PRODIGY study: duration of dual antiplatelet therapy under review

The PRODIGY study enrolled patients with ACS (including non ST-segment elevation and ST-segment elevation myocardial infarction) or chronic stable coronary artery disease (74% and 26%, respectively) and followed them for 2 years after coronary stent insertion. All patients (about 2000) received clopidogrel and aspirin therapy for the first 30 days and were then randomised to receive an additional 5 or 23 months of clopidogrel therapy together with indefinite aspirin therapy. At entry the study also randomised patients to receive one of four types of coronary stents: bare-metal, paclitaxel-eluting, zotarolimus-eluting or everolimus-eluting.

Two years after stent insertion, clopidogrel therapy for 24 months compared with 6 months had no significant effect on cardiovascular outcomes but doubled rates of major bleeds and blood transfusions (Table 1).⁴

The PRODIGY study builds on findings from other studies that suggest there may be no benefit in continuing dual antiplatelet therapy beyond 12 months for people with drug-eluting stents.⁵ However, the PRODIGY study was not blinded (other than for outcome assessment) and not powered to rule out a small benefit with prolonged therapy (that is, not enough patients to discount an absolute difference in the primary outcome smaller than 3.5%).^4,6 In addition, the findings do not exclude the possibility that clopidogrel therapy for 12 months may have a more favourable balance of benefits and risks than stopping the drug at 6 months.⁷ Despite these uncertainties, the findings from the PRODIGY study indicate that there is an increased risk of a major bleed and possibly little benefit from indefinite dual antiplatelet therapy.

Reassess a person's ongoing need for dual antiplatelet therapy 12 months after insertion of a coronary stent. This should be done either by the patient's cardiologist or in consultation with them — do not discontinue antiplatelet therapy without first consulting the cardiologist.⁸ Risk factors for thrombotic events (e.g. the type, number and length of stents; diabetes; renal failure; left ventricular dysfunction) and risk factors for bleeding (e.g. recent history of bleeding, severe anaemia, renal insufficiency, age > 75 years, female sex, history of stroke or TIA) need to be assessed to determine if the balance of benefits and risks of continuing clopidogrel (or other P2Y₁₂ antagonist) is favourable for the individual.^3,8 Some guidelines recommend indefinite dual antiplatelet therapy for people at high risk of ischaemic events and low risk of bleeding⁸, although there is limited evidence to support this (see below).

In a subgroup analysis of the PRODIGY study, outcomes were similar, regardless of diabetes status, stent type, stability of cardiovascular disease, number of lesions or the complexity of lesions.⁴ However, the study was not powered to compare outcomes between people at low and high risk of ischaemic events and so does not rule out improved outcomes with prolonged dual antiplatelet treatment for people at high risk of ischaemic events, such as those with long stents, bifurcation stents, kidney disease or diabetes.

It is uncertain whether the findings of the PRODIGY study may apply to the newer P2Y₁₂ antagonists, prasugrel and ticagrelor, which are more potent inhibitors of platelet aggregation than clopidogrel. Prasugrel or ticagrelor in combination with aspirin are more effective than clopidogrel with aspirin in reducing ischaemic events in people with ACS at 14.5 months and 12 months, respectively*; however, they increase the risk of non-procedure-related bleeding, and less is known about the long-term safety and efficacy of these drugs. ^9,10 Prasugrel or ticagrelor are only recommended for people at low risk of bleeding (Table 2), so patient characteristics may differ from those in the PRODIGY study. See the NPS RADAR reviews on prasugrel and ticagrelor for more information about the place in therapy of these drugs.

* In key clinical trials, prasugrel was studied in people with ACS with or without ST-segment elevation who were scheduled for PCI¹⁰, while ticagrelor was studied in people with ACS with or without ST-segment elevation.⁹

In the PRODIGY study the type of stent made no difference to the overall findings. In addition, there was no difference in rates of late stenosis between the 24-month and 6-month treatment groups (2.6% and 2.9%^†, respectively; hazard ratio 1.07, 95% confidence interval 0.64 to 1.83).⁴ These findings are consistent with those of two studies (REAL-LATE and ZEST-LATE) that compared dual therapy (aspirin and clopidogrel) with aspirin monotherapy in people who had received a drug-eluting stent 12 months previously. In these studies involving about 2700 people in total, aspirin and clopidogrel treatment for 12–24 months was no more effective than aspirin monotherapy in reducing rates of myocardial infarction (MI) or cardiac death. ⁵

While these trials suggest that prolonged dual antiplatelet therapy may not protect people with drug-eluting stents from late stenosis, the findings should be regarded with caution. Current guidelines are informed by observational studies that suggest premature stopping of clopidogrel therapy may trigger MI and death, possibly due to late stent thrombosis among people with drug-eluting stents. ^11–13 Neither the PRODIGY study nor the LATE studies were blinded (other than assessment), which limits their reliability.

The results from a larger blinded study (> 15,000 people; the DAPT study) of dual antiplatelet therapy in people after coronary stent insertion are expected to be available in 2014.^7,14 This study will compare cardiovascular and bleeding outcomes at 12 months and 30 months in people with drug-eluting stents and receiving dual antiplatelet therapy (aspirin and clopidogrel or prasugrel), and should provide more conclusive evidence to support an optimal duration of therapy. ¹⁴

† Definite, probable or possible stent thrombosis

Current Australian guidelines recommend dual antiplatelet therapy for at least 12 months after PCI, including stent insertion for people with ST-segment-elevation MI (see Table 2).^3,15 These recommendations are based on earlier studies that compared 1 month with 9–12 months of clopidogrel therapy among people with non-ST-segment-elevation ACS (CURE study), and after elective PCI with insertion of bare-metal stents (CREDO study).^2,16 These studies had other differences in treatment protocols^‡, which may have biased findings in favour of longer treatment with dual antiplatelet agents. However, the results of the PRODIGY study give no cause to change the current recommendations.

‡ Clopidogrel versus placebo loading dose.