a bleeding event, versus 19.4% of patients on dual therapy with clopidogrel and a vitamin K antagonist (2). Accordingly, anticoagulation therapy after coronary intervention in a patient with concomitant atrial fibrillation is a tightrope walk between thrombotic and hemorrhagic complications. Finding the optimal anticoagulation therapy in patients with atrial fibrillation and stent implantation remains challenging and requires that the clinical situation (acute [ACS] or chronic coronary syndrome [CCS]), comorbidities, nature of the coronary stenosis to be treated, and other factors all be taken into account.

Antiplatelet therapy and oral anticoagulation.

Dual antiplatelet therapy (DAPT) provides protection against stent thrombosis, and oral anticoagulants (OACs) are protective against stroke related to atrial fibrillation. Triple therapy combines DAPT and an OAC. It is associated with a significantly increased risk of bleeding.

Methods

In preparation for this article, a selective literature search of German- and English-language publications was carried out on PubMed, for triple therapy in particular, as well as for relevant meta-analyses. The European guidelines on chronic coronary syndrome, myocardial revascularization, DAPT, and non-vitamin-K antagonists were also included. The revised version of the article also included the European guidelines on the management of patients with atrial fibrillation and acute non-ST-elevation coronary syndrome published in August 2020, as well as the guideline of the German College of General Practitioners and Family Physicians and the National Clinical Guideline on chronic coronary heart disease published by the German Medical Association.

Learning objectives

After reading this article, the reader should

• Be familiar with the active substances available for use for antiplatelet therapy after coronary stent implantation and for the prevention of thromboembolism in patients with atrial fibrillation.

• Be familiar with the basic options available for anticoagulation therapy after coronary stent implantation when oral anticoagulation is indicated.

• Know what special considerations apply in patients who are old or have impaired kidney function.

Oral anticoagulants in patients with atrial fibrillation

Approximately 2% of the general population in Europe suffers from atrial fibrillation, with incidence increasing markedly at older ages (3). The prevalence of atrial fibrillation is expected to increase significantly due to aging of the population, but also due to new technical diagnostic capabilities as well as to increased disease awareness (4).

Determining the risk of thromboembolism.

Thromboembolic risk in patients with atrial fibrillation is determined by the CHA₂DS₂-VASc score. Two or more points in men and three or more points in women indicate a need for long-term oral anticoagulation.

Atrial fibrillation is associated with an increased risk of thromboembolic complications such as myocardial infarction and stroke (5). Strokes that can be attributed to atrial fibrillation (approximately 20% of all strokes) are usually more severe and are associated with a poorer functional outcome (6). The risk of stroke is assessed by means of the CHA₂DS₂-VASc score (table 1). Long-term anticoagulation therapy is indicated for men scoring 2 or higher and for women scoring 3 or higher; it may even be considered when only one or two risk factors, respectively, are present (7). In prescribing OACs, the bleeding risk should be assessed in addition to the thromboembolic risk, and for this purpose the European atrial fibrillation guideline recommends using the HAS-BLED score (table 2) (7). However, an increased risk of bleeding (HAS-BLED score ≥3) should not prevent patients from being offered OACs. Instead, in such cases, modifiable risk factors should be addressed and close clinical follow-up planned. Because these two scores are based partly on the same predictors, medical anticoagulation therapy in patients with atrial fibrillation walks a tightrope between ischemic and hemorrhagic complications. Since the 1950s, OACs have taken the form of vitamin K antagonists (VKAs). As shown in the meta-analysis by Hart et al., these reduced the relative risk of stroke by 64% (2.7% absolute). Mortality was reduced by 26%. In a meta-analysis, antiplatelet drugs showed only a 22% relative risk reduction, corresponding to a 0.8% absolute reduction in the occurrence of stroke (8). DAPT also failed to demonstrate noninferiority to oral anticoagulation in preventing thromboembolic events or vascular death (annual rate 3.9% versus 5.6%, P = 0.0003) for the same rate of major bleeding (9).

Table 1. Estimating stroke risk using the CHA2DS2-VASc score.

C	Congestive heart failure	Clinical heart failure or objective evidence of moderate to severe left ventricular dysfunction	1 point
H	Hypertension	Resting blood pressure >140/90 mmHg or on antihypertensive medication	1 point
A2	Age ≥ 75 years		2 points
D	Diabetes mellitus	Fasting glucose >125 mg/dL (7 mmol/L) or on medication	1 point
S2	History of stroke/TIA/embolism		2 points
V	Vascular atherosclerotic disease (myocardial infarction or relevant CHD, PAOD, aortic plaque)		1 point
A	Age 65–74 years		1 point
Sc	Female sex (“sex category”)	More a risk modifier than a risk factor	1 point

Oral anticoagulation is recommended for patients with a CHA2DS2-VASc score of 2 points or more (for women, 3 points or more). It can be considered for patients with a score of 1 (or 2) and a low risk of bleeding (7).

CHD, coronary artery disease; PAD, peripheral arterial occlusive disease; TIA, transient ischemic attack

Table 2. Estimating bleeding risk using the HAS-BLED score*.

H	Hypertension	Uncontrolled arterial hypertension ≥ 160 mmHg systolic	1 point
A	Abnormal renal and liver function	Dialysis, renal transplant, creatinine >200 µmol/L	1 point
		Cirrhosis, bilirubin >2 × upper normal value, ASAT/ALAT/ALP >3 × upper normal value	1 point
S	Stroke	History of ischemic or hemorrhagic stroke	1 point
B	History of bleeding or predisposition to bleeding	History of major bleed or anemia or severe thrombocytopenia	1 point
L	Unstable/fluctuating INR values	TTR <60% in patients on vka therapy	1 point
E	Age >65 years (“elderly”)		1 point
D	Medication usage or alcohol consumption (“drugs”)	Concomitant use of antiplatelet agents or NSAIDs	1 point
		Excessive alcohol consumption	1 point

*A HAS-BLED score of 3 points or more is taken to indicate increased risk of bleeding. However, oral anticoagulation should not be withheld from these patients. Instead, modifiable risk factors should be adjusted and the patient should be monitored closely (7).

ASAT, aspartate aminotransferase; ALAT, alanine aminotransferase; ALP, alkaline phosphatase; NSAID, nonsteroidal anti-inflammatory drug; TTR, time in therapeutic range; VKA, vitamin K antagonist

Determining the risk of bleeding.

In the same patient population, the bleeding risk is determined by the HAS-BLED score. In a patient with a high risk (≥ 3 points), modifiable risk factors should be addressed and close clinical follow-up should be planned.

A meta-analysis of phase III clinical trials of all four non-vitamin K-dependent oral anticoagulants (NOACs) showed a significant 19% reduction (relative risk [RR] 0.81 [0.73; 0.91]; P <0.0001) in the rate of stroke or systemic embolism compared with the VKA warfarin. A mortality benefit (RR 0.90 [0.85; 0.95]; P = 0.0003) was also demonstrated for the NOACs, although with an increased rate of gastrointestinal bleeding (RR 1.25 [1.01; 1.55]; P = 0.04) (10). Major bleeding events were not significantly less frequent with NOACs (RR 0.86 [0.73; 1.00]; P = 0.06). No significant difference was shown in the incidence of ischemic stroke or myocardial infarction (10). A Danish observational study of 61 678 patients presents NOACs as a safe and effective alternative to the VKA warfarin. In this study, no significant difference was observed between the NOACs and the VKA with respect to ischemic stroke. The risk of death or any bleeding event or a major bleeding event was significantly lower in patients receiving apixaban or dabigatran than in those on VKA therapy (11). For patients with end-stage renal disease (ESRD), given sparse and conflicting data, the risk–benefit profile of VKA-based oral anticoagulation therapy is unclear. ESRD patients have been excluded from key NOAC trials. A retrospective analysis has shown that apixaban may have an advantage over warfarin (12). In Germany, all factor Xa inhibitors are not recommended for patients with a glomerular filtration rate (GFR) below 15 mL/min, and the thrombin inhibitor dabigatran is contraindicated when GFR is below 30 mL/min. In Europe, decisions to prescribe VKAs for patients with ESRD are made on an individual basis. According to North American guidelines, prescription of warfarin or apixaban can be considered in this patient group (class IIb recommendation: efficacy not supported by clear evidence) (13). The risk of bleeding while on oral anticoagulation therapy is clearly associated with age (14). In the previously mentioned meta-analysis of phase III trials of NOACs, a significant reduction in stroke or systemic embolic events was also shown for the age group of 75 years and older. In interaction testing, the bleed risk was shown to be independent of age (10). In patients in whom long-term OAC therapy is contraindicated, interventional left atrial appendage closure (LAAC) can be performed as an alternative. The 5-year data from the PREVAIL and PROTECT-AF trials show that, in patients with nonvalvular atrial fibrillation, LAAC with the Watchman occluder is associated with a reduction in stroke and systemic thromboembolism comparable to that achieved with warfarin (hazard ratio [HR] 0.96; P = 0.87), with an additional reduction in hemorrhagic stroke (HR 0.20; P = 0.002) and all-cause mortality (HR 0.73; P = 0.035) (15). In a recent comparison, LAAC was recently demonstrated to be noninferior to NOACs in respect of the primary composite outcome made up of thromboembolic and bleeding endpoints (16).

Comparison of NOACs with the VKA warfarin.

Compared with the vitamin K antagonist (VKA) warfarin, non-vitamin K-dependent oral anticoagulants (NOACs) are associated with a significantly reduced rate of stroke or systemic embolism but an increased rate of gastrointestinal bleeding.

Renal failure.

In Germany, all factor Xa inhibitors are not recommended in patients whose GFR is <15 mL/min. The thrombin inhibitor dabigatran is contraindicated from a GFR <30 mL/min.

Antiplatelet therapy after coronary stent implantation

It is estimated that every year approximately 1.4 to 2.2 million people in Europe have an indication for DAPT (17). Since coronary interventions and stent implantations began, postinterventional ischemic complications such as stent thrombosis or restenosis have jeopardized the long-term outcome of these procedures. DAPT with ASA and a P2Y₁₂ inhibitor (for example, clopidogrel) became the established gold standard of treatment (18, 19). DAPT reduced the combined primary endpoint made up of death, myocardial infarction, angiographic evidence of stent thrombosis, or renewed revascularization of the initial target lesion within 30 days, to 0.5% versus 3.6% with ASA monotherapy or 2.7% with combined ASA and warfarin (19). Newer P2Y₁₂ inhibitors (prasugrel, ticagrelor) promise more rapid, consistent, and potent platelet inhibition and are approved for DAPT in ACS treated by percutaneous coronary intervention (PCI). Ticagrelor can also be used in patients with ACS treated with coronary artery bypass graft surgery or for purely medical treatment of ACS. The use of ticagrelor in patients with CCS who have undergone elective PCI showed no advantage over the use of clopidogrel (20). DAPT with a new P2Y₁₂ inhibitor is recommended for 12 months after PCI in patients with ACS but no increased risk of bleeding (class I recommendation). If a high bleeding risk is anticipated, DAPT with ticagrelor or clopidogrel should be given for 6 months (17). In patients with non-ST-elevation myocardial infarction (NSTEMI), if the risk of bleeding is high or very high, DAPT with ASA and clopidogrel should be given for, respectively, 3 months or 1 month, followed by ASA or clopidogrel monotherapy (21). For noninterventional treatment of ACS in a patient without increased bleeding risk, DAPT for 12 months with ticagrelor or, if ticagrelor is contraindicated, with clopidogrel is recommended (17). If PCI is performed for CCS in a patient without increased risk of bleeding, 6 months of DAPT with clopidogrel is recommended. If the patient is at increased risk of life-threatening bleeding, the duration of DAPT can be reduced to between 3 months (class IIa recommendation) and 1 month (class IIb recommendation). Only in certain situations where there is a high risk of thromboembolism can the newer P2Y₁₂ inhibitors be considered for initial therapy even after PCI for CCS (22). A network meta-analysis recommends a short course (less than 6 months) of DAPT with clopidogrel after implantation of a drug-eluting stent, regardless of the patient’s clinical presentation, as this has been shown to have comparable safety and efficacy profiles to a 12-month course (23).

While age and prevalence of coronary heart disease (CHD) are positively correlated, the mortality rate after ACS increases sharply every 5 years after the age of 79 (24). At the same time, a lower prescription rate of cardiovascular drugs and a lower proportion (rate) of invasive treatment strategies have been demonstrated. Despite this, it has been shown that in particular elderly patients with ACS benefit from interventional therapy (25). In NSTEMI, interventional therapy in patients of advanced age (≥75 years) achieved an absolute risk reduction of 10.8% (10.8% versus 21.6%; P = 0.016) and a relative risk reduction of 56% in terms of death or recurrence of myocardial infarction within 6 months (26).

Components of DAPT.

DAPT consisting of acetylsalicylic acid (ASA) and a P2Y₁₂ inhibitor is the gold standard for prevention of postinterventional ischemic complications after coronary stent implantation.

Patients with CHD and atrial fibrillation

The combination of an OAC and an antiplatelet agent increases the risk of bleeding and should be avoided in patients with atrial fibrillation alone, without any other indication for antiplatelet therapy (27, 28). As part of a restricted (class IIb) recommendation, the European guideline on CCS published last year allows ASA or clopidogrel to be given in addition to OACs only in patients with a high risk of thromboembolism and no increased bleeding risk (22).

Since, as has already been mentioned, OACs do not give adequate protection against postinterventional ischemic complications after coronary stent implantation, and since, on the other hand, even DAPT has been shown to be comparatively ineffective in preventing thromboembolic events in patients with atrial fibrillation, a combination of both these approaches to anticoagulation therapy is required. Because of the significantly increased risk of bleeding associated with this kind of triple therapy, in recent years clinical research has focused on the search for an optimized anticoagulant therapy. Table 3 and eTable 1 give an overview of randomized trials of triple therapy.

Table 3. Main features of studies on VKA-based triple therapy.

	PIONEER-AF-PCI (31)			RE-DUAL-PCI (32)			AUGUSTUS (34)			ENTRUST-AF-PCI (33)
Treatment regimen	VKA + clopi. 1 × 75 mg + ASA 1 × 75 –100 mg*1	Riva. 1 × 15 mg + clopi. 1 × 75 mg	Riva. 2 × 2,5 mg + clopi. 1 × 75 mg  +  ASA 1 × 75–100 mg*2	VKA + clopi. 1 × 75 mg + ASA ≤ 100 mg*3	Dabi. 2 × 150 mg + clopi. 1 × 75 mg	Dabi. 2 × 110 mg + clopi. 1 × 75 mg*4	VKA + clopi. 1 × 75 mg + ASA (81 mg) / placebo		Apixa 2 × 5 mg + clopi. 1 × 75 mg + ASA (81 mg) / placebo	VKA + clopi. 1 × 75 mg + ASA 1 × 100 mg*5	Edox. 1 × 60 mg + clopi. 1 × 75 mg
No. of patients randomized	2124			2725			4614			1506
Dose reduction	Riva. 1 × 10 mg ifi GFR <50 ml/min			None			Apixa. 2 × 2.5 mg if at least 2 of 3 apply: age ≥ 80 years, BW < 60 kg, serum creatinine ≥ 133 µmol/l			Edox. 1 × 30 mg if GFR <50 ml/min, bw ≤ 60 kg, or p-gp inhib.
GFR exclusion	<30 ml/min			<30 ml/min			<30 ml/min			<15 ml/min
Duration of triple ther.	1, 6, or 12 months			3 months if DES			6 months			1–12 months
Study design	Open-label with blinded determination of endpoints						Open-label VKA/apixa. + double-blind ASA/placebo			Open-label with blinded determination of endpoints
Follow-up	12 months			14 months			6 months			12 months
CHADS- VASc score	79.2% ≥ 3	73.3% ≥ 3	76.3% ≥ 3	3.8	3.3	3.7	4 (median)			4 (median)
HAS-BLED score	70.5% ≥ 3	72.4% ≥ 3	67.9% ≥ 3	2.8	2.6	2.7	3 (median)			3 (median)
PCI with ACS/CCS/non-PCI ACS	No data			50.5/49.5/–			37.3/38.8/23.9			51.7/48.3/–
Bleeding endpoint	Major or minor bleeds according to TIMI classification or bleeds requiring treatment			Major bleeds or clinically significant nonmajor bleeds			Major and clinically significant bleeds after 6 months’ treatment			ISTH-defined major or clinically significant nonmajor bleeds; data annualized
Incidence of bleed events	26.70%	16.8%*6	18%*6	26.9% dabi. 110	20.2%*7	15.4%*7	Apixa. vs. VKA	10.5%*8	14.70%	25.60%	20.70%
				25.7% dabi. 150			ASA vs. placebo	16.1%*8	9.00%
Composite efficacy endpoint	Cardiovascular death, myocardial infarction, stroke			Thrombembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization combined for both dosages			Death or ischemic event (myocardial infarction, confirmed or probable stent thrombosis, stroke, urgent revascularization)			Cardiovascular death, stroke, systemic embolism, myocardial infarction, and confirmed stent thrombosis; annualized
Efficacy rate	6.00%	6.50%	5.60%	13.40%	13.7% (dabi. 110 and 150 combined)		Apixa. vs. VKA	6.70%	7.10%	6.90%	7.30%
							ASA vs. placebo	6.50%	7.30%

Apixa; apixaban; ASA, acetylsalicylic acid; clopi., clopidogrel; dabi., dabigatran; edox., edoxaban; riva., rivaroxaban; triple ther., triple therapy (with VKA, ASA, and P2Y12 inhibitor, mainly clopidogrel)

ACS, acute coronary syndrome; BW, body weight; CCS, chronic coronary syndrome; DES, drug-eluting stent; GFR, glomerular filtration rate; ISTH, International Society on Thrombosis and Haemostasis; PCI, percutaneous coronary intervention; P-gp inhib., P-glycoprotein inhibitor; TIMI, Thrombolysis in Myocardial Infarction; VKA, vitamin K antagonist; vs., versus

*¹ Triple therapy for 1, 6, or 12 months, prespecified. Patients on the 1– and 6-month therapy durations subsequently received VKA and ASA 1 × 75–100 mg for the remainder of the 12 months.

*² The duration of the triple therapy comprising the lowest dose of rivaroxaban was 1, 6 or 12 month, prespecified. Patients on the 1– and 6-month therapy durations subsequently received rivaroxaban 1 × 15 mg (1 × 10 mg if GFR < 50 mL/min) and low-dose ASA (1 × 75–100 mg) for the remainder of the 12 months.

*³ Triple therapy for 1 month with bare metal stent / 3 months with drug-eluting stent, followed by dual therapy with VKA and P2Y 12 inhibitor.

*⁴ Outside the United States, patients ≥ 80 years (or, in Japan, ≥ 70 years) were randomized to dual therapy with 110 mg dabigatran or triple therapy.

*⁵ ASA 1 × 100 mg for 1–12 months depending on clinical presentation (ACS or CCS), CHADS-VASc, and HAS-BLED score.

*⁶ Significant compared with triple therapy (two-sided 95% confidence interval).

*⁷ Significant compared with triple therapy (noninferiority limit of 1.38 for the upper limit of the 95% confidence interval).

*⁸ Significant. Special study design to test two independent hypotheses (two-sided 95% confidence interval); significance data taken from original publications.

eTable 1a. Expanded overview of studies of VKA-based triple therapy.

	WOEST study (29)		ISAR-TRIPLE (30)		PIONEER-AF-PCI (31)
Treatment regimen	VKA + Clopi. 1 × 75 mg		Triple ther. with ASA und VKA +		VKA +	Riva. 1 × 15 mg +	Riva. 2 × 2.5 mg +
					Clopi. 1 × 75 mg +	Clopi. 1 × 75 mg	Clopi. 1 × 75 mg +
	ASA 80–100 mg	Placebo	6 weeks clopi.	6 months clopi.	ASA 1 × 75–100 mg		ASA 1 × 75–100 mg
	Indication for oral anticoagulation: atrial fibrillation (69%), mechanical valve prosthesis (11%), other (30%)						After termination of prespecified triple ther., riva. 1 × 15 mg + low-dose ASA until the end of the 12th month
No. of patients randomized	573		614		2 124
Dose reduction	None		None			Riva. 1 × 10 mg if GFR <50 ml/min
GFR exclusion			None			<30 ml/min	<30 ml/min
Time to randomization	Up to 4 h after PCI		No stated		3 days
Duration of triple ther.	12 months (66.5% of patients with triple ther. had ASA after 12 months)		6 weeks vs. 6 months		1, 6, or 12 months
Study design	Open		Open		Open
Follow-up	12 months		9 months		12 months
CHADS-࿬VASc score	Not reported		95.3% >2	92.7% >2	3.7 ± 1.6
HAS-BLED score	Not reported		Not reported		3.0 ± 0.9
PCI with ACS/CCS/non-PCI ACS	30% ACS	25% ACS	33.2% ACS	30.9% ACS	N/STEMI: 17.8%/10.7%; 18.5%/12.3%; 18.3%/13.8%
Other P2Y12 inhibitors apart from clopidogrel,%			0		3.7	6.9	6.4
TTR	Not reported		Not reported		65%
Bleeding endpoint	Any bleeds		Secondary bleeding endpoint: major bleeds (TIMI classification)		Major or minor bleeds (TIMI classification) or bleeds requiring treatment
	44.4%	19.4%	5.3%	4%	26.7%	16.8%	18%
Major bleeds (TIMI)
	5.6%	3.2%	5.3%	4%	3.3%	2.1%	1.9%
Composite efficacy endpoint	Death, stroke, myocardial infarction, stent thrombosis, target vessel revascularization		Secondary composite ischemia endpoint made up of cardiac death, myocardial infarction, definitive stent thrombosis, and ischemic stroke		Cardiovascular death, myocardial infarction, stroke
	17.6%	11.1%	4%	4.3%	6%	6.5%	5.6%
Myocardial infarction	4.6%	3.2%	2%	0%	3.5%	3%	2.7%
Overall mortality	6.3%	2.5%	4%	5.2%	3.2%	2.9%	3.1%

ACS, acute coronary syndrome; ASA, acetylsalicylic acid; BMS, bare metal stent; CCS, chronic coronary syndrome; clopi., clopidogrel; GFR, glomerular filtration rate; PCI, percutaneous coronary intervention; riva., rivaroxaban; STEMI, ST-elevation myocardial infarction; triple ther., triple therapy (with VKA, ASA, and P2Y12 inhibitors, mainly clopidogrel); TTR, time [of INR] in therapeutic range; VKA, vitamin K antagonist.

The WOEST study was groundbreaking. It showed for the first time that treatment with a VKA and clopidogrel without ASA resulted in significantly fewer bleeding events than combination therapy with ASA, and without increasing the incidence of ischemic events. Limitations of this study were the heterogeneity of its patient population (only 69% of participants received ASA because of atrial fibrillation), the unusually long duration of the triple therapy (12 months), the open-label design, and the small number of patients (29).

The ISAR-TRIPLE study, by contrast, compared just 6 weeks of triple therapy with the then standard of 6 months. It found no significant differences in thrombotic events or bleeding rates. Patients on NOACs were not included in the study (30).

DAPT in patients with CCS or ACS.

After stent implantation for chronic coronary syndrome (CCS), the P2Y₁₂ inhibitor clopidogrel is usually prescribed; for patients with acute coronary syndrome (ACS), prasugrel or ticagrelor is prescribed.

The PIONEER-AF-PCI trial (31), which trialed two dose-reduced regimens of rivaroxaban that are not approved for thromboembolism prophylaxis in patients with atrial fibrillation, or are approved only for patients with impaired renal function, showed—like the RE-DUAL-PCI trial (32), which studied two standard doses of dabigatran—significantly fewer bleeding events in patients on those regimens than in the triple therapy study arm; PIONEER-AF-PCI: 16.8% in group 1 [rivaroxaban 1 × 15 mg + P2Y₁₂ inhibitor], 18.0% in group 2 [rivaroxaban 2 × 2.5 mg + P2Y₁₂ inhibitor + ASA 1 × 75–100 mg], and 26.7% in group 3 [VKA + P2Y₁₂ inhibitor + 1 × ASA 75–100 mg]; HR for group 1 versus 3, 0.59 [0.47; 0.76]; P <0.001; HR for group 2 versus group 3, 0.63 [0.50; 0.80]; P <0.001; RE-DUAL-PCI: 15.4% in the dual therapy arm with 2 × 110 mg dabigatran + P2Y₁₂ inhibitor versus 26.9% in the VKA-based triple therapy group (HR 0.52 [0.42; 0.63]; P<0.001 for noninferiority as well as for superiority) and 20.2% in the dual therapy arm with 2 × 150 mg versus 25.7% in the corresponding triple therapy arm, which did not include patients over 80 years of age outside the United States (HR 0.72 [0.58; 0.88]; P<0.001 for noninferiority). No significant difference in thrombotic events was shown.

In the ENTRUST-AF-PCI trial, noninferiority was demonstrated for standard-dose edoxaban in comparison with VKA-based triple therapy with respect to major and clinically relevant nonmajor bleeding events (20.7% in the dual therapy arm receiving edoxaban + P2Y₁₂ inhibitor versus 25.6% in the VKA-based triple therapy group (HR 0.83 [0.65; 1.05]; P = 0.001 for noninferiority, P = 0.1154 for superiority [data annualized]) (33).

The AUGUSTUS trial, which had the special design of randomizing patients first to receive a VKA or apixaban and then to receive ASA or placebo—each in addition to a P2Y₁₂ inhibitor—showed that the antithrombotic regimen consisting of apixaban and a P2Y₁₂ inhibitor (mainly clopidogrel) had the lowest bleeding rates in comparison with regimens containing a VKA, ASA, or both. The additional administration of ASA did not influence secondary study endpoints (death, hospitalizations, ischemic events) (34).

All studies agreed in showing lower absolute numbers of thromboembolic events in patients receiving triple therapy with VKA, but too few patients were included for significance to be shown. In absolute numbers major bleeding events were reduced by 1% to 2% in patients on NOAC-based therapy. In formal terms, the VKA-based triple therapy groups in the last-mentioned studies (31– 34) were overdosed, having a reported target INR of 2–3 compared with the target range of 2–2.5 recommended by guidelines (7, 17, 22, 35).

Bleeding events during dual therapy.

Compared with triple therapy, dual therapy with a VKA and clopidogrel reduces clinically significant bleeding events. Dual therapy with a NOAC and clopidogrel results in the same number of or fewer major bleeding events.

A recently published meta-analysis of the four last-mentioned trials, which also included new data from the AUGUSTUS trial comparing a NOAC and single antiplatelet therapy to VKA-based triple therapy, found no significant difference in terms of stent thrombosis (HR 1.38 [0.86; 2.20]), myocardial infarction (HR 1.18 [0.92; 1.52]), and all-cause mortality (HR 1.07 [0.87; 1.33]), with a 44% reduction in clinically significant bleeding (HR 0.56 [0.39; 0.80]). According to this evaluation, 3 stent thromboses are caused for every 58 clinically significant bleeding events prevented (36).

In our opinion, the risk of stent thrombosis in patients receiving dual therapy has not been conclusively determined, because the above-mentioned studies were designed to investigate bleeding events, not thromboembolic events. To answer this question would require studies in an even larger patient population. Since this is not a realistic prospect, prescribing antithrombotic therapy for patients who have undergone PCI and have concomitant atrial fibrillation, and in whom oral anticoagulation is indicated, is a decision that should be adapted to both the thromboembolic and the bleeding risk of each individual patient on the basis of current guidelines. Any existing risk factors for the development of stent thrombosis should also be taken into account. In addition to complex coronary lesions, these would include reduced left ventricular function, malignant disease, peripheral arterial occlusive disease, thrombocytosis, diabetes mellitus, and smoking (37).

It should be further noted that even patients in the dual NOAC therapy arms received triple therapy initially, during cardiac catheterization and until randomization. Only a negligible proportion of patients had dual antiplatelet therapy with prasugrel or ticagrelor. Accordingly, the data are inadequate with regard to triple therapy with these substances and it is not recommended (22).

Recommendations for antithrombotic therapy after coronary stent implantation

Thromboembolic events during dual therapy.

The studies were not designed to detect differences relating to thromboembolic events (patient numbers too low).

For patients in whom OAC therapy is indicated, periprocedural administration of ASA and clopidogrel is recommended, and in the absence of contraindications a NOAC is preferable to a VKA. If VKA therapy is indicated, during combination therapy the time spent in the therapeutic range (INR 2–2.5) should be as high as possible (>70%) (22, 38). The recently published ESC guidelines on acute non-ST-elevation coronary syndrome and on atrial fibrillation recommend a maximum of 1 week of triple therapy. When the patient is discharged from hospital, this should be switched to a dual therapy consisting of an OAC (preferably a NOAC) and a P2Y₁₂ inhibitor (preferably clopidogrel) for a total of 12 months (class I recommendation). Only if the patient’s thromboembolic risk is high the triple therapy should be extended to up to 1 month. If, on the other hand, bleeding risk predominates, the duration of dual therapy can be reduced from 12 to 6 months (class IIa recommendation). After that, oral anticoagulation alone is sufficient (figure).

Figure.

Triple therapy in patients with atrial fibrillation after PCI/stent implantation.

As an alternative to peri-interventional continuous VKA administration, VKA can be stopped before the intervention and switched for a NOAC after the intervention. This should be considered especially for patients whose recorded INR (“international normalized ratio”) shows a time in the target range of less than 70% (TTR <70%). In patients with ACS treated with medication alone, an antiplatelet agent should be given in combination with an OAC. Treatment with apixaban 2 × 5 mg and clopidogrel for 6 months may be considered.

* Or until discharge from hospital

Dose reduction criteria:

Apixaban (standard: 2 × 5 mg/day): dose reduction to 2 × 2.5 mg in patients with GFR between 15 and 30 mL/min or with 2 of the following 3 criteria: age ≥ 80 years, body weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL [133 µmol/L].

Dabigatran (standard: 2 × 150 mg/day): dose reduction to 2 × 110 mg recommended in patients aged ≥ 80 years or with concomitant verapamil use. Dose reduction should be considered in patients aged 75–80 years or with GFR 30–50 mL/min, known gastritis, esophagitis, or gastroesophageal reflux, or increased bleeding risk from any other cause.

Edoxaban (standard: 1 × 60 mg/day): dose reduction to 1 × 30 mg/day in patients with GFR between 15 and 50 mL/min, or body weight ≤ 60 kg, or concomitant use of the following P-glycoprotein inhibitors: ciclosporin, dronedarone, erythromycin, or ketoconazole.

Rivaroxaban: (standard: 1 × 20 mg): dose reduction to 1 × 15 mg in patients with GFR between 15 and 50 mL/min. Warning: The rivaroxaban dose of 1 × 20 mg recommended in guidelines has not been tested in a randomized trial for use in dual or triple therapy.

ACS, acute coronary syndrome; ASA, acetylsalicylic acid; CCS, chronic coronary syndrome; CHD, coronary heart disease; CTO, chronic total occlusion of a coronary vessel; GFR, glomular filtration rate; NOAC, nonvitamin-K-dependent oral anticoagulant; OAC, oral anticoagulant; PPI, proton pump inhibitor;

P2Y₁₂, P2Y₁₂ inhibitor, usually clopidogrel; STEMI, ST-elevation myocardial infarction; VKA, vitamin-K-dependent oral anticoagulant.

Meta-analysis.

A meta-analysis of the four NOAC trials found a net benefit of NOAC-based dual therapy.

Recommendations.

In the absence of contraindications, if platelet therapy is also required, a NOAC should be preferred to a VKA. After coronary stent implantation, triple therapy for a maximum of 1 week is usually recommended.

The German National Clinical Guideline on chronic CHD remains vague in its recommendations. If OAC therapy is indicated, “after elective stent implantation, dual therapy with an OAC and an antiplatelet agent is recommended,” and triple therapy “for the shortest time possible should be considered for a few individual patients at high ischemic risk” (28). We regard as outdated the recommendation of the German College of General Practitioners and Family Physicians for standardized 6-month triple therapy for patients with ACS treated with PCI (35). Patients suitable to take NOACs should be given them at the maximum approved dose in combination with antiplatelet therapy (class I recommendation) (22). Why this recommendation has been made for rivaroxaben, as well, which has been tested onlyat a dose that is subtherapeutic for stroke prevention, as part of a dual therapy approach, is unclear on the basis of the available data. As a class IIa recommendation, supplemental prescription of the reduced dose of rivaroxaban (1 × 15 mg) or dabigatran (2 × 110 mg) is recommended if the bleeding risk exceeds the risk of thromboembolism.

When prescribing triple therapy, it should always be borne in mind that, according to data from the AUGUSTUS study, a comparatively small absolute reduction of 0.4% in stent thromboses is paid for with an absolute increase of 7.1% in clinically significant bleeding (39). The authors of that study further state that 328 patients would need to be treated with triple therapy to prevent one stent thrombosis event, but a major or minor bleeding event occurs when only 10 patients have been so treated (28). Thus, to evaluate the net clinical benefit, the risk of thromboembolic complications must be taken into account alongside that of bleeding complications.

Recent data indicate that the benefit of PCI in patients with CCS is doubtful and not associated with an improved prognosis, at least in those without moderate or severe ischemia (40, e1). Nevertheless, both greater symptomatic improvement and an improved quality of life have been demonstrated after coronary intervention as compared with medical treatment alone (e2). Therefore, in this situation, even stricter patient selection for PCI is required among patients with atrial fibrillation in whom OAC therapy is indicated, including taking into account the subsequent requirement for combined antiplatelet and anticoagulation therapy.

NOAC-based dual or triple therapy.

For NOAC-based dual or triple therapy, the NOAC should be prescribed at the maximum approved dosage for thromboembolism prevention in patients with atrial fibrillation (warning: rivaroxaban was tested at a subtherapeutic dose).

To reduce bleeding events, all patients receiving DAPT, dual or triple therapy should also have prophylactic administration of a proton pump inhibitor (e3). Recommendations for the perioperative use of oral anticoagulants and antiplatelet agents will be found in the eFigure.

Stent implantation in patients with CCS in whom OACs are indicated.

In patients with CCS and atrial fibrillation who require OACs, coronary stent implantation requires very careful patient selection according to strict criteria.

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Only one answer is possible per question. Please select the answer that is most appropriate.

Question 1

What proportion of patients with atrial fibrillation have concomitant coronary artery disease?

a) 8%; b) 18%; c) 34%; d) 44%; e) 54%

Question 2

Which patients with atrial fibrillation should receive anticoagulation therapy?

1. Only patients whose CHA₂DS₂-VASc score is ≥ 3.

2. Only patients who have had a previous thromboembolic event such as TIA, stroke, or systemic embolism.

3. All patients whose CHA₂DS₂-VASc score is greater than their HAS-BLED score.

4. In men, anticoagulation therapy should be considered in the presence of just one risk factor in the CHA₂DS₂-VASc score.

5. All patients with atrial fibrillation should receive anticoagulation therapy. The CHA₂DS₂-VASc score is only relevant for treatment decisions relating to bridging.

Question 3

What are the risks to weigh up when prescribing new oral anticoagulants (NOACs) versus vitamin K antagonists (VKA)?

1. NOACs can increase blood pressure, whereas VKAs increase the risk of arrhythmias.

2. Most NOACs are associated with lower rates of stroke and systemic embolism than VKAs, but with more gastrointestinal bleeds.

3. VKAs are associated with lower rates of stroke but with more gastrointestinal bleeds than NOACs.

4. VKAs reduce the glomerular filtration rate and thus often lead to renal failure, whereas NOACs are frequently associated with arrhythmias.

5. In patients with diabetes, VKAs may impair liver function, whereas NOACs increase insulin resistance.

Question 4

What is the lowest HAS-BLED score that indicates an increased risk of bleeding?

a) 0.5 points; b) 1 point; c) 1.5 points; d) 2 points; e) 3 points or more

Question 5

What is the usual recommendation for antithrombotic therapy after coronary stent implantation in a patient with atrial fibrillation and a history of myocardial infarction?

1. Triple therapy for a maximum of 1 week, switching on discharge from hospital to dual therapy with oral anticoagulant and clopidogrel for 12 months.

2. Triple therapy for at least 2 weeks, followed by either continued triple therapy or else clopidogrel and ASA.

3. A single bolus of a NOAC and clopidogrel immediately after the intervention; dual therapy with the same NOAC and ASA after hospital discharge.

4. Triple therapy initiated no later than 24 hours after the intervention and continued for 6–12 months.

5. Clopidogrel and ASA for 2 weeks, with the addition of at least one NOAC on discharge from hospital

Question 6

Which anticoagulant was shown in the ENTRUST-AF PCI trial to be noninferior to VKA-based triple therapy in terms of major and clinically significant nonmajor bleeds?

a) Dabigatran; b) edoxaban; c) rivaroxaban; d) apixaban; e) clopidogrel

Question 7

According to a recently published meta-analysis, how many stent thromboses are caused for every 58 clinically significant bleed events prevented?

a) 1; b) 3; c) 5; d) 7; e) 9

Question 8

Under which of these conditions should a patient on anticoagulation therapy be given a proton pump inhibitor?

1. Patient is on ASA monotherapy

2. Patient is on clopidogrel monotherapy

3. Patient has a gastric band

4. Patient is over 65 years of age

5. Patient is on dual or triple therapy

Question 9

Which treatment regimen is recommended with a high level of evidence in a patient who has undergone percutaneous coronary intervention for acute coronary syndrome?

1. Antiplatelet therapy with ASA and a proton pump inhibitor for 6 months

2. Combination of warfarin with a NOAC for 12 months

3. Dual antiplatelet therapy with a new P2Y₁₂ inhibitor for 12 months

4. Dual antiplatelet therapy with active agents of choice for at least 3 months

5. Prasugrel and ticagrelor therapy for 6 months

Question 10

What does the abbreviation CHA₂DS₂-VASC stand for?

1. Congestive heart failure, hypertension, age, diabetes mellitus, stroke, vascular atherosclerotic disease, age, sex category

2. Cardiac intervention, hypotension, arteriosclerosis, dysrhythmia, sinus venous thrombosis, vascular dementia, aortic insufficiency, bronchial asthma, schizophrenia

3. Compensatory therapy, hyperlipidemia, Adams-Stokes disease, dyspnea, spongioencephalitis, vasospasm, amyotrophic lateral sclerosis, streptococci

4. Congenital disorder, hemophilia, acrohyperhidrosis, dysproteinemia, sinus tachycardia, ventricular septal defect, arterial hypotension, stress fracture

5. Consultation, hemolysis, Addison‘s disease, deafness, saccular aneurysm, valsalva maneuver, arterial occlusive disease, sickle cell anemia

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eTable 1b. Expanded overview of studies of VKA-based triple therapy.

	RE-DUAL-PCI (32)			AUGUSTUS (34)
Treatment regimen	VKA +	Dabi. 2 × 150 mg +	Dabi. 2 × 110 mg +	VKA +		Apixa. 2 × 5 mg +
	Clopi. 1 × 75 mg +	Clopi. 1 × 75 mg	Clopi. 1 × 75 mg	Clopi. 1 × 75 mg +		Clopi. 1 × 75 mg +
	ASA ≤ 100 ng			ASA (81 mg) / placebo		ASA (81 mg) / placebo
			Outside the United States, patients ≥ 80 years (or, in Japan, ≥ 70 years) were randomized to triple therapy or dabi. 2 × 110 mg			Placebo (patients treated with P2Y12 inhibitors were randomized to, (1) VKA or apixa., (2) ASA or placebo)
No. of patients randomized	2725			4614
Dose reduction		None	None			Apixa. 2 × 2.5 mg if at least 2 of 3 apply: age ≥ 80 years, BW < 60 kg, serum creatinine ≥ 133 µmol/l
GFR exclusion		<30 ml/min	<30 ml/min		<30 ml/min
Time to randomization	5 days			Within 14 days (median 6 days)
Duration of triple ther.	1 month if BMS, 3 months if DES			6 months
Study design	Open-label with blinded determination of endpoints			Open-label VKA/apixa. + double-blind ASA/placebo
Follow-up	14 months			6 months
CHADS-࿬VASc score	3.7 ± 1.5			3.9 ± 1.6
HAS-BLED score	2.7 ± 0.7			2.9 ± 0.9
PCI with ACS/CCS/non-PCI ACS	50.5/49.5/-			37.3/38.8/23.9
Other P2Y12 inhibitors apart from clopidogrel, %	9.7	13.1	13.6	Overall 7.4
TTR	64%			59%
Bleeding endpoint	Major or clinically significant no-nmajor bleeds			Major and clinically significant bleeds after 6 months of treatment
	26.9% dabi. 110	20.20%	15.40%	Apixa. vs. VKA	10.50%	14.70%
	25.7% dabi. 150			ASA vs. Placebo	16.10%	9.00%
Major bleeds (TIMI)	3.8% dabi. 110			Apixa. vs. VKA	1.70%	2.10%
	3.9% dabi. 150	2.10%	1.40%	ASA vs. placebo	2.40%	1.30%
Composite efficacy endpoint	Thrombembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization combined for both dosages			Death or ischemic event (myocardial infarction, confirmed or probable stent thrombosis, stroke, urgent revascularization)
	13.40%	13.70%		Apixa. vs. VKA	6.70%	7.10%
				ASA vs. placebo	6.50%	7.30%
Myocardial infarction	3.0% dabi. 110			Apixa. vs. VKA	3.10%	3.50%
	2.9% dabi. 150	3.40%	4.50%	ASA vs. placebo	2.90%	3.60%
Overall mortality	4.9% dabi. 110			Apixa. vs. VKA	3.30%	3.20%
	4.6% dabi. 150	3.90%	5.60%	ASA vs. placebo	3.10%	3.40%

ACS, acute coronary syndrome; ASA, acetylsalicylic acid; BMS, bare metal stent; BW, body weight; CCS, chronic coronary syndrome; clopi., clopidogrel; dabi., dabigatran; DES, drug-eluting stent; GFR, glomerular filtration rate; PCI, percutaneous coronary intervention; triple ther., triple therapy (with VKA, ASA, and P2Y12 inhibitors, mainly clopidogrel); TTR, time [of INR] in therapeutic range; VKA, vitamin K antagonist

eTable 1c. Expanded overview of studies of VKA-based triple therapy.

	ENTRUST-AF-PCI (33)
Treatment regimen	VKA +	Edox. 1 × 60 mg
	Clopi. 1 × 75 mg +
	ASA 1 × 100 mg
No. of patients randomized	1 506
Dose reduction		Edox. 1 × 30 mg if GFR <50 ml/min, bw ≤ 60 kg, or p-gp inhib.
GFR exclusion		<15 ml/min.
Time to randomization	Within 5 days (median 45 hours)
Duration of triple ther.	1 – 12 months
Study design	Open-label with blinded determination of endpoints
Follow-up	12 months
CHADS-࿬VASc score	4 (median)
HAS-BLED score	3 (median)
PCI with ACS/CCS/non-PCI ACS	51.7/48.3/–
Other P2Y12 inhibitors apart from clopidogrel, %	7.9	7.2
TTR	Not reported
Bleeding endpoint	ISTH-defined major or clinically significant nonmajor bleeds; data annualized
	26%	20.7%
Major bleeds (TIMI)
	3.18%	2%
Composite efficacy endpoint	Cardiovascular death, stroke, systemic embolism, myocardial infarction, and confirmed stent thrombosis; annualized
	6,90%	7,30%
Myocardial infarction	No data available
Overall mortality	No data available

ACS, acute coronary syndrome; ASA, acetylsalicylic acid; BW, body weight; CCS, chronic coronary syndrome; clopi., clopidogrel; edox., edoxaban; GFR, glomerular filtration rate; PCI, percutaneous coronary intervention; P-gp inhib., P-glycoprotein inhibitor; triple ther., triple therapy (with VKA, ASA, and P2Y₁₂ inhibitors, mainly clopidogrel);

TTR, time [of INR] in therapeutic range; VKA, vitamin K antagonist