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PARADIGM-HF Trial: Why Sacubitril/Valsartan Changed HFrEF Care · This Is Why with Dr. Busti

• 0:00
  SPEAKER_00: Okay, consider this scenario.
• 0:02
  SPEAKER_00: You have a patient with symptomatic heart failure with reduced ejection fraction.
• 0:07
  SPEAKER_00: Why replace an ACE inhibitor that seems to be working?
• 0:11
  SPEAKER_00: And why would saccubitral and balsartin, an angiotensin receptor neprolycin inhibitor, offer something different?
• 0:21
  SPEAKER_00: The Paradigm HF or heart failure trial tested that question against an allopril and an established treatment.
• 0:29
  SPEAKER_00: And understanding why the comparison made sense helps explain why this study changed practice.
• 0:37
  SPEAKER_00: And with that, I'm Dr.
• 0:38
  SPEAKER_00: Bustaye, your host on This Is Why, where we take medical knowledge from what to why so that we can meaningfully impact how we practice healthcare.
• 0:51
  SPEAKER_00: In this series on landmark clinical trials, we'll explore practice-changing studies like this one within the context of the broader evidence so that we can better understand how and why these types of clinical trials apply in real-world practice.
• 1:09
  SPEAKER_00: Now, this isn't meant to be an exhaustive journal club.
• 1:13
  SPEAKER_00: Okay, instead, our goal is to distill each study to its essential place and in proper context so that we can better understand why we do what we do every day.
• 1:25
  SPEAKER_00: In this lecture, I'm going to be talking about the paradigm heart failure trial.
• 1:30
  SPEAKER_00: Okay, so the first question is why was this trial needed?
• 1:35
  SPEAKER_00: We need to start with the problem we're trying to solve.
• 1:38
  SPEAKER_00: In heart failure, guys, remember with the reduced ejection fraction, the problem isn't limited only to impaired pumping.
• 1:48
  SPEAKER_00: It also includes other common factors, things like sustained activation of the renin, angiotensin, aldosterone, as well as the sympathetic nervous systems.
• 2:03
  SPEAKER_00: That can those things can make matters worse.
• 2:07
  SPEAKER_00: Angiotensin too, constriction on blood vessels, increasing resistance against that heart that it has to pump against.
• 2:16
  SPEAKER_00: Aldosterone, we know, promotes sodium water retention.
• 2:22
  SPEAKER_00: Persistent signaling also, over time, right, contributes to the adverse remodeling, changes in the actual heart structure that can further impair the overall function.
• 2:36
  SPEAKER_00: That's why blocking these pathways mattered.
• 2:40
  SPEAKER_00: Okay, now ACE inhibitors, beta blockers, mineralocorticoid receptor antagonists had already improved outcomes by this time in the evolution of the evidence.
• 2:51
  SPEAKER_00: But patients still experienced hospitalizations and premature death.
• 2:58
  SPEAKER_00: And so the question wasn't whether the established treatment worked, it was whether we could do better.
• 3:07
  SPEAKER_00: Now we know that the heart produces signals that push in the other direction.
• 3:14
  SPEAKER_00: When its walls experience increased stretch or stress, okay, especially when that impaired contraction is occurring, it releases naturic peptides, including ANP and BNP.
• 3:34
  SPEAKER_00: Now we often encounter these as biomarkers in our labs, but they also have biological actions.
• 3:42
  SPEAKER_00: They bind to receptors that activate guanolcyclase, increasing intracellular messengers called cyclic GMP.
• 3:52
  SPEAKER_00: And that signal supports a number of things: vessel relaxation, sodium excretion, and opposition to abnormal growth and fibrosis.
• 4:05
  SPEAKER_00: The important connection is from a hormone signal to less vascular resistance, less sodium retention, and potentially more favorable cardiac structure.
• 4:21
  SPEAKER_00: Now, these peptides can already be elevated in heart failure.
• 4:25
  SPEAKER_00: This is not simply a deficiency.
• 4:28
  SPEAKER_00: Rather, the protective response doesn't fully counter the disease.
• 4:34
  SPEAKER_00: Now, neprolycin is an enzyme that breaks down these peptides.
• 4:40
  SPEAKER_00: Inhibiting that breakdown offered a way to strengthen an existing protective response.
• 4:50
  SPEAKER_00: And that's where saccubitrol comes in.
• 4:53
  SPEAKER_00: Now it's technically a prodrug.
• 4:56
  SPEAKER_00: It gets converted to the active metabolite LBQ657, which is known to inhibit that neprolycin.
• 5:06
  SPEAKER_00: But neprolycin doesn't break down only healthful peptides that we want.
• 5:13
  SPEAKER_00: It also breaks down angiotensin 2.
• 5:18
  SPEAKER_00: So by inhibiting neprolycin alone, we allow angiotensin 2 to stay around longer and it activates those angiotensin subtype 1 receptors.
• 5:32
  SPEAKER_00: Doing that therefore leaves us with more of a negative effect than what we're trying to oppose.
• 5:42
  SPEAKER_00: And that's where valsartin comes in.
• 5:44
  SPEAKER_00: It addresses that problem by blocking the angiotensin 2 at the AT1 receptor.
• 5:52
  SPEAKER_00: And the combination of those two medications therefore preserves protective peptide signaling while also blocking important angiotensin mediated effects on all three of those main areas: basal constriction, sodium water retention, and remodeling.
• 6:13
  SPEAKER_00: That's the rationale for combining the two actions in an ARNI drug class, which is angiotensin receptor neprolycin inhibitor.
• 6:25
  SPEAKER_00: So why not pair neprolycin inhibition with an ACE inhibitor instead?
• 6:32
  SPEAKER_00: Well, because remember guys, both enzymes participate in the breakdown of bretokinin.
• 6:39
  SPEAKER_00: Why that matter?
• 6:40
  SPEAKER_00: Well, because inhibiting both actually increases the risk of angioedema concerns.
• 6:48
  SPEAKER_00: And we saw that early on with experiences of other medications that were demonstrated.
• 6:56
  SPEAKER_00: Now using an angiotensin receptor blocker avoids concurrent ACE inhibition.
• 7:03
  SPEAKER_00: And so although angioedema risk is not completely eliminated, it was reduced.
• 7:10
  SPEAKER_00: Okay, so, or it's thought to reduce, right?
• 7:12
  SPEAKER_00: So now the question that led to the paradigm heart failure trial becomes clearer, I hope.
• 7:20
  SPEAKER_00: And it was could this combined strategy prevent even more cardiovascular deaths or heart failure-related hospitalizations than some of the standard therapy alone, like an allopril?
• 7:34
  SPEAKER_00: So you have a convincing mechanism alone, but it couldn't only answer that question.
• 7:39
  SPEAKER_00: You need evidence, right?
• 7:41
  SPEAKER_00: And neither could a favorable, you know, laboratory result.
• 7:45
  SPEAKER_00: We needed a randomized, controlled trial measuring outcomes that matter to patients.
• 7:55
  SPEAKER_00: All right, so what did the paradigm heart failure trial actually test?
• 8:01
  SPEAKER_00: This is where we start breaking down the study design.
• 8:05
  SPEAKER_00: Okay, so follow me.
• 8:07
  SPEAKER_00: The paradigm heart failure trial was a randomized double blind trial.
• 8:13
  SPEAKER_00: They randomized 8,442 patients.
• 8:17
  SPEAKER_00: Okay.
• 8:18
  SPEAKER_00: 8,399 were included in the efficacy analysis.
• 8:23
  SPEAKER_00: Okay.
• 8:24
  SPEAKER_00: Now participants had known chronic symptomatic heart failure with reduced ejection fraction.
• 8:33
  SPEAKER_00: The entry threshold began at 40% EF or less and was later tightened to 35% or less.
• 8:43
  SPEAKER_00: Most had New York heart functional classification, two or three related heart failure and symptoms.
• 8:48
  SPEAKER_00: And before randomization, guys, participants went through a run-in period.
• 8:54
  SPEAKER_00: First, it was with analopril and then followed, then with saccubitural valsartin combined therapy.
• 9:02
  SPEAKER_00: They had to tolerate the target doses of both to proceed.
• 9:07
  SPEAKER_00: That detail will matter when we interpret the tolerability, guys.
• 9:14
  SPEAKER_00: Now, the randomized comparison was enalapril 10 milligrams twice daily versus the combined, then called LCZ 696, 200 milligrams twice daily.
• 9:30
  SPEAKER_00: That combination dose corresponds to today's sacchubitral, valsartin 97 uh dash 103, 103 milligrams, twice daily target.
• 9:48
  SPEAKER_00: Now other background heart failure treatments were continued, and that's important.
• 9:54
  SPEAKER_00: So the ARNI replaced ACE inhibitor inhibition.
• 9:58
  SPEAKER_00: It wasn't added on top of enallopril.
• 10:03
  SPEAKER_00: So the primary endpoint was time to cardiovascular death or first hospitalization for worsening heart failure.
• 10:12
  SPEAKER_00: Okay, it was a composite.
• 10:14
  SPEAKER_00: Either event counts, and the analysis focuses on the first qualifying event.
• 10:23
  SPEAKER_00: Now the median follow-up was 27 months.
• 10:26
  SPEAKER_00: The trial stopped early after crossing pre-specified efficacy boundaries.
• 10:33
  SPEAKER_00: Now keep the comparison in mind as we review the findings.
• 10:38
  SPEAKER_00: The investigators weren't asking whether the treatment was better than nothing.
• 10:44
  SPEAKER_00: They were asking whether the strategy was better than a treatment clinicians already had good reason to use and even trusted.
• 10:54
  SPEAKER_00: So what were the important findings?
• 10:58
  SPEAKER_00: Well, that primary outcome occurred in 21.8% of the saccubitral valsartin group compared with 26.5% of the anallopril group.
• 11:11
  SPEAKER_00: That's important and relevant.
• 11:14
  SPEAKER_00: The hazards ratio was 0.8 with a 95% confidence interval of 0.73 to 0.87.
• 11:25
  SPEAKER_00: In other words, a 20% lower relative hazard of cardiovascular death or first heart failure-related hospitalization.
• 11:37
  SPEAKER_00: Now translate that into an absolute difference.
• 11:43
  SPEAKER_00: Subtracting the reported percentage gives 4.7 percentage points.
• 11:50
  SPEAKER_00: Approximately 47 fewer patients experiencing the primary outcome per 1,000 treated over the course of the trial.
• 12:02
  SPEAKER_00: Now these are two ways of describing the results.
• 12:06
  SPEAKER_00: They're not interchangeable numbers.
• 12:18
  SPEAKER_00: And that absolute difference belongs to this population and its follow-up.
• 12:24
  SPEAKER_00: It's not an annual estimate or a promise for every patient we treat today.
• 12:31
  SPEAKER_00: The benefit wasn't confined also to hospitalization.
• 12:34
  SPEAKER_00: Cardiovascular death occurred in 13.3% versus 16.5%.
• 12:42
  SPEAKER_00: First heart failure hospitalizations occurred in 12.8% versus 15.6%.
• 12:50
  SPEAKER_00: And death from any cause was also lower, 17% versus 19.8% with a hazards ratio of 0.84.
• 13:03
  SPEAKER_00: For each comparison, saccubitral valsartin is the first number and analpril is that second number.
• 13:10
  SPEAKER_00: The clinical message is that both cardiovascular mortality and hospitalization moved in a favorable direction towards saccubitral and balsartin.
• 13:21
  SPEAKER_00: But greater benefit didn't mean fewer problems in every category.
• 13:28
  SPEAKER_00: That's right.
• 13:41
  SPEAKER_00: Now potassium above 6 millimoles per liter and the creatinine reaching a target of at least 2.5 milligrams per deciliter were less frequent than with analpril.
• 13:53
  SPEAKER_00: Now these laboratory findings don't establish a benefit on the trial's renal composite endpoint, and they don't make uh kidney or potassium monitoring optional.
• 14:05
  SPEAKER_00: Angiodema was another thing that came up, right?
• 14:08
  SPEAKER_00: It was uncommon, but numerically more frequent with the ARNI combined group, right?
• 14:15
  SPEAKER_00: The between group difference wasn't statistically significant, which is not the same as proving equal risk.
• 14:23
  SPEAKER_00: So we have a meaningful outcome advantage with blood pressure and tolerability still central to the implementation.
• 14:33
  SPEAKER_00: So why did this change practice and where are the limits?
• 14:38
  SPEAKER_00: The practice changing finding was improvement beyond an established active comparity on top of other background treatment.
• 14:48
  SPEAKER_00: The lesson wasn't that ACE inhibitors had stopped working, it was that we now had evidence for a different strategy that could further improve outcomes in eligible patients.
• 15:02
  SPEAKER_00: Now, later analysis of deaths from the paradigm heart failure found reductions in both sudden death and death from worsening heart failure.
• 15:11
  SPEAKER_00: That's useful context, but it's still the same trial population and not an independent replication or proof that the drug directly prevents dysrhythmias.
• 15:24
  SPEAKER_00: We also need to separate out a known drug action from a fully proven explanation of its survival effect.
• 15:34
  SPEAKER_00: We know the drug targets and the physiologic rationale is coherent.
• 15:40
  SPEAKER_00: We don't know precisely how much of the outcome benefit came from each downstream effect.
• 15:47
  SPEAKER_00: The trial compared complete treatment strategies.
• 15:51
  SPEAKER_00: It didn't isolate the effect of saccubitral against the same valsartan background.
• 15:59
  SPEAKER_00: Now return to that run-in period.
• 16:02
  SPEAKER_00: Okay, patients couldn't tolerate the target doses, didn't end up making it into the randomization comparison.
• 16:10
  SPEAKER_00: So the results don't mean every patient walking into the clinic will actually tolerate those doses.
• 16:17
  SPEAKER_00: And patients with important hypotension or severe renal impairment were excluded.
• 16:24
  SPEAKER_00: And a few had class four symptoms.
• 16:28
  SPEAKER_00: So early stopping of this trial also limited, at some degree, the planned duration of observation.
• 16:35
  SPEAKER_00: Novarta sponsored the trial, and the clinical endpoints were assessed by a blinded adjudication committee.
• 16:43
  SPEAKER_00: Those are relevant appraisal details, not substitutes for evaluating the design and the results.
• 16:48
  SPEAKER_00: Finally, something we need to consider is that this trial preceded today's general routine of SGLT2 inhibitor use.
• 16:57
  SPEAKER_00: We shouldn't assume its exact absolute benefit will be identical on every contemporary regimen.
• 17:06
  SPEAKER_00: So moving forward or on, what did later studies add and where does the ARNI now fit?
• 17:16
  SPEAKER_00: Okay, well, subsequent evidence helps answer three practical questions.
• 17:21
  SPEAKER_00: First, could treatment begin during a hospitalization?
• 17:26
  SPEAKER_00: The pioneer heart failure studied patients after hemodynamic stabilization, and they found a greater reduction in the NT ProBMP with saccubitual valsartin than with an allopril.
• 17:42
  SPEAKER_00: That supported earlier initiation in appropriate patients.
• 17:46
  SPEAKER_00: Its primary endpoint was a biomarker, however, not mortality.
• 17:51
  SPEAKER_00: Second question: Was there any evidence consistent with improved cardiac structure?
• 17:59
  SPEAKER_00: Well, in the proved heart failure, uh reductions in the NT ProBMP were associated with reverse remodeling, improvements in measurements of the heart size as well as the function.
• 18:13
  SPEAKER_00: But this was a single-arm study, so it supports the biologic explanation without proving why survival improved.
• 18:23
  SPEAKER_00: Third, did the findings extend to every related population?
• 18:29
  SPEAKER_00: Paragon heart failure, it was done in patients with higher ejection fractions, and the Paradise MI study looked at after myocardial infarction.
• 18:40
  SPEAKER_00: They did not establish superiority for their overall pre-specified primary endpoints.
• 18:48
  SPEAKER_00: That doesn't mean that no patient in those studies can benefit.
• 18:52
  SPEAKER_00: It means that the chronic symptomatic heart failure with reduced EF result cannot simply be transferred or unchanged to every form of heart failure or every post-MI patient.
• 19:07
  SPEAKER_00: So where does that leave us today?
• 19:10
  SPEAKER_00: Well, groups like American Heart, American College of Cardiology, the Heart Failure Society guidance recommends ARNI therapy for appropriate symptomatic heart failure patients with reduced EF, generally in place of an ACE inhibitor or separate angiotensin receptor blocker when feasible and tolerated.
• 19:36
  SPEAKER_00: Now it also belongs alongside an evidence-based beta blocker, a mineral corticoid receptor antagonist, and SGLT2 inhibitor, not in place of them.
• 19:50
  SPEAKER_00: So we don't need to wait for another deterioration or require a trial of an ACE inhibitor before starting ARNI therapy in appropriate patients.
• 20:01
  SPEAKER_00: Initiation and titration should reflect stability, tolerance, and access.
• 20:06
  SPEAKER_00: When ARNI isn't feasible, an appropriate ACE inhibitor or ansiotensin receptor blocker remains an alternative.
• 20:15
  SPEAKER_00: So how does all of this then further translate into everyday clinical practice?
• 20:21
  SPEAKER_00: Well, start by reviewing blood pressure, volume, status, kidney function, the potassium, the medication list, and whether that patient can obtain and consistently take the treatment.
• 20:34
  SPEAKER_00: The first practical rule is replace, don't overlap, right?
• 20:38
  SPEAKER_00: After the last ACE inhibitor dose, allow for approximately 36 hours before starting saccubitral balsartin.
• 20:49
  SPEAKER_00: The same separation is needed when switching back to an ACE inhibitor.
• 20:55
  SPEAKER_00: Now remember the braidakinin explanation, overlapping ACE with Neprolycin inhibition increases that risk of angioedema.
• 21:06
  SPEAKER_00: That specific washout isn't required when switching from a separate angiotensin receptor blocker, but the ARB must still be stopped.
• 21:16
  SPEAKER_00: Now valsartin is already in that combination.
• 21:20
  SPEAKER_00: The usual labeled adult starting dose is 49-51 milligrams twice daily by mouth.
• 21:28
  SPEAKER_00: The lower 24-26 milligram twice daily dose is used in specified circumstances, including no or low prior ACE inhibitor or angiotensin receptor exposure, severe renal impairment, or moderate hepatic impairment.
• 21:46
  SPEAKER_00: The dose is increased every two to four weeks toward that target dose, around 97 to 103 milligrams twice a day as tolerated.
• 21:56
  SPEAKER_00: Now, severe patients with severe renal impairment.
• 22:00
  SPEAKER_00: Being excluded from the paradigm heart failure trial doesn't make it an absolute labeled contraindication.
• 22:05
  SPEAKER_00: It calls for a lower starting dose and careful assessment.
• 22:10
  SPEAKER_00: Trial eligibility and prescribing restrictions are not necessarily the same things.
• 22:15
  SPEAKER_00: Next, you want to assess symptoms and the blood pressure, monitor that renal function and the potassium during both the initiation and the titration phase.
• 22:25
  SPEAKER_00: Remember, there was that statistically favorable trial comparison doesn't necessarily remove any individual risk that we might see in real world.
• 22:35
  SPEAKER_00: What about those high-risk scenarios?
• 22:37
  SPEAKER_00: Well, guidelines advise against ARNI and anyone with a history of angioedema.
• 22:42
  SPEAKER_00: Okay, the labeling specifically contraindicates previous ACE inhibitor or ARB-related angioedema.
• 22:49
  SPEAKER_00: That's important.
• 22:50
  SPEAKER_00: There's other risks and things, but one is a uh carries a fetal toxicity warning and should be stopped promptly if pregnancy is detected.
• 23:00
  SPEAKER_00: Okay, now one final pharmacology connection that helps with follow-up is that BNP can rise after starting ARNI therapy, especially early.
• 23:12
  SPEAKER_00: Because remember that neprolycin participates in its breakdown.
• 23:17
  SPEAKER_00: Anti-proBNP is not a neprolycin substrate, so it's less directly affected by the drug's action.
• 23:25
  SPEAKER_00: But BNP doesn't become useless at all.
• 23:29
  SPEAKER_00: Okay?
• 23:29
  SPEAKER_00: Both markers retain some degree of prognostic information.
• 23:34
  SPEAKER_00: A rising BNP still needs clinical interpretation.
• 23:38
  SPEAKER_00: Don't automatically dismiss it as, oh, it's the medicine.
• 23:41
  SPEAKER_00: And don't interpret either marker without the patient's overall condition being considered.
• 23:46
  SPEAKER_00: So the practical takeaway, guys, is that we need to return back to my initial opening question.
• 23:53
  SPEAKER_00: Why change treatment in someone who seems stable?
• 23:58
  SPEAKER_00: Well, because symptom stability and the best achievable long-term outcomes are not necessarily the same thing.
• 24:07
  SPEAKER_00: Paradigm heart failure trials showed that in eligible patients with symptomatic heart failure with reduced EF, saccubitral combined with valsartin, improved important outcomes compared to analopril alone.
• 24:22
  SPEAKER_00: Okay?
• 24:22
  SPEAKER_00: Now the pharmacology makes the strategy understandable.
• 24:27
  SPEAKER_00: Block important harmful signaling while strengthening an existing protective response.
• 24:34
  SPEAKER_00: The randomized trial established the clinical benefit.
• 24:37
  SPEAKER_00: Later studies help clarify its use and set boundaries and limits.
• 24:43
  SPEAKER_00: Remember the results, but also remember its context.
• 24:47
  SPEAKER_00: Better outcomes than an active comparator, but not a guarantee for every patient and not a replacement for the rest of guideline directed therapies.
• 24:58
  SPEAKER_00: Alright?
• 24:59
  SPEAKER_00: So that is the trial and context.
• 25:03
  SPEAKER_00: This is why my goal, guys, is to move beyond what the data shows to understand why it matters so that we can apply it more effectively in clinical practice.
• 25:15
  SPEAKER_00: Again, if you enjoyed or found this helpful, please share this episode with your friends, colleagues, especially those who are in training when they're learning to apply the evidence in the proper context of the things that they learn at the core knowledge level.
• 25:29
  SPEAKER_00: And be sure to subscribe and keep learning the why.
• 25:32
  SPEAKER_00: Never give up on that.
• 25:33
  SPEAKER_00: And we'll see you next time.