This mini-CAT is based on the first PICO (week 1) of the 6^th rotation, which for me was Internal Medicine at New York Presbyterian Queens, Flushing, NY. I chose to further research this question as this is a potentially practice changing debate.

Clinical Question: There is a patient admitted to the Medicine floor status post transcatheter aortic valve replacement (TAVR). His medical history offers no independent indications for anticoagulation therapy or for dual antiplatelet therapy. He states he is generally forgetful and is worried about his ability to comply with a complicated pharmacological treatment regimen. He is therefore requesting his medication regimen be as simplified as possible. The internal medicine PA is discussing possibly implementing single antiplatelet therapy (SAPT) rather than dual antiplatelet therapy (DAPT) with the cardiologist for post TAVR management.

Search Question: For patients post transcatheter aortic valve replacement, is single antiplatelet therapy as effective as the standard dual antiplatelet therapy in preventing post-surgical bleeding events?

PICO Question:

P	I	C	O
Transcatheter aortic valve replacement	Single antiplatelet therapy	Dual antiplatelet therapy	Bleeding
TAVR	Mono antiplatelet therapy	Dual antithrombotic regimen	Bleeding event
Transcatheter aortic valve implantation	Antiplatelet monotherapy	DAPT	Major bleeding
TAVI	Aspirin monotherapy	Aspirin plus clopidogrel	Life threatening bleeding
	Mono antithrombotic regimen		Minor bleeding
	SAPT

Search tools and strategy used/Results Found

Cochrane Library

• SAPT  49
• SAPT after TAVR  2

Google Scholar

• SAPT versus DAPT  999
  • Filter Since 2017  857
• SAPT after TAVR  200
  • Filter Since 2017  171
• SAPT TAVR bleeding event  687
  • Filter Since 2017  336

National Center for Biotechnology Information

• SAPT versus DAPT  157
• SAPT versus DAPT TAVI  37
• SAPT versus DAPT TAVR  29
  • Filter 5 years, Medline journals  15
• SAPT TAVR bleeding  29
  • Filter 5 years, Medline journals  12

Pubmed

• SAPT versus DAPT  28
• SAPT versus DAPT TAVI  7
• SAPT versus DAPT TAVR  6

Wiley Online Library

• SAPT DAPT  58
  • Filter 5 years + journal  48
• SAPT DAPT TAVR  10
  • Filter 5 years + journal  9
• SAPT DAPT TAVI
  • Filter 5 years + journal  11

For the articles to answer this miniCAT adequately I wanted to focus on systematic reviews as these offer the highest levels of evidence with strict criteria for inclusion and discussion. Meta-analyses are also of focus because they offer a similarly high level of evidence by statistically analyzing multiple datasets independently to determine statistical importance. If these are unavailable randomized controlled trials were the next level of evidence I looked for. Randomized controlled trials allow for direct comparison with measures to control for confounding variables between the two treatment modalities by virtue of its randomization.

With continuing research, actual clinical practice is constantly evolving. Treatment guidelines are therefore constantly updated to reflect evidence-based medicine. This necessitates the articles be published within the last five years so it can reflect our most updated body of knowledge.

After reviewing hundreds of research articles for the last 10 years I find that the concept of high-quality evidence does not vary greatly among different academic cultures. Furthermore, the standard of care and clinical treatment goals also do not vary greatly. For these reasons I am confident in including research based in other countries.

I include Google Scholar in the databases I searched as it allows academic research to be more accessible to the general public, something I personally advocate for. It also offered the most results to expand my research and general understanding of this topic discussion. Cochrane offered the least results quantitatively. Wiley Online Library and Pubmed yielded few results as well. NCBI offered the best search results quantitatively and qualitatively, and was the easiest to navigate to ensure the articles were Medline indexed.

Ultimately, I chose four systematic reviews/meta-analyses and one randomized controlled trial. All of these articles were published within the last four years—one systematic review/meta-analysis published in 2018, the rest published in 2020 and 2021. The very current publication dates of these articles strengthen the validity of the results which will be discussed in the Clinical Bottom Line and Clinical Significance.

Citation Brouwer J, Nijenhuis VJ, Delewi R, Hermanides RS, Holvoet W, Dubois CLF, Frambach P, De Bruyne B, van Houwelingen GK, Van Der Heyden JAS, Toušek P, van der Kley F, Buysschaert I, Schotborgh CE, Ferdinande B, van der Harst P, Roosen J, Peper J, Thielen FWF, Veenstra L, Chan Pin Yin DRPP, Swaans MJ, Rensing BJWM, van ‘t Hof AWJ, Timmers L, Kelder JC, Stella PR, Baan J, Ten Berg JM. Aspirin with or without Clopidogrel after Transcatheter Aortic-Valve Implantation. N Engl J Med. 2020 Oct 8;383(15):1447-1457. doi: 10.1056/NEJMoa2017815. Epub 2020 Aug 30. PMID: 32865376.

Abstract Background: The effect of single as compared with dual antiplatelet treatment on bleeding and thromboembolic events after transcatheter aortic-valve implantation (TAVI) in patients who do not have an indication for long-term anticoagulation has not been well studied. Methods: In a randomized, controlled trial, we assigned a subgroup of patients who were undergoing TAVI and did not have an indication for long-term anticoagulation, in a 1:1 ratio, to receive aspirin alone or aspirin plus clopidogrel for 3 months. The two primary outcomes were all bleeding (including minor, major, and life-threatening or disabling bleeding) and non-procedure-related bleeding over a period of 12 months. Most bleeding at the TAVI puncture site was counted as non-procedure-related. The two secondary outcomes were a composite of death from cardiovascular causes, non-procedure-related bleeding, stroke, or myocardial infarction (secondary composite 1) and a composite of death from cardiovascular causes, ischemic stroke, or myocardial infarction (secondary composite 2) at 1 year, with both outcomes tested sequentially for noninferiority (noninferiority margin, 7.5 percentage points) and superiority. Results: A total of 331 patients were assigned to receive aspirin alone and 334 were assigned to receive aspirin plus clopidogrel. A bleeding event occurred in 50 patients (15.1%) receiving aspirin alone and in 89 (26.6%) receiving aspirin plus clopidogrel (risk ratio, 0.57; 95% confidence interval [CI], 0.42 to 0.77; P = 0.001). Non-procedure-related bleeding occurred in 50 patients (15.1%) and 83 patients (24.9%), respectively (risk ratio, 0.61; 95% CI, 0.44 to 0.83; P = 0.005). A secondary composite 1 event occurred in 76 patients (23.0%) receiving aspirin alone and in 104 (31.1%) receiving aspirin plus clopidogrel (difference, -8.2 percentage points; 95% CI for noninferiority, -14.9 to -1.5; P<0.001; risk ratio, 0.74; 95% CI for superiority, 0.57 to 0.95; P = 0.04). A secondary composite 2 event occurred in 32 patients (9.7%) and 33 patients (9.9%), respectively (difference, -0.2 percentage points; 95% CI for noninferiority, -4.7 to 4.3; P = 0.004; risk ratio, 0.98; 95% CI for superiority, 0.62 to 1.55; P = 0.93). A total of 44 patients (13.3%) and 32 (9.6%), respectively, received oral anticoagulation during the trial. Conclusions: Among patients undergoing TAVI who did not have an indication for oral anticoagulation, the incidence of bleeding and the composite of bleeding or thromboembolic events at 1 year were significantly less frequent with aspirin than with aspirin plus clopidogrel administered for 3 months. (Funded by the Netherlands Organization for Health Research and Development; POPular TAVI EU Clinical Trials Register number, 2013-003125-28; ClinicalTrials.gov number, NCT02247128.).

Citation Kuno T, Takagi H, Sugiyama T, Ando T, Miyashita S, Valentin N, Shimada YJ, Kodaira M, Numasawa Y, Kanei Y, Hayashida K, Bangalore S. Antithrombotic strategies after transcatheter aortic valve implantation: Insights from a network meta-analysis. Catheter Cardiovasc Interv. 2020 Aug;96(2):E177-E186. doi: 10.1002/ccd.28498. Epub 2019 Oct 14. PMID: 31609071.

Abstract Objectives: We aimed to investigate the efficacy and safety of different antithrombotic strategies in patients undergoing transcatheter aortic valve implantation (TAVI) using network meta-analyses. Background: Meta-analyses comparing single antiplatelet therapy (SAPT) vs. dual antiplatelet therapy (DAPT), ± oral anticoagulant (OAC) was conducted to determine the appropriate post TAVI antithrombotic regimen. However, there was limited direct comparisons across the different therapeutic strategies. Methods: MEDLINE and EMBASE were searched through December 2018 to investigate the efficacy and safety of different antithrombotic strategies (SAPT, DAPT, OAC, OAC + SAPT, and OAC + DAPT) in patients undergoing TAVI. The main outcome were all-cause mortality, major or life-threatening bleeding events, and stroke. Results: Our search identified 3 randomized controlled trials and 10 nonrandomized studies, a total of 20,548 patients who underwent TAVI. All OACs were vitamin K antagonists. There was no significant difference on mortality except that OAC + DAPT had significantly higher rates of mortality compared with others (p < .05, I2 = 0%). SAPT had significantly lower rates of bleeding compared with DAPT, OAC+SAPT, and OAC+DAPT (hazard ratio [HR]: 0.59 [0.46-0.77], p < .001, HR: 0.58 [0.34-0.99], p = .045, HR: 0.41 [0.18-0.93], p = .033, respectively, I2 = 0%). There was no significant difference on stroke among all antithrombotic strategies. Conclusion: Patients who underwent TAVI had similar all-cause mortality rates among different antithrombotic strategies except OAC+DAPT. Patients on SAPT had significantly lower bleeding risk than those on DAPT, OAC + SAPT, and OAC + DAPT. Our results suggest SAPT is the preferred regimen when there is no indication for DAPT or OAC. When DAPT or OAC is indicated, DAPT + OAC should be avoided. Keywords: anticoagulant; antiplatelet; antithrombotic; network meta-analysis; transcatheter aortic valve implantation.

Citation Raheja H, Garg A, Goel S, Banerjee K, Hollander G, Shani J, Mick S, White J, Krishnaswamy A, Kapadia S. Comparison of single versus dual antiplatelet therapy after TAVR: A systematic review and meta-analysis. Catheter Cardiovasc Interv. 2018 Oct 1;92(4):783-791. doi: 10.1002/ccd.27582. Epub 2018 Mar 8. PMID: 29516608.

Abstract Objective: We aim to evaluate the efficacy of dual versus single anti-platelet therapy (SAPT) after TAVR through a systematic review and meta-analysis of published research. Background: Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is a commonly practiced strategy after transcatheter aortic valve replacement (TAVR). However, there is lack of sufficient evidence supporting this approach. Method: We searched PubMed, EMBASE, the Cochrane Central Register of Controlled trials, and the clinical trial registry maintained at clinicaltrials.gov for randomized control trials (RCT) and observational studies comparing DAPT with SAPT post TAVR. Event rates were compared using a forest plot of relative risk with 95% confidence intervals using a random-effects model assuming inter-study heterogeneity. Results: A total of six studies (3 RCTs and 3 observational studies, n = 840) were included in the final analysis. Compared to SAPT, DAPT was associated with increased risk of significant bleeding (life threatening and major) [RR = 2.52 (95% CI 1.62-3.92, P < 0.0001)] with the number needed to harm for major or life-threatening bleeding calculated to be 10.4. There was no significant difference in the incidence of stroke [RR = 1.06 (95% CI, 0.43-2.60, P = 0.90)], spontaneous myocardial infarction [RR = 2.08 (95% CI, 0.56-7.70, P = 0.27)] and all-cause mortality [RR = 1.18 (95% CI, 0.68-2.05, P = 0.56] in the DAPT and SAPT groups. Conclusion: In this small meta-analysis of DAPT versus SAPT after TAVR, DAPT did not prevent stroke, myocardial infarction or death while the risk of bleeding was higher. Results from ongoing trials are awaited to determine the best anti-thrombotic approach after TAVR. Keywords: P2Y receptor antagonist; TAVI; TAVR; anthithrombotic; antiplatelet; aspirin; transcatheter aortic valve implantation; transcatheter aortic valve replacement.

Citation Ullah W, Zghouzi M, Ahmad B, Biswas S, Zaher N, Sattar Y, Pacha HM, Goldsweig AM, Velagapudi P, Fichman DL, Prasad A, Alraies MC. Meta-Analysis Comparing the Safety and Efficacy of Single vs Dual Antiplatelet Therapy in Post Transcatheter Aortic Valve Implantation Patients. Am J Cardiol. 2021 Apr 15;145:111-118. doi: 10.1016/j.amjcard.2020.12.087. Epub 2021 Jan 15. PMID: 33454348.

Abstract The relative safety and efficacy of aspirin versus dual antiplatelet therapy (DAPT; aspirin+clopidogrel) in patients who underwent transcatheter aortic valve implantation (TAVI) and did not have a long-term indication for oral anticoagulation remains controversial. Digital databases were searched to identify relevant articles. The major safety end point was bleeding, while the efficacy end points included after-TAVI ischemic and thrombotic events. Data were analyzed using a random effect model to calculate the pooled unadjusted odds ratio (OR) for dichotomous outcomes. Eleven studies comprising 4805 patients (aspirin 2258, DAPT 2547) were included in the quantitative analysis. Patients receiving aspirin-alone had significantly lower odds of all cause bleeding (OR 0.41, 95% CI 0.29 to .057, p <0.00001), major vascular bleeding (OR 0.51, 95% CI 0.34 to 0.77, p = 0.001), Valve Academic Research Consortium 2 (VARC-2) major bleeding (OR 0.50, 95% CI 0.30 to 0.83 p = 0.008), VARC-2 minor bleeding (OR 0.55, 95% CI 0.31 to 0.97, p = 0.04), transfusion requirement (OR 0.39, 95%CI 0.15 to 0.0.98, p = 0.05) and major vascular complications (OR0.41, 95% CI 0.26 to 0.66, p = 0.0002) compared with after-TAVI patients receiving both aspirin and clopidogrel. These was no significant difference in the odds of VARC-2 life threatening bleeding (OR 0.52, 95% CI 0.25 to 1.07, p = 0.08), prosthetic valve thrombosis (OR 1.17, 95% CI 0.22 to 6.30, p = 0.85), cardiac tamponade (OR 0.77, 95% CI 0.20 to 2.98, p = 0.70), conversion to open procedure (OR 1.99, 95 % CI 0.42 to 9.44, p = 0.39), MI (OR 0.79 95% CI 0.38 to 1.64, p = 0.52), transient ischemic attack (TIA) (OR 0.89, 95% CI 0.12 to 6.44, p = 0.91), major stroke (OR 0.68 95 % CI 0.43 to 1.08, p = 0.10), disabling stroke (0R 1.01, 95% CI 0.41 to 2.48, p = 0.99), cardiovascular mortality (OR 0.81 95% CI 0.38 to 1.74, p = 0.59) and all-cause mortality (OR 0.86, 95% CI 0.63 to 1.16, p = 0.31) between the 2 groups. In conclusion, after-TAVI patients who received aspirin alone had lower bleeding events with no significant differences in mortality and stroke rate compared with those who received DAPT.

Citation Zuo W, Yang M, He Y, Hao C, Chen L, Ma G. Single or dual antiplatelet therapy after transcatheter aortic valve replacement: an updated systemic review and meta-analysis. J Thorac Dis. 2019;11(3):959-968. doi:10.21037/jtd.2019.01.87

Abstract Background Although current guidelines recommend dual antiplatelet therapy (DAPT) with aspirin and clopidogrel as an antiplatelet strategy after transcatheter aortic valve replacement (TAVR), it is not based on clinical evidence. Here we aim to review updated evidence systemically and assess safety and efficacy of the two antiplatelet regimens. Methods PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched to retrieve studies involving single antiplatelet therapy (SAPT) versus DAPT after TAVR. We screened the records and extracted the data from publications independently. Relative risks (RRs) and the corresponding 95% confidence intervals (CIs) were used to compare the efficacy and safety of SAPT with that of DAPT in fixed-effects model with Mantel-Haenszel method. The quality of evidence was assessed by the scoring system, GRADE (Grading of Recommendations Assessment, Development, and Evaluation). Results A total of 2,489 patients from 8 studies were enrolled in this meta-analysis. Compared with DAPT, SAPT was associated with a lower all-cause mortality (RR =0.57; 95% CI, 0.36–0.89; P=0.014) and major/life-threatening bleeding (RR =0.62; 95% CI, 0.50–0.76; P=0.000) in 30 days. Furthermore, there was no significant difference found between SAPT and DAPT group in terms of 30-day stroke (RR =0.85; 95% CI, 0.45–1.63; P=0.631) and death beyond 3 months (RR =0.96; 95% CI, 0.81–1.15; P=0.664). Conclusions This meta-analysis suggests that compared with DAPT, SAPT after TAVR is more likely to lead to a decline of 30-day mortality along with the reduced risk of bleeding and no increased risk of stroke. However, more clinical data and evidence from randomized controlled trials are warranted to clarify the optimal post-TAVR antiplatelet strategy. Keywords: Transcatheter aortic valve replacement (TAVR), antiplatelet therapy, aspirin, clopidogrel, P2Y12 receptor antagonist

Author & Date	Level of Evidence	Sample & Setting	Outcome(s) Studied	Key Findings	Limitations & Biases
Brouwer J, Nijenhuis VJ, Delewi R, Hermanides RS, Holvoet W, Dubois CLF, Frambach P, De Bruyne B, van Houwelingen GK, Van Der Heyden JAS, Toušek P, van der Kley F, Buysschaert I, Schotborgh CE, Ferdinande B, van der Harst P, Roosen J, Peper J, Thielen FWF, Veenstra L, Chan Pin Yin DRPP, Swaans MJ, Rensing BJWM, van ‘t Hof AWJ, Timmers L, Kelder JC, Stella PR, Baan J, Ten Berg JM.   2020	Randomized Controlled Trial	331 patients receiving aspirin alone. 334 patients receiving aspirin plus clopidogrel. All patients undergoing TAVI without indication for oral anticoagulation. The patients were recruited from 17 European sites from December 2013 to March 2019.	Primary outcomes: Minor, major, and life-threatening or disabling bleeding, and non-procedure related bleeding over 12 months.   Secondary outcomes: Death from cardiovascular causes, non-procedure related bleeding, stroke from any cause, myocardial infarction.	An independent data and safety monitoring board monitored and adjudicated all reported outcomes and their components whose members were blind to trial group assignments. Patients were matched in a 1:1 ratio. Outcomes were measured by VARC definitions which is a standardized classification of bleeding post TAVR. 50 patients (15.1%) of patients on aspirin alone and 89 patients (26.6%) receiving aspirin plus clopidogrel had bleeding any time. Secondary outcomes occurred in 76 patients (23.0%) receiving aspirin alone and in 104 patients (31.1%) receiving aspirin and clopidogrel. Stroke occurs in 17 patients (5.1%) receiving aspirin alone and in 19 patients (5.7%) receiving aspirin plus clopidogrel. Symptomatic clinical aortic-valve thrombosis occurred in 3 patients (0.9%) in the aspirin alone group and in 1 patient (0.3%) in the aspirin-clopidogrel group.	Open label trial so the patients and investigators were aware of the treatment assignment. The trial has a composite endpoint of bleeding or thromboembolic events rather than a solitary endpoint of thromboembolic event. Trial was designed to assess clinical outcomes and did not require CT imaging for subclinical valve thrombosis.
Kuno T, Takagi H, Sugiyama T, Ando T, Miyashita S, Valentin N, Shimada YJ, Kodaira M, Numasawa Y, Kanei Y, Hayashida K, Bangalore S.   2020	Meta-Analysis & Systematic Review	3 randomized controlled trials and 10 nonrandomized studies for a total of 20,548 patients who underwent TAVI.     [Literature search for all studies published until December 29, 2018 investigating the impact of antithrombotic strategies on survival, bleeding events, and stroke after TAVI found on MEDLINE and EMBASE. Studies had to be peer-reviewed by journals, the design was comparative studies of patients with different antithrombotic strategies SAPT, DAPT, oral anticoags.]	All cause mortality, major or life threatening bleeding events, stroke.	No significant difference in mortality among SAPT, DAPT, OAC, and OAC +SAPT. Triple therapy had significantly higher rates of mortality compared to other antithrombotic strategies. SAPT had significantly lower rates of bleeding compared to other treatment strategies.   There was no statistically significant heterogenicity among the patients. SAPT had significantly lower rates of bleeding compared to DAPT but no survival difference/difference in mortality by sensitivity analyses.	Observational studies with consequent selection and ascertainment bias were included to investigate anticoagulation therapy after TAVI. The higher percentages of atrial fibrillation could have influenced the results (mortality, stroke, bleeding). There are baseline differences between each antithrombotic strategy—patients on DAPT were more likely to have CAD and patients on OAC had Afib and prior cerebrovascular disease. These confounding factors could not be eliminated using propensity score matched analysis or adjusted HR. Authors did not have access to individual patient data to independently confirm results.
Raheja H, Garg A, Goel S, Banerjee K, Hollander G, Shani J, Mick S, White J, Krishnaswamy A, Kapadia S.   2018	Systematic Review & Meta-analysis	3 RCTs and 3 observational studies, for a total of 840 patients.   [Literature search for randomized control trials and observational studies comparing DAPT to SAPT post TAVR published from January 1, 2000 to July 31, 2017, from PubMEd, EMBASE, and Cochrane Register of Controlled trials and clinical trial registry from clinicaltrials.gov.]	All cause mortality, stroke, myocardial infarction, and major and life threatening bleeding at the longest available follow up.	DAPT was associated with a statistically significant increased risk of bleeding classified as life threatening and major but no significant difference in the incidence of stroke, MI, and all-cause mortality at 6 months post-surgery. Separate 30-day analysis was performed by authors showing all-cause mortality to be similar in SAPT and DAPT patients.	Relatively small sample size with a low event rate—potentially influencing the power of the analysis. Heterogeneity in duration or type of antiplatelets used. No access to raw patient data preventing any controlling for potential confounders. Outcomes were only studied at the longest available follow up (4.8 months) after TAVR.
Ullah W, Zghouzi M, Ahmad B, Biswas S, Zaher N, Sattar Y, Pacha HM, Goldsweig AM, Velagapudi P, Fichman DL, Prasad A, Alraies MC.   2020	Systematic Review and Meta-Analysis	11 studies with 4805 patients in total; 2258 taking aspirin; 2547 taking DAPT.   [Literature search for all RCTs and observational cohort studies comparing DAPT to SAPT with no indication for OAC]	Primary outcome: major bleeding   Other: risk of MI, valve thrombosis, stroke	4 authors independently  screened all results for relevance. Overall quality of the included RCTs and OCS were high–the RCTs were open label violating the “allocation concealment” but randomization reduced the risk of selection bias. Aspirin alone was associated with significantly lower odds of all cause bleeding, major vascular bleeding, transfusion requirement, and major vascular complications compared to DAPT with aspirin and clopidogrel. The rate of VARC minor and major bleeding and cardiovascular and all cause mortality was significantly lower in the aspirin alone group <6 months, but identical at >6 month follow up. With SAPT VARC life threatening bleeds were reduced by 48%; VARC minor bleed reduced by 55% with SAPT; VARC major bleed reduced by 50% compared to DAPT.	RCTs were open label and the authors were not able to assess individual components of composite outcomes. Follow up duration was short for these studies. Patient level data was missing so procedure technique for TAVI could not be related to outcomes. No stratified subgroup analysis for follow up duration, baseline bleeding tendency, study design, inclusion criterias due to paucity of results.
Zuo W, Yang M, He Y, Hao C, Chen L, Ma G   2019	Systematic Review and Meta-analysis	8 studies (3 RCTs and 5 cohort observational studies) for a total of 2489 patients   [Literature review of PubMed, Embase, Cochrace Register of Controlled Trials.]	Primary outcome: 30-day death post procedure   Secondary outcome: stroke, life-threatening or major bleeding, spontaneous myocardial infarction	SAPT had significantly reduced incidence of all cause mortality compared to DAPT. SAPT reduced the risk of life-threatening or major bleeding compared to DAPT in the observational studies but not the RCTs. No difference in the incidence of stroke and MI.	Small sample size due to lack of relevant published studies, therefore limiting statistical power of this analysis. Few studies reported clinical outcomes beyond 30 days.

Conclusion(s)

Brouwer et al. concluded that aspirin alone is associated with a lower incidence of bleeding and a lower incidence of composite bleeding or thromboembolic events in patients without indication for long-term use of oral anticoagulation after TAVI, when compared to patients on aspirin plus clopidogrel at 1 year of follow-up. “Aspirin alone was noninferior, but not superior, to aspirin plus clopidogrel for the composite of thromboembolic events, including death from cardiovascular causes, ischemic stroke, or myocardial infarction.”

Kuno et al. concluded that SAPT is the preferred treatment regimen when there is no other indication for DAPT or OAC post-TAVI due to low bleeding rates.

Raheja et al. concluded DAPT did not prevent stroke, MI, mortality when compared to SAPT, and was associated with an increased risk of major and life-threatening bleeding compared to SAPT.

Ullah et al. concluded aspirin only treatment in patients with severe aortic stenosis and no other indication for anticoagulation who underwent TAVI significantly reduced the chances of all types of bleeding events, minor and major vascular complications when compared to DAPT.

Zuo et al. concluded SAPT after TAVR may have a lower 30-day mortality than DAPT due to a reduced incidence of bleeding with no increased risk of stroke or MI compared to DAPT.

My overall conclusion based on these five studies is that SAPT would provide similar antithrombotic effects compared to DAPT post TAVI/TAVR in a patient without any other indication for anticoagulation while also reducing the increased risk of adverse bleeding effects associated with DAPT.

Clinical Bottom Line

I will weigh the studies in the following order: 1 Kuno et al. 2 Ullah et al. 3 Brouwer et al. 4 Zuo et al. 5 Raheja et al.

1 I weigh the Kuno et al. article first because it is the largest systematic review and meta-analysis about this topic with over 20,000 patients. The authors did not put any limitations on the date the studies were published so they were able to analyze all available data. This meta-analysis is strengthened by the uniquely large sample size of this study. There was no statistically significant heterogenicity among the participants helping to minimize the effects of confounding variables on the results. The authors’ decision to include each study and their overall analysis are bolstered by several sensitivity analyses: one excluding the largest study, another utilizing only the 3 RCTs and 3 propensity score matched analyses. The results and statistical significance were essentially unchanged proving that no one study acted as an outlier disproportionately affecting the results.

2 I weigh the article Ullah et al. second because this is second largest systematic review and meta-analysis with almost 5000 participants. Additionally, this systematic review had four independent reviewers to determine what studies were to be included, unlike most others which only have two independent reviewers. The use of the well-established standardized andvalidated definition of bleeding [VARC] allowed for a systematic assessment and risk stratification of mortality and prognosis in patients. Another factor strengthening the conclusions of Ullah et al. is that all the included articles were found to be of high quality despite the common use of open-label trial. Randomization adequately reduced the risk of selection bias.

3 I weigh the Brouwer et al. article third because this randomized controlled trial allowed for direct 1:1 comparison of the two treatment modalities. The study design utilized a program to ensure true blind randomization of the patients. The overall methodological design utilizing information over 17 different European sites (multiple countries) also adds weight to the authors’ conclusions. European healthcare, medical practice, and clinical outcomes are of similar quality as American medicine allowing these results to be extrapolated to clinical practice here. Further strengthening this study and adding weight to the results is the fact that no patients were lost to follow-up and so the authors were able to obtain data about primary and secondary outcomes for 100% of participants. Like the Ullah et al. article these authors chose to use the international VARC definitions for bleeding and prognosis. Similarly, this adds credence to their study design and results. The use of VARC among multiple studies also ensures the interpretation of the “bleeding” outcome is standardized between these two studies, strengthening the conclusion(s).

4 I weigh the Zuo et al. article fourth because it is a recently published systematic review (more recently than the last article holding the least weight). This article also had more participants, 2400, than the 2018 article with only 840. These authors used subgroup analysis to evaluate outcomes among different types of studies (e.g. RCTs and observational cohort studies). While the primary outcome of this study was all-cause mortality and not bleeding, bleeding was the secondary outcome and similarly assessed through statistical analysis therefore the conclusions of this article adequately help answer this research question.

5 Lastly, I weigh the Raheja et al. article the least because it is the oldest article, published in 2018, with the smallest sample size, only 840 participants. It is important to note that of the 6 articles included, 3 are RCTs, 2 are propensity matched cohorts which do allow for direct comparison of the two treatment modalities. However, unlike the Kuno et al. article these authors chose to put a date limit on the research that could be included, only studies published from 2000 to 2017. The results of this article are also influenced by the heterogenicity of the antiplatelet therapy used among studies and lack of access to raw patient data. Confounding variables like kidney function could not be eliminated therefore the results are potentially skewed by this. The other articles discussed the use of SAPT and DAPT specifically in the absence of any indication for OAC to prevent confounding effects. Of the six articles included in this meta-analysis only one included any indication for OAC as an exclusion criterion.

Magnitude of any Effects

None of these articles offer direct commentary on the magnitude of the effects, or the effect size as a measure of experimental effect. This is most likely due to heterogenicity among included studies and the small sample sizes discussed, however there are statistically significant results reported by each of the authors:

Brouwer et al. utilize a two-sided P value of 0.05 or less for statistical significance. Primary outcomes [bleeding of any type] occurred 15.1% (50 patients) in the aspirin alone group compared to 26.6% (89 patients) in the aspirin plus clopidogrel group. The risk ratio was 0.57 with 95% confidence interval, 0.42 to 0.77 where P=0.001.

Kuno et al. proved there was no significant heterogeneity (I2=0%, p=.71), and inconsistency (p=.27)

P-scores were 93.7% for SAPT and 35.3% for DAPT. SAPT had significantly lower rates of bleeding compared with DAPT with Hazards Ratio [95% confidence interval or CI]: 0.59 [0.46–0.77], p<.001.

Raheja et al. calculate no significant differences in DAPT compared to SAPT [RR 1.18; 95% CI 0.68-2.05] for all cause mortality. There was a significantly higher risk of bleeding in the DAPT group than the SAPT group [RR 2.52; 95% CI 1.62-3.92, P<0.0001]. The number needed to harm was calculated to be 10.4. For bleeding within 30 days of the procedure the risk was significantly higher in the DAPT group compared to the SAPT group [RR 2.38; 95% CI 1.44-3.93, P=0.0007].

Ullah et al. show the use of aspirin alone to be associated with significantly lower odds of all cause bleeding (OR 0.41, 95% CI 0.29 to .057, p < 0.00001); major vascular bleeding (OR 0.51, 95% CI 0.34 to 0.77, p = 0.001); VARC-2 major bleeding (OR 0.50, 95% CI 0.30 to 0.83 p = 0.008); VARC-2 minor bleeding (OR 0.55, 95% CI 0.31 to 0.97, p = 0.04); transfusion requirement (OR 0.39, 95% CI 0.15 to 0.0.98, p = 0.05) compared to patients receiving aspirin plus clopidogrel. These was no significant difference in the odds of VARC-2 life threatening bleeding (OR 0.52, 95% CI 0.25 to 1.07, p = 0.08) compared to DAPT.

Zuo et al. state SAPT showed a benefit over DAPT in reducing the risk of life-threatening or major bleeding (RR = 0.62; 95%CI, 0.50 – 0.76; P = 0.000). The consistent results were obtained in observational studies (RR = 0.62; 95% CI, 0.50 – 0.78; P = 0.000) whereas no significance was observed in RCTs (RR = 0.55; 95% CI, 0.28–1.08; P = 0.082).

Clinical Significance (not just statistical significance)

Current guidelines recommend at least three months of DAPT post TAVR. Evidence based medicine requires adjustments be made with new research, and for our practice to reflect that. Current research supports the use of single antiplatelet therapy for this patient because he has no other indications for anticoagulation or DAPT. SAPT offers the benefit of a reduced risk of adverse minor, major, and life-threatening bleeding events, as well as a simpler medication schedule which is historically associated with improved compliance. Of clinical significance, though not the main outcome discussed therein is the similar rates of stroke, myocardial infarction, and all-cause mortality which is acknowledged by all five articles. Implementing SAPT therefore does not predispose negatively influence prognosis or mortality any more than DAPT. I would clinically recommend SAPT post TAVR for this patient as it is the safer alternative without additional risk(s).

Other considerations important in weighing this evidence to guide clinical practice

Moving forward there needs to be more long-term research directly comparing the incidence of bleeding (and other outcomes like stroke, MI, all-cause mortality, etc) in SAPT and DAPT treatment regimens post-TAVR. Post-surgical follow-up now averages 3 to 6 months, with only one study following up at 12 months (Brouwer et al.). While meta-analyses traditionally offer the highest levels of evidence by consolidating and statistically analyzing several studies, there is an ongoing trend of a paucity of articles to choose from as well as methodological inconsistencies limiting analysis. A long term RCT or retrospective propensity matched cohort study could fill in these research gaps and contribute to our current understanding of the differences between SAPT and DAPT. Until this is directly addressed, we are left to wonder if SAPT has any long-term benefits on bleeding and survivability post TAVR.

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Meta-Analysis-Comparing-the-Safety-and-Efficacy-of-Single-vs-Dual-Antiplatelet-Therapy-in-Post-Transcatheter-Aortic-Valve-Implantation-Patients

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