kaulcsmc.bsky.social @kaulcsmc.bsky.social · 05/06/2025Post-treatment discontinuation eGFR trajectory is somewhat reassuring. No? 110
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 05/06/2025I think it is a positive first step, but whether there is a convincing evidence of an additive effect of combination therapy requires proof in an outcome study. For now, combination therapy has won the bragging rights, but I would not go so far as to proclaim this is a practice-changing trial. 151
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 05/06/2025Is there a dose-response or a threshold relationship with UACR reduction and clinical outcome benefit? In other words, will a >50% reduction translate into a greater kidney or CV benefit than >30% reduction? 140
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 05/06/2025Hyperkalemia on combo vs nsMRA: RR 0.82, 95% CI 0.50-1.36 No clearcut evidence that hyperkalemia risk is mitigated by combining sglt2i with nsMRA (? Inadequate power/Sample Size) 141
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 02/04/2025No 'additive' cardioprotective effect of GLP-1RA on background use of SGLT2i in HARMONY, AMPLITUDE-O and most recently SOUL. Cardioprotective effects of GLP-1RA are 'independent' of SGLT2i ahajournals.org/doi/epdf/10.11… 10.1016/j.jacc.2023.05.048 170
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 31/03/2025Pragmatic trials like comparative effectiveness studies require realistically ‘sober’ assumptions to account for the issues you stated. Lipid hypothesis lingered on for several decades until LDL-C lowering was proven to reduce CV risk. Analogy applies to INOCA/ANOCA/MINOCA. Need novel targeted Rxs. 120
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 31/03/202595% CI is compatible with a 6% benefit (clinically trivial) to 37% harm (clinically important). If CI contained a clinically important benefit, say HR of 0.80 or a more plausible HR of 0.85 to 0.90, but CI was wide spanning across HR of 1, then an inference of inconclusive result would be justified. 120
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 29/03/2025Trial powered for a HR of 0.80 which was excluded by the 95% CI. Is it still a null outcome? 120
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 29/03/2025Warrior trial PEP result shown below. Is this a NULL trial or a NEGATIVE trial? Trial powered for HR 0.80 which was excluded by 95% CI How many null or negative PRAGMATIC trials before we seriously consider/scrutinize the utility of such trials? 240
Reposted by @kaulcsmc.bsky.socialFlorian Zores @fzores.eurosky.social · 16/03/2025Very proud of this work with @kaulcsmc.bsky.social just published in Progress in Cardiovascular Diseases Are ORBITA trials practice-changing? We discuss whether the enthousiasm of some after ORBITA-2 is really justified. www.sciencedirect.com/science/arti... #medsky #cardioskysciencedirect.comAre ORBITA trials practice-changing? 072
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 14/03/2025Snake oil salesmen of the 21st century! Here they come. endpts.com/rfk-jr-conve...endpts.comRFK Jr. convened roundtable around ways to reduce stem cell regulationHHS Secretary Robert F. Kennedy Jr. and his staff last Wednesday hosted a regenerative medicine roundtable primarily to discuss how to lower regulatory barriers for stem cell treatments, three people ... 031
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/02/2025Are the Device Approval Standards Lax? JACC Cardiovasc Interv. 2025 Feb 10;18(3):380-384. doi: 10.1016/j.jcin.2024.08.037. PMID: 39939040. Device Approval in the United States: The FDA Is on Target. JACC Cardiovasc Interv. 2025 Feb 10;18(3):385-387. doi: 10.1016/j.jcin.2024.10.044. PMID: 39939041. 000
Reposted by @kaulcsmc.bsky.socialSwapnil Hiremath 🍁🇨🇦 @hswapnil.medsky.social · 13/01/2025Editorial on the renal results of FINEARTS HF in @jaccjournals.bsky.social from @kaulcsmc.bsky.social and moi Free link: authors.elsevier.com/a/1kQ%7Ec2d9... #NephSky #CardioSky #Finerenone 0156
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 19/12/2024Imagine if I excluded centers in a multicenter trial of SAVR vs TAVR where TAVR outperformed SAVR, I could show that SAVR was superior to TAVR in high-risk patients with AS (PARTNER-1A). 262
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 27/11/2024Should Heart Failure Trials routinely report on all-cause hospitalizations? Should clinicians, guidelines & payers favor interventions that favorably impact cause-specific & all-cause outcomes? jamanetwork.com/journals/jaman… jamanetwork.com/journals/jaman jamanetwork.com 191
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 23/11/2024Who are the optimal candidates for acoramidis therapy? When should it be considered first-line therapy? Does the proposed cost provide value? 160
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 23/11/2024As expected! www.statnews.com/2024/11/22/b...statnews.comBridgeBio wins FDA approval for heart disease drugThe FDA approved a new medicine from BridgeBio for patients with ATTR-CM, a progressive heart disease 140
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 22/11/2024NI margin in EVEREST II trial of MitraClip vs MV surgery for MR was 31% absolute difference, a margin through which one could drive 3 buses lined side by side. Trial met NI despite the fact that HR excluded 1.0, i.e., MitraClip was INFERIOR to surgery, yet NONINFERIOR! www.nejm.org/doi/full/10....nejm.orgPercutaneous Repair or Surgery for Mitral Regurgitation | NEJMMitral-valve repair can be accomplished with an investigational procedure that involves the percutaneous implantation of a clip that grasps and approximates the edges of the mitral leaflets at the ... 010
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 22/11/2024Even though the observed rates were lower than assumed (22%), had NI margin been fixed as risk ratio of 1.18 ([22+4]/22), the overall results would still have met NI as RR was 0.90, 0.77-1.05. An excellent example of how a NI trial should be designed and executed. Congrats to trial investigators. 011
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 20/11/2024So you are suggesting you need longer f/u and greater LDL and Lp(a) reduction, both of which favor PREVAIL. So what is the probability of success? 100
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 20/11/20244/ Key Qs What is probability of success with obicetrapib? Why should obicetrapib succeed when 2 other CETPi did not? Is absolute or relative LDL reduction key driver of benefit? Is duration of treatment important? Is LDL lowering with CETPi different from other LDL lowering Rx? 030
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 20/11/20243/ PREVAIL(Obicetrapib), N=9541, F/U: ~4y Mean LDL 103; LDL⬇️35-40%, Lp(a)⬇️45% (based on BROOKLYN) PEP (4-MACE): Powered for 15-20% RRR Recruitment completed; event-driven trial Targeting higher baseline LDL & higher risk patients 140
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 20/11/20242/ REVEAL (Anacetrapib), N=30,449, F/U: 4.1y Mean LDL 61; LDL⬇️41%, Lp(a)⬇️25% PEP (3-MACE): 10.8% vs 11.8%, HR 0.91, 0.85-0.97 Development halted (long half-life, modest Rx effect) 110
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 20/11/20241/ Is LDL-C lowering by CETP inhibitor cardioprotective? Brief history ACCELERATE (Evacetrapib), N=12092, F/U: 28m Mean LDL 81; LDL⬇️37%, Lp(a)⬇️22% PEP (MACE-5): 12.9% vs 12.8% HR 1.01, 0.91-1.11 Trial stopped early due to futility x.com/mdavidsonmd/...x.comx.com 351
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 19/11/2024Nonetheless, the clinical relevance of the favorable, but modest, MRI changes induced by Tirzepatide remain unclear. 010
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 19/11/2024What this graph tells us is that about 12% (R squared) of variability in LV mass can be explained by weight loss, thereby indicating that reduction in LV mass might be related to a possible direct cardiac effect or a paracrine effect, possibly modulated via paracardiac adipocytes. 110
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/11/2024But need to know which criteria for CRNM bleed was driving it? There were 3 or 4 criteria specified? A visit to hospital or ER is more relevant than some other ones. 100
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/11/20247/ So, what to make of a trial with 50% lower events than expected (sum total of 85 events over 3y in a trial enrolling 1600 patients), lots of missing data, & biased choice of safety outcome? Enthusiasts of LAAC will celebrate 'win', but should clinicians & payers join in? 071
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/11/20246/ But wait, should safety outcome not have captured procedural bleeding which is⬆️with LAAC? Had ISTH major bleed outcome (including procedural bleeding) been used, superiority would not have been met, and hence the win criterion would not have been met, strictly speaking! 230
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/11/20245/ Criterion for a win in NI trial: NI efficacy and superior safety. Prespecified win criterion in OPTION: NI efficacy & superior safety (nonprocedural bleeding which is biased against DOAC arm). Criterion met. So, technically a win, and LAAC earns the bragging rights, FINALLY! 110
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/11/20244/ Adjustment for missing data? “No statistical techniques were used to impute missing data”. Given this magnitude of missingness, is ITT analysis valid? 120
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/11/20243/ Mortality (29 vs 34) twice as more frequent as stroke or SE (low numbers of 14 vs 16 likely due to ablation) Crossover rate 82, 66 after PEP event Lots of missing data, 141 (8.8%) which exceeded PEP event rate! 60 (7.4%) vs 84 (10.5%): differential missingness! 100
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/11/20242/ NI met for PP analysis, met for OT analysis on RD scale, but not clear if met for RR scale ? impact of missing data SEP (maj bleed+procedural bleed), NI margin 5.25% RD, 1.48 RR Result:3.9% vs 5.0% (assumed 11%), RD -1.1%, UL 1.0%, HR 0.77, 0.48-1.24 NI met for RD & RR margin 100
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/11/2024 1/ OPTION LAAC device vs DOAC post a fib ablation N=1600, f/u 3y PEP (death, stroke or SE) NI margin 5% RD, 1.5 RR Result: 41 vs 44, 5.3% vs 5.8% (c/w 10% assumed), RD: -0.5%, UL 1.8%; HR 0.91, 0.59-1.39 NI met for RD and RR margin www.nejm.org/doi/full/10....nejm.orgLeft Atrial Appendage Closure after Ablation for Atrial Fibrillation | NEJMOral anticoagulation is recommended after ablation for atrial fibrillation among patients at high risk for stroke. Left atrial appendage closure is a mechanical alternative to anticoagulation, but ... 2114
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/11/2024Until Bluesky reaches a critical mass cardiology audience, best to post in both places. 120
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/11/2024Does Tirzepatide provide an acceptable efficacy/safety tradeoff in light of uncertainty around mortality data? 010
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/11/20242/ Worsening HF drove PEP, but importantly, intensification of oral diuretic therapy did not drive PEP Unfavorable lean on mortality! CV death: 10 (2.7%) vs 5 (1.4%), ARD=1.3% All cause death: 19 (5.2%) vs 15 (4.1%), ARD=1.1%, HR 1.25, 0.63-2.45 Missing vital status: 4 vs 11! Why? 121
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/11/20241/ SUMMIT Torzepatide in HFpEF in patients with BMI>30 (N=731) F/U 2y PEP: 1. CV death or worsening HF 2. Change in KCCQ-CSS Key results: PEP, HR 0.62, 0.41-0.95, p=0.03 kCCQ improved along with 6MWD, weight loss, SBP, & CRP. Slight ⬆️ in HR GI AEs ⬆️ www.nejm.org/doi/full/10....nejm.orgTirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity | NEJMObesity increases the risk of heart failure with preserved ejection fraction. Tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor... 241
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/11/2024Here is the link to the paper published in NEJM www.nejm.org/doi/full/10....nejm.orgIntensive Blood-Pressure Control in Patients with Type 2 Diabetes | NEJMEffective targets for systolic blood-pressure control in patients with type 2 diabetes are unclear. We enrolled patients 50 years of age or older with type 2 diabetes, elevated systolic blood press... 020
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/11/20244/ So, why did BPROAD ‘succeed’ in comparison to ACCORD-BP or ESPRIT (diabetes subgroup)? Is A1C of 7.6% optimal target in hypertensive patients? Is the effect size (0.44/100 PY) clinically meaningful and large enough to guide public policy? 342
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/11/20243/ ESPRIT (N=11255) SBP delta 15.7 mmHg PEP (CV death, MI, stroke, HF, revasc.): HR 0.88, 0.78-0.99 Stroke: 0.86, 0.73-1.02 Diabetic subgroup (N=4359) PEP (CV death, MI, stroke, HF, revasc.): HR 0.91, 0.77-1.08 110
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/11/20242/ No difference in: MI: 68 vs 81 HF: 31 vs 46 CV death: 60 vs 79 ACM: 169 vs 179 60% achieved target SBP < 120 in intensive Rx arm. To put BPROAD in perspective, ACCORD-BP (N=4773) SBP delta: 14.2 PEP (CV death, MI, stroke): 0.88, 0.73-1.06 110
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 16/11/20241/ BPROAD (N=12821) F/U 4.2y SBP delta: 16.7 (118.3 vs 135 median) A1C at 48m = 7.6% PEP (CV death, MI, stroke or HF): 393 vs 492, 0.79, 0.69-0.90 ARD = 1.55% (6.13% vs 7.68%) PEP driven by stroke: 284 vs 356, HR 0.79, 0.67-0.92 Stroke dominated PEP No diff. in serious AE 174
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 15/11/2024do you think 5% margin over 10% active control rate is wide? what if observed active control rate is lower than assumed? 100
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 15/11/20245/ Trials of Spirinolactone in CVD/CKD space HFrEF (post-MI): + (RALES) HFpEF: +/- (TOPCAT) CKD: Null (BARACK-D) Post-MI routinely: ? (CLEAR) What are the odds it will work in post-MI patients? 030
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 15/11/20244/ Will LAAO device finally win the bragging rights to claim a win? How do you define a win in a NI trial? 220
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 15/11/20243/ OPTION LAAO vs DOAC post A fib ablation. PEP: death, stroke or SE (NI assessment with margin of 5% c/w active control of 10%) SEP: non procedural major bleeding Primary safety endpoint: all comer major bleeding. 130
kaulcsmc.bsky.social @kaulcsmc.bsky.social · 15/11/20242/ What are the odds that BPROAD will validate this hypothesis? And what effect size (ARD in 4-MACE) will persuade you to aim for SBP target of <120 in diabetes in clinical practice? 130
