In adults with stable angina, PCI vs. a placebo procedure reduced angina symptoms at 12 wk.

SOURCE CITATION: Rajkumar CA, Foley MJ, Ahmed-Jushuf F, et al; ORBITA-2 Investigators. A placebo-controlled trial of percutaneous coronary intervention for stable angina. N Engl J Med. 2023;389:2319-2330. 38015442.

Feasibility of double-blinded, placebo-controlled interventional study for assessing catheter ablation efficacy in persistent atrial fibrillation: Insights from the ORBITA AF feasibility study.

BACKGROUND: To date, there are no randomized, double-blinded clinical trials comparing catheter ablation to DC cardioversion (DCCV) with medical therapy in patients with persistent atrial fibrillation (PersAF). Conducting a large-scale trial to address this question presents considerable challenges, including recruitment, blinding, and implementation. We conducted a pilot study to evaluate the feasibility of conducting a definitive placebo-controlled trial. METHODS: This prospective trial was carried out at Barts Heart Centre, United Kingdom, employing a randomized, double-blinded, placebo-controlled design. Twenty patients with PersAF (duration <2 years) were recruited, representing 10% of the proposed larger trial as determined by a power calculation. The patients were randomized in a 1:1 ratio to receive either PVI ± DCCV (PVI group) or DCCV + Placebo (DCCV group). The primary endpoint of this feasibility study was to evaluate patient blinding. Patients remained unaware of their treatment allocation until end of study. RESULTS: During the study, 35% of patients experienced recurrence of PersAF prior to completion of 12 months follow-up. Blinding was successfully maintained amongst both patients and medical staff. The DCCV group had a trend to higher recurrence and repeat procedure rate compared to the PVI group (recurrence of PersAF 60% vs 30%; p = .07 and repeat procedure 70% vs 40%; p = .4). The quality of life experienced by individuals in the PVI group showed improvement, as evidenced by enhanced scores on the AF specific questionnaire (AF PROMS) (3 [±4] vs 21 [±8]) and SF-12 mental-component raw score (51.4 [±7] vs 43.24 [±15]) in patients who maintained sinus rhythm at 12 months. CONCLUSION: This feasibility study establishes the potential for conducting a blinded, placebo-controlled trial to evaluate the efficacy of PVI versus DCCV in patients with PersAF.

A Placebo-Controlled Trial of Percutaneous Coronary Intervention for Stable Angina.

BACKGROUND: Percutaneous coronary intervention (PCI) is frequently performed to reduce the symptoms of stable angina. Whether PCI relieves angina more than a placebo procedure in patients who are not receiving antianginal medication remains unknown. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of PCI in patients with stable angina. Patients stopped all antianginal medications and underwent a 2-week symptom assessment phase before randomization. Patients were then randomly assigned in a 1:1 ratio to undergo PCI or a placebo procedure and were followed for 12 weeks. The primary end point was the angina symptom score, which was calculated daily on the basis of the number of angina episodes that occurred on a given day, the number of antianginal medications prescribed on that day, and clinical events, including the occurrence of unblinding owing to unacceptable angina or acute coronary syndrome or death. Scores range from 0 to 79, with higher scores indicating worse health status with respect to angina. RESULTS: A total of 301 patients underwent randomization: 151 to the PCI group and 150 to the placebo group. The mean (±SD) age was 64±9 years, and 79% were men. Ischemia was present in one cardiac territory in 242 patients (80%), in two territories in 52 patients (17%), and in three territories in 7 patients (2%). In the target vessels, the median fractional flow reserve was 0.63 (interquartile range, 0.49 to 0.75), and the median instantaneous wave-free ratio was 0.78 (interquartile range, 0.55 to 0.87). At the 12-week follow-up, the mean angina symptom score was 2.9 in the PCI group and 5.6 in the placebo group (odds ratio, 2.21; 95% confidence interval, 1.41 to 3.47; P<0.001). One patient in the placebo group had unacceptable angina leading to unblinding. Acute coronary syndromes occurred in 4 patients in the PCI group and in 6 patients in the placebo group. CONCLUSIONS: Among patients with stable angina who were receiving little or no antianginal medication and had objective evidence of ischemia, PCI resulted in a lower angina symptom score than a placebo procedure, indicating a better health status with respect to angina. (Funded by the National Institute for Health and Care Research Imperial Biomedical Research Centre and others; ORBITA-2 ClinicalTrials.gov number, NCT03742050.).

Erroneous Rapid Exchange Balloon Inflation During Coronary Angioplasty in a Male Patient in His 70s With Chronic Stable Angina.

This case report discusses an erroneous rapid exchange balloon inflation during coronary angioplasty in a patient who presented with a right coronary artery lesion on angiography.

Clinical Outcome of Revascularization Deferral With Instantaneous Wave-Free Ratio and Fractional Flow Reserve: A 5-Year Follow-Up Substudy From the iFR-SWEDEHEART Trial.

Background Although physiology-based assessment of coronary artery stenosis using instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) are established methods of guiding coronary revascularization, its clinical outcome in long-term deferral needs further evaluation, especially with acute coronary syndrome as a clinical presentation. The aim was to evaluate the long-term clinical outcome of deferral of revascularization based on iFR or FFR. Methods and Results This is a substudy of the iFR-SWEDEHEART (Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve in Patients With Stable Angina Pectoris or Acute Coronary Syndrome) randomized clinical trial, where patients deferred from revascularization from each study arm were selected. Nine hundred eight patients deferred from coronary revascularization with iFR (n=473) and FFR (n=435) were followed for 5 years. The national quality registry, SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies), was used for patient data collection and clinical follow-up. The end point was major adverse cardiac events and their individual components all-cause death, cardiovascular death, noncardiovascular death, nonfatal myocardial infarction, and unplanned revascularization. No significant difference was found in major adverse cardiac events (iFR 18.6% versus FFR 16.8%; adjusted hazard ratio, 1.08 [95% CI, 0.79-1.48]; P=0.63) or their individual components. Conclusions No differences in clinical outcomes after 5-year follow-up were noted when comparing iFR versus FFR as methods for deferral of coronary revascularization in patients presenting with stable angina pectoris and acute coronary syndrome. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02166736.

Impact of policy alterations on elective percutaneous coronary interventions in Japan.

OBJECTIVE: Establishing appropriate percutaneous coronary intervention (PCI) in stable angina pectoris (SAP) has become a distinctive performance measure worldwide. Clinical guidelines call for documenting ischaemia in patients with SAP prior to elective PCI. The Japanese Ministry of Health, Labour and Welfare introduced a new reimbursement policy in April 2018 to promote the appropriate and judicious implementation of PCI. The 2018 reimbursement changes clarified the required proof of ischaemia. Tests to evaluate functional ischaemia and coronary stenosis have been added as a requirement for reimbursement. We examined whether this reimbursement revision had an impact on PCI procedures for SAP in Japan. METHODS: We used administrative claims data in Japan's Diagnosis Procedure Combination database from April 2014 through March 2020. We used interrupted time series analyses with a control to ascertain the impacts on elective PCI procedures before and after the Japanese reimbursement revision. The primary outcome was the change in elective PCI procedures per month. Emergent PCI procedures served as a control group. RESULTS: A total of 773 240 PCI procedures were identified between April 2014 and March 2020: 388 817 and 180 462 elective PCIs before and after the reimbursement revision, respectively. After the 2018 reimbursement revision, significant trend changes were found in elective PCI procedures per month (-106.3, 95% CI -155.8 to -56.8, p<0.01), while the number of emergent PCIs remained stable throughout the study period. CONCLUSIONS: After revising the reimbursement tariff for elective PCIs in 2018, there was a significant reduction in elective PCI procedures per month.

Paclitaxel drug-coated balloon-only angioplasty for de novo coronary artery disease in elective clinical practice.

OBJECTIVE: We aimed to investigate the safety of drug-coated balloon (DCB)-only angioplasty compared to drug-eluting stent (DES), as part of routine clinical practice. BACKGROUND: The recent BASKETSMALL2 trial demonstrated the safety and efficacy of DCB angioplasty for de novo small vessel disease. Registry data have also demonstrated that DCB angioplasty is safe; however, most of these studies are limited due to long recruitment time and a small number of patients with DCB compared to DES. Therefore, it is unclear if DCB-only strategy is safe to incorporate in routine elective clinical practice. METHODS: We compared all-cause mortality and major cardiovascular endpoints (MACE), including unplanned target lesion revascularisation (TLR) of all patients treated with DCB or DES for first presentation of stable angina due to de novo coronary artery disease between 1st January 2015 and 15th November 2019. Data were analysed with Cox regression models and cumulative hazard plots. RESULTS: We present 1237 patients; 544 treated with DCB and 693 treated with DES for de novo, mainly large-vessel coronary artery disease. On multivariable Cox regression analysis, only age and frailty remained significant adverse predictors of all-cause mortality. Univariable, cumulative hazard plots showed no difference between DCB and DES for either all-cause mortality or any of the major cardiovascular endpoints, including unplanned TLR. The results remained unchanged following propensity score-matched analysis. CONCLUSION: DCB-only angioplasty, for stable angina and predominantly large vessels, is safe compared to DES as part of routine clinical practice, in terms of all-cause mortality and MACE, including unplanned TLR.

Development and user-testing of a digital patient decision aid to facilitate shared decision-making for people with stable angina.

BACKGROUND: Research shows that people with stable angina need decision support when considering elective treatments. Initial treatment is with medicines but patients may gain further benefit with invasive percutaneous coronary intervention (PCI). Choosing between these treatments can be challenging for patients because both confer similar benefits but have different risks. Patient decision aids (PtDAs) are evidence-based interventions that support shared decision-making (SDM) when making healthcare decisions. This study aimed to develop and user-test a digital patient decision aid (CONNECT) to facilitate SDM for people with stable angina considering invasive treatment with elective PCI. METHODS: A multi-phase study was conducted to develop and test CONNECT (COroNary aNgioplasty dECision Tool) using approaches recommended by the International Patient Decision Aid Standards Collaboration: (i) Steering Group assembled, (ii) review of clinical guidance, (iii) co-design workshops with patients and cardiology health professionals, (iv) first prototype developed and 'alpha' tested (semi-structured cognitive interviews and 12-item acceptability questionnaire) with patients, cardiologists and cardiac nurses, recruited from two hospitals in Northern England, and (v) final PtDA refined following iterative user-feedback. Quantitative data were analysed descriptively and qualitative data from the interviews analysed using deductive content analysis. RESULTS: CONNECT was developed and user-tested with 34 patients and 29 cardiology health professionals. Findings showed that CONNECT was generally acceptable, usable, comprehensible, and desirable. Participants suggested that CONNECT had the potential to improve care quality by personalising consultations and facilitating SDM and informed consent. Patient safety may be improved as CONNECT includes questions about symptom burden which can identify asymptomatic patients unlikely to benefit from PCI, as well as those who may need to be fast tracked because of worsening symptoms. CONCLUSIONS: CONNECT is the first digital PtDA for people with stable angina considering elective PCI, developed in the UK using recommended processes and fulfilling international quality criteria. CONNECT shows promise as an approach to facilitate SDM and should be evaluated in a clinical trial. Further work is required to standardise the provision of probabilistic risk information for people considering elective PCI and to understand how CONNECT can be accessible to underserved communities.

Transitions of Care Among Patients Undergoing Percutaneous Coronary Intervention for Stable Angina: Insights From the Veterans Affairs Clinical Assessment Reporting and Tracking Program.

Background Effective transitions from the procedural to outpatient setting are essential to ensure high-quality cardiovascular care across health care systems, particularly among patients undergoing invasive cardiac procedures. We evaluated the association of postprocedural follow-up visits and antiplatelet prescriptions with clinical outcomes among patients undergoing percutaneous coronary intervention for stable angina at community or Veterans Affairs (VA) hospitals. Methods and Results Patients who actively received care within the VA Healthcare System and underwent percutaneous coronary intervention for stable angina at a community or VA hospital between October 1, 2015, and September 30, 2019, were identified. We compared mortality for patients receiving community or VA care, and among subgroups of community-treated patients by the presence of a postprocedural follow-up visit within 30 days or prescription for antiplatelet (P2Y12) medication within 120 days of the procedure. Among 12 837 patients who survived the first 30 days, 5133 were treated at community hospitals, and 7704 were treated in the VA. Prescriptions for antiplatelet therapy were less common for those treated in the community (85%) compared with the VA at 1 year (95%; hazard ratio [HR], 0.46; 95% CI, 0.44-47). Compared with VA-treated patients, the hazards for death were similar for patients treated in the community with a follow-up visit (HR, 1.17; 95% CI, 0.97-1.40) or with a fill for an antiplatelet therapy (HR, 1.08; 95% CI, 0.90-1.30). However, patients treated in the community without a follow-up visit had an 86% (HR, 1.86; 95% CI, 1.40-2.48) increased hazard of death, and those without antiplatelet prescription fill had a 144% increased hazard of death (HR, 2.44; 95% CI, 1.85-3.21) compared with all VA-treated patients. Conclusions Patients treated at community facilities have a decreased chance of receiving antiplatelet prescriptions after percutaneous coronary intervention with a concordant increased hazard of mortality, emphasizing the importance of transitions of care across health care systems when assessing cardiovascular quality.

A double-blind randomised placebo-controlled trial of percutaneous coronary intervention for the relief of stable angina without antianginal medications: design and rationale of the ORBITA-2 trial.

Percutaneous coronary intervention (PCI) is frequently performed for stable angina. However, the first blinded trial, ORBITA, did not show a placebo-controlled increment in exercise time in patients with single-vessel disease, at 6 weeks, on maximal antianginal therapy. ORBITA-2 will assess the placebo-controlled efficacy of PCI on angina frequency in patients with single- or multivessel disease, at 12 weeks, on no antianginal therapy. ORBITA-2 is a double-blind placebo-controlled trial randomising participants with (i) angina at presentation, (ii) documented angina during the 2-week pre-randomisation symptom assessment phase, (iii) objective evidence of ischaemia, (iv) single- or multivessel disease, and (v) clinical eligibility for PCI. At enrolment, antianginals will be stopped, and angina questionnaires completed. Participants will record their symptoms on a smartphone application daily throughout the trial and will undergo exercise treadmill testing and stress echocardiography at pre-randomisation. They will then undergo coronary angiography with unblinded invasive physiology assessment. Eligible participants will then be sedated to a deep level of conscious sedation and randomised 1:1 between PCI and placebo. After the 12-week blinded follow-up period, they will return for questionnaires, exercise testing and stress echocardiography assessment. If angina becomes intolerable, antianginals will be introduced using a prespecified medication protocol. The primary outcome is an angina symptom score using an ordinal clinical outcome scale for angina. Secondary outcomes include exercise treadmill time, angina frequency, angina severity and quality of life. Trial registration: ClinicalTrials.gov: NCT03742050.

Comparison of safety and effectiveness between the right and left radial artery approach in percutaneous coronary intervention.

INTRODUCTION AND OBJECTIVES: There is a paucity of data comparing the left radial approach (LRA) and right radial approach (RRA) for percutaneous coronary intervention (PCI) in all-comers populations and performed by operators with different experience levels. Thus, we sought to compare the safety and clinical outcomes of the RRA and LRA during PCI in "real-world" patients with either stable angina or acute coronary syndrome (ACS). METHODS: To overcome the possible impact of the nonrandomized design, a propensity score was calculated to compare the 2 radial approaches. The study group comprised 18 716 matched pairs with stable angina and 46 241 with ACS treated with PCI and stent implantation between 2014 and 2017 in 151 tertiary invasive cardiology centers in Poland (the ORPKI Polish National Registry). RESULTS: The rates of death and periprocedural complications were similar for the RRA and LRA in stable angina patients. A higher radiation dose was observed with PCI via the LRA in both clinical presentations (stable angina: 1067.0±947.1 mGy vs 1007.4±983.5 mGy, P=.001; ACS: 1212.7±1005.5 mGy vs 1053.5±1029.7 mGy, P=.001). More contrast was used in LRA procedures but only in ACS patients (174.2±75.4mL vs 167.2±72.1mL, P=.001). Furthermore, periprocedural complications such as coronary artery dissection (0.16% vs 0.09%, P=.008), no-reflow phenomenon (0.65% vs 0.49%, P=.005), and puncture site bleeding (0.09% vs 0.05%, P=.04) were more frequently observed with the LRA in ACS patients. There was no difference in mortality between the 2 groups (P=.90). CONCLUSIONS: Our finding of poorer outcomes with the LRA may be related to lower operator experience with this approach. While both the LRA and RRA are safe in the setting of stable angina, the LRA was associated with a higher rate of periprocedural complications during PCI in ACS patients.

Burden and Predictors of Chest Pain-Related Health-Care Utilization Following Percutaneous Coronary Intervention.

Chest pain (CP) has been reported in 20% to 40% of patients 1 year after percutaneous coronary intervention (PCI), though rates of post-PCI health-care utilization (HCU) for CP in nonclinical trial populations are unknown. Furthermore, the contribution of noncardiac factors - such as pulmonary, gastrointestinal, and psychological - to post-PCI CP HCU is unclear. Accordingly, the objectives of this study were to describe long-term trajectories and identify predictors of post-PCI CP-related HCU in real-world patients undergoing PCI for any indication. This retrospective cohort study included patients receiving PCI for any indication from 2003 to 2017 through a single integrated health-care system. Post-PCI CP-related HCU tracked through electronic medical records included (1) office visits, (2) emergency department (ED) visits, and (3) hospital admissions with CP or angina as the primary diagnosis. The strongest predictors of CP-related HCU were identified from >100 candidate variables. Among 6386 patients followed an average of 6.7 years after PCI, 73% received PCI for acute coronary syndrome (ACS), 19% for stable angina, and 8% for other indications. Post-PCI CP-related HCU was common with 26%, 16%, and 5% of patients having ≥1 office visits, ED visits, and hospital admissions for CP within 2 years of PCI. The following factors were significant predictors of all 3 CP outcomes: ACS presentation, documented CP >7 days prior to the index PCI, anxiety, depression, and syncope. In conclusion, CP-related HCU following PCI was common, especially within the first 2 years. The strongest predictors of CP-related HCU included coronary disease attributes and psychological factors.

Risk of Myocardial Infarction and Death After Noncardiac Surgery Performed Within the First Year After Coronary Drug-Eluting Stent Implantation for Acute Coronary Syndrome or Stable Angina Pectoris.

This study aimed to examine the 30-day risk of myocardial infarction (MI) and death in patients who underwent noncardiac surgery within 1 year after coronary drug-eluting stent implantation for acute coronary syndrome (ACS) or stable angina pectoris (SAP) and to compare it with the risk in surgical patients without known coronary artery disease. Patients with drug-eluting stent implantation for ACS (n = 2,291) or SAP (n = 1,804) who underwent noncardiac surgery were compared with a cohort from the general population without known coronary artery disease matched on the surgical procedure, hospital contact type, gender, and age. In patients with ACS, the 30-day MI risk was markedly increased when surgery was performed within 1 month after stenting (10% vs 0.8%; adjusted odds ratio [ORadj] 20.1, 95% confidence interval [CI] 8.85 to 45.6), whereas mortality was comparable (10% vs 8%, ORadj 1.17, 95% CI 0.76 to 1.79). When surgery was performed between 1 and 12 months after stenting, the 30-day absolute risk for MI was low but higher than in the comparison cohort (0.6% vs 0.2%, ORadj 2.18, 95% CI 0.89 to 5.38), whereas the mortality risks were similar (2.0% vs 1.8%, ORadj 1.03, 95% CI 0.69 to 1.55). In patients with SAP, the 30-day MI risk was low but higher than in the comparison cohort (0.4% vs 0.2%, ORadj 1.90, 95% CI 0.70 to 5.14), whereas the mortality risks were similar (2.2% vs 2.1%, ORadj 0.91, 95% CI 0.61 to 1.37). In conclusion, patients with ACS and SAP who underwent surgery between 1 and 12 months after stent implantation had a risk for MI and death that was similar to the risk observed in surgical patients without coronary artery disease.

Comparison of Long-Term Outcomes Following Coronary Revascularization in Men-vs-Women with Unprotected Left Main Disease.

Gender differences have been recognized in several aspects of coronary artery disease (CAD). However, evidence for gender differences in long-term outcomes after left main coronary artery (LMCA) revascularization is limited. We sought to evaluate the impact of gender on outcomes after percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) for unprotected LMCA disease. We evaluated 4,320 patients with LMCA disease who underwent CABG (n = 1,456) or PCI (n = 2,864) from the Interventional Research Incorporation Society-Left MAIN Revascularization registry. The primary outcome was a composite of death, myocardial infarction (MI), or stroke. Among 4,320 patients, 968 (22.4%) were females and 3,352 (77.6%) were males. Compared to males, females were older, had a higher prevalence of hypertension and insulin-requiring diabetes, more frequently presented with acute coronary syndrome, but had less extensive CAD and less frequent left main bifurcation involvement. The adjusted risk for the primary outcome was not different after PCI or CABG in females and males (hazard ratio [HR] 1.09; 95% confidence interval [CI]: 0.73-1.63 and HR 0.97; 95% CI: 0.80-1.19, respectively); there was no significant interaction between gender and the revascularization strategy (P for interaction = 0.775). In multivariable analysis, gender did not appear to be an independent predictor for the primary outcome. In revascularization for LMCA disease, females and males had a comparable primary composite outcome of death, MI, or stroke with either CABG or PCI without a significant interaction of gender with the revascularization strategy.

Comparison of Long-Term Outcomes in Men versus Women Undergoing Percutaneous Coronary Intervention.

There has been a significant decrease in mortality associated with coronary artery disease (CAD) in recent decades, although at discordant rates between men and women. Using a well-established multicenter registry, we sought to examine the impact of gender on long-term mortality stratified by indication for percutaneous coronary intervention (PCI). Data from 54,440 consecutive patients (12,805, 23.5% women) undergoing PCI from the Victorian Cardiac Outcomes Registry (2013 to 2018) were analyzed. We aimed to compare gender-related differences of patients undergoing PCI for stable angina pectoris (SAP), non-ST-elevation acute coronary syndrome (NSTEACS) and ST-elevation myocardial infarction (STEMI). The primary outcome was long-term all-cause mortality. Female patients were older across all indications (SAP: 67 vs 71 years, NSTEACS: 64 vs 69 years, STEMI 61 vs 67 years; p value for all <0.001), with age-adjusted higher rates of diabetes mellitus (p value for all <0.02) and renal impairment (p value for all <0.001), and were more likely to have femoral artery access for intervention (p value for all <0.001). Unadjusted in-hospital and 30-day mortality rates were comparable between men and women across all indications. Compared to men, women had a higher rate of unadjusted long-term mortality (9.0% vs 7.37%; p <0.001). However, after adjusting for variables significant on univariate analysis, female gender was independently associated with improved long-term survival (HR 0.76, 95% CI 0.66 to 0.87; p <0.001). In conclusion, contrary to previous studies, despite being older with a differing clinical profile and interventional approach, women undergoing PCI have a long-term survival advantage.

Relation of the Number of Cardiovascular Conditions and Short-term Symptom Improvement After Percutaneous Coronary Intervention for Stable Angina Pectoris.

With aging of the population, cardiovascular conditions (CC) are increasingly common in individuals undergoing PCI for stable angina pectoris (AP). It is unknown if the overall burden of CCs associates with diminished symptom improvement after PCI for stable AP. We prospectively administered validated surveys assessing AP, dyspnea, and depression to patients undergoing PCI for stable AP at our institution, 2016-2018. The association of CC burden and symptoms at 30-days post-PCI was assessed via linear mixed effects models. Included individuals (N = 121; mean age 68 ± 10 years; response rate = 42%) were similar to non-included individuals. At baseline, greater CC burden was associated with worse dyspnea, depression, and physical limitations due to AP, but not AP frequency or quality of life. PCI was associated with small improvements in AP and dyspnea (p ≤ 0.001 for both), but not depression (p = 0.15). After multivariable adjustment, including for baseline symptoms, CC burden was associated with a greater improvement in AP physical limitations (p = 0.01) and depression (p = 0.002), albeit small, but not other symptom domains (all p ≥ 0.05). In patients undergoing PCI for stable AP, increasing CC burden was associated with worse dyspnea, depression, and AP physical limitations at baseline. An increasing number of CCs was associated with greater improvements, though small, in AP physical limitations and depression. In conclusion, the overall number of cardiovascular conditions should not be used to exclude patients from PCI for stable AP on the basis of an expectation of less symptom improvement.