The Dual Antiplatelet Therapy Trial after the FDA Update: Noncardiovascular Deaths, Cancer and Optimal Treatment Duration

Abstract

Background: The landmark Dual Antiplatelet Therapy (DAPT) trial revealed an impressive reduction of stent thrombosis and myocardial infarction after prolonged 30-month DAPT compared to the conventional 12-month regimen. However, aside from the expected extra bleeding risks, more cancers and noncardiovascular deaths (NCVD) were observed in the 30-month DAPT arm. Objective: We aimed to comprehend the totality of DAPT trial evidence in the light of the FDA medical review. Results: A significant excess of solid cancers that was picked up after prasugrel treatment in the TRITON trial (Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes) and later observed with vorapaxar treatment in the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) has now been confirmed by the FDA DAPT review for 30-month therapy with prasugrel [hazard ratio (HR) 1.3] and clopidogrel (HR 1.2). The latest randomized evidence with antiplatelet agents rejected the drug-specific cancer risks, clearly indicating the class effect. The NCVD risks were elevated after treatment with both thienopyridines, but were more prominent after clopidogrel treatment (HR 1.91) than prasugrel treatment (HR 1.17). About half of the NCVD were considered to be caused by cancers occurring after the 24 months of extended antiplatelet therapy. Impression: The DAPT trial confirmed that long-term antiplatelet therapy is associated with cancer that contributes to NCVD. Based on the full disclosure of cancer data by the DAPT study, it can be reflected that the optimal duration of antiplatelet therapy with thienopyridines should be limited to no more than 2 years. This duration allows the preservation of most vascular benefits while avoiding additional cancers and NCVD.

Ticagrelor shift from PLATO to PEGASUS: Vanished mortality benefit, excess cancer deaths, massive discontinuations, and overshooting target events

“…The differences in PLATO and PEGASUS cancer-related outcomes are presented atTable 3. The PEGASUS consistent with the DAPT trial results(14) exhibiting similar to prasugrel or clopidogrel extra cancer risks after ticagrelor beyond 1 year therapy(15).Sepsis:Despite more common infections after ticagrelor, PLATO reported surprising reduction in deaths due to sepsis with 7 (0.1%) after ticagrelor versus 23 fatalities (0.2%) after clopidogrel(2). In contrast, PEGASUS revealed a trend towards more infection/sepsis-related deaths after ticagrelor (n=31) than after aspirin (n=24) (RR=1.29; 95%CI 0.76 -2.20, p=0.35)(10).…”

Antiplatelet agents for cancer treatment: a real perspective or just an echo from the past?

“…The alarming data that such an approach may be associated with increased cancer incidence forced re-analysis of the main trials from this point of view [ 29 – 31 ]. The adverse effects of antiplatelet therapy were first observed during the TRITON trial in which prasugrel versus clopidogrel was assessed in patients with acute coronary syndromes and for vorapaxar treatment in the TRACER trial [ 30 ]. Ticagrelor treatment (reversibly binding oral P2Y12 receptor blocker) assessed in the PEGASUS trial was also associated with significant excess in cancer death [ 132 ].…”

“…Ticagrelor treatment (reversibly binding oral P2Y12 receptor blocker) assessed in the PEGASUS trial was also associated with significant excess in cancer death [ 132 ]. DAPT therapy from a 30-month trial with prasugrel and clopidogrel provided abundant data [ 30 ]. This trial revealed that a long-term antiplatelet approach is associated with cancer development that contributes to about half of noncardiovascular deaths (NCVD).…”

“…For this reason, antiplatelet therapy with thienopyridines is recommended not to exceed 2 years. Such an approach reduces cancer risk, while most vascular benefits are still preserved [ 30 ]. Likewise, triple therapy aggressive regimens, lasting more than 1 year, are not recommended and intake of additional NSAIDS in combination with these regimens must be considered carefully for cardiovascular risk [ 133 ].…”

Dual antiplatelet therapy with clopidogrel and aspirin increases mortality in 4T1 metastatic breast cancer-bearing mice by inducing vascular mimicry in primary tumour

“…Given the possible role of platelets in promotion of malignant diseases and metastatic spread, effects of anti-platelet therapy on metastasis have been intensively studied in animal models [ 3 , 6 , 7 ] as well as in humans. Today there is overwhelming evidence from epidemiological studies [ 8 – 12 ] and clinical trials [ 13 , 14 ] that supports the involvement of platelets in metastatic spread.…”