natgillin/translations-raw huggingface dataset:
· Hvis du tåler den første infusion godt, kan næste infusion gives i løbet af 30 minutter. 
· If the first infusion is well tolerated, the infusion on your next visit may be given over 30 minutes.
Indehaveren af markedsføringstilladelsen skal aftale indholdet og formen af uddannelsesmateriale for Kadcyla (trastuzumabemtansin) og en kommunikationsplan med den relevante nationale myndighed før lancering af Kadcyla (trastuzumabemtansin) i hvert enkelt medlemsland. 
The MAH shall agree the content and format of the Kadcyla (trastuzumab emtansine) educational material and a communication plan with the National Competent Authority in the Member State before Kadcyla (trastuzumab emtansine) is launched in each Member State.
Det Europæiske Lægemiddelagentur har dispenseret fra kravet om at fremlægge resultaterne af studier med trastuzumabemtansin i alle undergrupper af den pædiatriske population ved indikationen brystkræft (se pkt. 
The European Medicines Agency has waived the obligation to submit the results of studies with trastuzumab emtansine in all subsets of the paediatric population in breast cancer (see section 4.2 for information on paediatric use).
Der er ikke set akkumulering af trastuzumabemtansin efter gentagen dosering ved intravenøs infusion hver 3. uge. 
No accumulation of trastuzumab emtansine was observed after repeated dosing of intravenous infusion every 3 weeks.
I studie TDM4370g/BO21977 sås vedvarende gavn af behandling med trastuzumabemtansin hos størstedelen af de evaluerede, præ-specificerede subgrupper, hvilket understøtter de overordnede resultaters robusthed. 
In study TDM4370g/BO21977, consistent treatment benefit of trastuzumab emtansine was seen in the majority of pre-specified subgroups evaluated, supporting the robustness of the overall result.
Infusionsrelaterede reaktioner forsvandt i løbet af adskillige timer til en dag, efter infusion var afsluttet. 
Infusion-related reactions resolved over the course of several hours to a day after the infusion was terminated.
Patienter med forhøjet baseline-ALAT (f.eks. pga. levermetastaser) kan være disponeret for leverskade med højere risiko for hepatiske bivirkninger af grad 3-5 eller forhøjede værdier af leverfunktionsundersøgelser. 
Patients with baseline elevation of ALT (e.g. due to liver metastases) may be predisposed to liver injury with a higher risk of a Grade 3-5 hepatic event or liver function test increase.
Figur 1 Kaplan-Meier-kurver over overlevelse uden invasiv sygdom i KATHERINE 
Figure 1 Kaplan-Meier Curve of Invasive Disease-Free Survival in KATHERINE
· Du skal bruge sikker prævention for at undgå at blive gravid, mens du er i behandling med 
· Use effective contraception to avoid becoming pregnant while you are being treated with Kadcyla.
Amning kan påbegyndes 7 måneder efter, behandlingen er afsluttet. 
Women may begin breast-feeding 7 months after concluding treatment.
Det skal bekræftes, at det generiske navn er trastuzumabemtansin. 
It must be verified that the non-proprietary name is trastuzumab emtansine.
Der sås ingen sammenhæng mellem trastuzumabemtansin-eksponering (AUC), maksimal serumkoncentration af trastuzumabemtansin (Cmax), total trastuzumab-eksponering (AUC) eller Cmax af DM1 og aminotransferase-stigninger. 
No relationship was observed between trastuzumab emtansine exposure (AUC), trastuzumab emtansine maximum serum concentration (Cmax), total trastuzumab exposure (AUC), or Cmax of DM1 and increases in transaminase.
Der er også observeret en kumulativ effekt på aminotransferaser (andelen af patienter med grad 1-2 ALAT/ASATafvigelser øges med antallet af serier). 
A cumulative effect on transaminases has also been observed (the proportion of patients with Grade 1-2 ALT/AST abnormalities increases with successive cycles).
Kontakt straks lægen eller sundhedspersonalet, hvis du oplever én eller flere af følgende alvorlige bivirkninger, mens du får Kadcyla: 
Tell your doctor or nurse straight away if you notice any of the following serious side effects while you are given Kadcyla:
I nogle af de observerede tilfælde havde patienterne trombocytopeni eller var også i antikoagulant eller antitrombotisk behandling, mens der i andre tilfælde ikke var yderligere kendte risikofaktorer. 
In some of the observed cases the patients had thrombocytopenia, or were also receiving anti-coagulant therapy or antiplatelet therapy; in others there were no known additional risk factors.
Med undtagelse af irreversibel perifer aksonal toksicitet (kun observeret hos aber ved ³10 mg/kg) og toksisk virkning på reproduktionsorganer (kun observeret hos rotter ved 60 mg/kg) er der i GLP-toksicitetsstudier set delvist eller fuldstændigt reversibel, dosisafhængig toksicitet i begge dyremodeller. 
In the GLP toxicity studies, with the exception of irreversible peripheral axonal toxicity (observed only in monkeys at ³ 10 mg/kg) and reproductive organ toxicity (observed only in rats at 60 mg/kg), partially or completely reversible dose dependent toxicities were identified in both animal models.
Der er ikke udført formelt farmakokinetisk studie eller indsamlet farmakokinetiske populationsdata hos patienter med svært nedsat leverfunktion (Child-Pugh class C). 
No formal pharmacokinetic study has been conducted and no population PK data was collected in patients with severe hepatic impairment (Child-Pugh class C).
Eventuelle symptomer kan være gulfarvning af huden og det hvide i øjet (gulsot). 
Some symptoms could be yellowing of your skin and whites of your eyes (jaundice).
Du skal straks fortælle lægen, hvis du bemærker et af de symptomer, som er beskrevet ovenfor. 
You should tell your doctor immediately if you notice any of the above symptoms.
Samtidig brug af potente CYP3A4-hæmmere (fx ketoconazol, itraconazol, clarithromycin, atazanavir, indinavir, nefazodon, nelfinavir, ritonavir, saquinavir, telithromycin og voriconazol) og trastuzumabemtansin bør undgås på grund af risiko for øget DM1-eksponering og toksicitet. 
Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) with trastuzumab emtansine should be avoided due to the potential for an increase in DM1 exposure and toxicity.
Den mediane progressionsfri overlevelse var 9,2 måneder i trastuzumab plus docetaxel-armen og 14,2 måneder i trastuzumabemtansin-armen (hazard ratio 0,59; p=0,035) med en median opfølgningstid på ca. 14 måneder i begge arme. 
The median PFS was 9.2 months in the trastuzumab plus docetaxel arm and 14.2 months in the trastuzumab emtansine arm (hazard ratio, 0.59; p = 0.035), with a median follow-up of approximately 14 months in both arms.
Leveren er det primære organ til eliminering af DM1 og DM1-holdige katabolitter. 
The liver is a primary organ for eliminating DM1 and DM1-containing catabolites.
Patienter skal monitoreres løbende for tegn eller symptomer på neurotoksicitet. 
Patients should be clinically monitored on an ongoing basis for signs/symptoms of neurotoxicity.
Behov for yderligere dosisreduktion 
Requirement for further dose reduction
· Nerve (neurologiske) problemer: Kadcyla kan beskadige nerverne. 
· Neurological problems: Kadcyla can damage nerves.
· Leverproblemer: Kadcyla kan forårsage inflammation i eller beskadige leverceller, som kan forårsage, at leveren holder op med at virke normalt. 
· Liver problems: Kadcyla can cause inflammation or damage to cells in the liver that can stop the liver from functioning normally.
SÆRLIGE OPBEVARINGSBETINGELSER Opbevares i køleskab (2ºC - 8ºC) 
SPECIAL STORAGE CONDITIONS Store in a refrigerator (2ºC - 8ºC)
Der er ingen kendt antidot mod overdosering med trastuzumabemtansin. 
There is no known antidote for trastuzumab emtansine overdose.
Hvis samtidig brug af en potent CYP3A4-hæmmer ikke kan undgås, kan det overvejes at udsætte trastuzumabemtansin-behandlingen, indtil den potente CYP3A4-hæmmer er ude af blodet (ca. 3 halveringstider for hæmmeren), hvis dette er muligt. 
If concomitant use of strong CYP3A4 inhibitors is unavoidable, consider delaying trastuzumab emtansine treatment until the strong CYP3A4 inhibitors have cleared from the circulation (approximately 3 elimination half-lives of the inhibitors) when possible.
Patienterne skal observeres nøje for overfølsomheds-/allergiske reaktioner, som kan manifestere sig klinisk på samme måde som en infusionsrelateret reaktion. 
Patients should be observed closely for hypersensitivity/allergic reactions, which may have the same clinical presentation as an IRR.
Patient- og tumorkarakteristika ved baseline var velafbalanceret mellem behandlingsgrupperne. 
Baseline patient and tumour characteristics were well balanced between treatment groups.
· Blødningsproblemer: Kadcyla kan få antallet af blodplader i blodet til at falde. 
· Bleeding problems: Kadcyla can lower the number of platelets in your blood.
Det anbefales at monitorere trombocytværdier inden hver dosis trastuzumabemtansin. 
It is recommended that platelet counts are monitored prior to each trastuzumab emtansine dose.
Interstitiel lungesygdom (ILD) eller pneumonitis 
Pulmonary Toxicity Interstitial lung disease (ILD) or pneumonitis
NCI-CTCAE er anvendt til vurdering af toksicitet i forbindelse med indberetning af bivirkningerne. 
ADRs were reported using NCI-CTCAE for assessment of toxicity.
Dysfunktion af venstre ventrikel 
Left Ventricular Dysfunction
Neutropeni, leukopenia 
Neutropenia, Leucopoenia
Patienter med trombocytopeni (≤100.000/mm3) og patienter i antikoagulansbehandling (fx warfarin, heparin, lavmolekylære hepariner) skal monitoreres tæt under behandling med trastuzumabemtansin. 
Patients with thrombocytopenia (≤ 100,000/mm3) and patients on anti-coagulant treatment (e.g. warfarin, heparin, low molecular weight heparins) should be monitored closely while on trastuzumab emtansine treatment.
I de fleste tilfælde er mængden af leverenzymer dog kun let og kun midlertidigt forhøjet; der er ingen symptomer, og leverfunktionen påvirkes ikke. 
However, in most cases during Kadcyla treatment, liver enzyme levels are elevated mildly and temporarily, do not cause any symptoms, and do not affect liver function.
Tabel 2 Vejledning i dosisændring Dosisændringer hos patienter med eBC 
Table 2 Dose Modification Guidelines Dose Modifications for Patients with EBC Adverse reaction Severity
I fase I- og fase II-studier blev 6,4% (24/376) af patienterne testet positive for antitrastuzumabemtansin-antistoffer. 
In the Phase I and Phase II studies, 6.4% (24/376) of patients tested positive for anti- trastuzumab emtansine antibodies.
· Hjerteproblemer: Kadcyla kan svække hjertemusklen. 
· Heart problems: Kadcyla can weaken the heart muscle.
Kadcyla indeholder: · Aktivt stof: trastuzumabemtansin. 
What Kadcyla contains · The active substance is trastuzumab emtansine.
Patienterne blev behandlet med trastuzumabemtansin eller trastuzumab ved i alt 14 serier, med mindre der var sygdomsrecidiv, samtykket blev trukket tilbage eller der opstod uacceptabel toksicitet, alt efter hvad der forekom først. 
Patients were treated with trastuzumab emtansine or trastuzumab for a total of 14 cycles unless there was recurrence of disease, withdrawal of consent, or unacceptable toxicity, whichever occurred first.
Levertoksicitet, leversvigt, nodulær regenerativ hyperplasi, portal hypertension 
Hepatotoxicity, Hepatic failure, Nodular regenerative hyperplasia, Portal hypertension
Kadcyla (trastuzumabemtansin) er IKKE en generisk version af Herceptin (trastuzumab), og de 2 lægemidler har forskellige egenskaber, indikationer og doseringer. 
Kadcyla (trastuzumab emtansine) is NOT a generic version of Herceptin (trastuzumab) and has different properties, indications and dose.
Der er set venstre ventrikel uddrivningsfraktion (LVEF) <40% hos patienter behandlet med trastuzumabemtansin, og symptomatisk hjertesvigt er derfor en potentiel risiko (se pkt. 
Left ventricular ejection fraction (LVEF) < 40% has been observed in patients treated with trastuzumab emtansine, and therefore symptomatic congestive heart failure (CHF) is a potential risk (see section 4.8).
· Du vil få 3,6 mg Kadcyla for hvert kilo, du vejer. 
How much you will be given · You will be given 3.6 mg of Kadcyla for every kilogram of your body weight.
Patienter behandlet for hjernemetastaser kunne inkluderes, hvis de ikke havde behov for symptomkontrollerende behandling. 
Patients with treated brain metastases were eligible for enrollment if they did not require therapy to control symptoms.
Biotransformation (trastuzumabemtansin og DM1) Trastuzumabemtansin forventes at dekonjugeres og kataboliseres ved proteolyse i cellulære lysosomer. 
Biotransformation (trastuzumab emtansine and DM1) Trastuzumab emtansine is expected to undergo deconjugation and catabolism by means of proteolysis in cellular lysosomes.
Dysfunktion af venstre ventrikel sås hos 3,0% af patienterne med eBC, i grad 3 eller 4 hos 0,5% af patienterne. 
Left ventricular dysfunction occurred in 3.0% of patients with EBC, with Grade 3 or 4 in 0.5% of patients.
Trastuzumab, en komponent i trastuzumabemtansin, kan forårsage fosterskader eller fosterdød, hvis det administreres til en gravid kvinde. 
Trastuzumab, a component of trastuzumab emtansine, can cause foetal harm or death when administered to a pregnant woman.
I KATHERINE-studiet (BO27938) blev 3,7% (15/401) af patienterne testet positive for anti-trastuzumabemtansin-antistoffer, hvoraf 5 også var positive for neutraliserende antistoffer. 
In the KATHERINE (BO27938) study, 3.7% (15/401) of patients tested positive for anti-trastuzumab emtansine antibodies, of which 5 were also positive for neutralizing antibodies.
Administration af trastuzumabemtansin er veltolereret hos rotter og aber i doser op til henholdsvis 20 og 10 mg/kg, svarende til 2.040 mg DM1/m2 i begge arter, hvilket nogenlunde svarer til den kliniske dosis af trastuzumabemtansin til patienter. 
Administration of trastuzumab emtansine was well tolerated in rats and monkeys at doses up to 20 and 10 mg/kg, respectively, corresponding to 2040 mg DM1/m2 in both species, which is approximately equivalent to the clinical dose of trastuzumab emtansine in patients.
MARKEDSFØRINGSTILLADELSESNUMMER (-NUMRE) EU/1/13/885/001 
MARKETING AUTHORISATION NUMBER(S) EU/1/13/885/001
Trastuzumabemtansins farmakokinetik hos patienter med let (kreatinin-clearance CLcr 60-89 ml/min, n=254) eller moderat (CLcr 30-59 ml/min, n=53) nedsat nyrefunktion svarede til det, der sås hos patienter med normal nyrefunktion (CLcr ³90 ml/min, n=361). 
Pharmacokinetics of trastuzumab emtansine in patients with mild (creatinine clearance CLcr 60 to 89 mL/min, n = 254) or moderate (CLcr 30 to 59 mL/min, n = 53) renal impairment were similar to those in patients with normal renal function (CLcr ³ 90 mL/min, n = 361).
Generelle risikofaktorer for kardiale bivirkninger, og de, der er identificeret i brystkræftstudier med trastuzumab som adjuverende behandling, inkluderer stigende alder (>50 år), lav LVEF ved baseline (<55%), lav LVEF inden eller efter adjuverende behandling med paclitaxel, tidligere eller samtidig brug af antihypertensiva, tidligere behandling med et antracyklin og højt BMI (>25 kg/m2). 
General risk factors for a cardiac event and those identified in adjuvant breast cancer studies with trastuzumab therapy include advancing age (> 50 years), low baseline LVEF values (< 55%), low LVEF levels prior to or following the use of paclitaxel in the adjuvant setting, prior or concomitant use of antihypertensive medicinal products, previous therapy with an anthracycline and high BMI (> 25 kg/m2).
Blodplader får dit blod til at størkne, så du kan opleve uventede blå mærker eller blødninger (fx næseblod eller blødning fra tandkødet). 
Platelets help your blood to clot so you might get unexpected bruising or bleeding (such as nose bleeds, bleeding from gums).
Over tid kan dette give symptomer som oppustethed eller opsvulmet mave på grund væskeophobning eller blødning fra unormale blodkar i spiserøret eller endetarmen. 
Over time, this may lead to symptoms such as a bloated sensation or swelling of the abdomen due to fluid accumulation or bleeding from abnormal blood vessels in the gullet or rectum.
De observerede tilfælde kan have været påvirket af co-morbiditet og/eller samtidig behandling med andre lægemidler med kendt levertoksisk potentiale. 
Observed cases may have been confounded by comorbidities and/or concomitant medicinal products with known hepatotoxic potential.
Hvis en potent CYP3A4-hæmmer administreres samtidig, og trastuzumabemtansin ikke kan udsættes, skal patienten monitoreres omhyggeligt for bivirkninger. 
If a strong CYP3A4 inhibitor is coadministered and trastuzumab emtansine treatment cannot be delayed, patients should be closely monitored for adverse reactions.
Det anbefales at seponere behandlingen med trastuzumabemtansin permanent hos patienter, der diagnosticeres med interstitiel lungesygdom eller pneumonitis, bortset fra strålepneumonitis ved adjuverende behandling, hvor trastuzumabemtansin skal seponeres permanent ved ³Grad 3 eller ved Grad 2, hvis der ikke er respons på standardbehandling (se pkt. 
It is recommended that treatment with trastuzumab emtansine be permanently discontinued in patients who are diagnosed with ILD or pneumonitis, except for radiation pneumonitis in the adjuvant setting, where trastuzumab emtansine should be permanently discontinued for ³ Grade 3 or for Grade 2 not responding to standard treatment.
Epistaxis, hoste, dyspnø 
Epistaxis, Cough, Dyspnoea
Det er i kliniske rammer vist, at trastuzumab er udviklingstoksisk, selvom det ikke var forudset i det præ-kliniske program. 
Developmental toxicity of trastuzumab has been identified in the clinical setting although it was not predicted in the non-clinical program.
● når risikostyringssystemet ændres, særlig som følge af, at der er modtaget nye oplysninger, der kan medføre en væsentlig ændring i risk/benefit-forholdet, eller som følge af, at en vigtig milepæl (lægemiddelovervågning eller risikominimering) er nået. 
An updated RMP should be submitted: · At the request of the European Medicines Agency; · Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.
Patienter med hviledyspnø på grund af komplikationer fra fremskreden malignitet og/eller co-morbiditet, og som samtidig får strålebehandling af lungerne, kan have øget risiko for pulmonale bivirkninger. 
Patients with dyspnoea at rest due to complications of advanced malignancy, co-morbidities, and receiving concurrent pulmonary radiation therapy may be at increased risk of pulmonary events.
Betydningen af indberettede bivirkninger som fx træthed, hovedpine, svimmelhed og sløret syn på evnen til at føre motorkøretøj og betjene maskiner er ukendt. 
The significance of reported adverse reactions such as fatigue, headache, dizziness and blurred vision on the ability to drive or use machines is unknown.
Der bør udføres standardtest af hjertefunktion (ekkokardiogram eller isotopkardiografi (MUGAscanning)) inden behandlingsstart samt med jævne mellerum (fx hver 3. måned) under behandlingen. 
Standard cardiac function testing (echocardiogram or multigated acquisition (MUGA) scanning) should be performed prior to initiation of treatment and also at regular intervals (e.g. every three months) during treatment.
Kadcyla skal ordineres af en læge med erfaring i behandling af kræftpatienter og administreres som intravenøs infusion under supervision af erfarne sundhedspersoner (dvs. klar til at håndtere allergiske/anafylaktiske infusionsreaktioner og med umiddelbar adgang til komplette genoplivningsfaciliteter (se pkt. 
Kadcyla should only be prescribed by a physician and administered as an intravenous infusion under the supervision of a healthcare professional who is experienced in the treatment of cancer patients (i.e. prepared to manage allergic/anaphylactic infusion reactions and in an environment where full resuscitation facilities are immediately available (see section 4.4)).
Forhøjede transaminaser var indberettet hos 32,4% af patienterne med eBC. 
Increased transaminases were reported in 32.4% of patients with EBC.
I tilfælde af overdosis skal patienten monitoreres nøje for bivirkninger og relevant symptomatisk behandling institueres. 
In case of overdose, the patient should be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.
Anbefalet dosis trastuzumabemtansin er 3,6 mg/kg kropsvægt administreret som intravenøs infusion hver 3. uge (21-dages cyklus). 
The recommended dose of trastuzumab emtansine is 3.6 mg/kg bodyweight administered as an intravenous infusion every 3 weeks (21-day cycle).
· Hvis Kadcyla-infusionsvæsken siver ud i vævet omkring infusionsstedet, kan du opleve ømhed, rødme eller hævelse af huden omkring infusionsstedet. 
· If the Kadcyla infusion solution leaks into the area around the infusion site you may develop tenderness or redness of your skin, or swelling at the infusion site.
Hvis du oplever én eller flere af disse bivirkninger, efter du har afsluttet behandlingen med Kadcyla, skal du kontakte lægen eller sundhedspersonalet og fortælle dem, at du har fået Kadcyla. 
If you get any of the side effects after your treatment with Kadcyla has stopped, talk to your doctor or nurse and tell them that you have been treated with Kadcyla.
MARKEDSFØRINGSTILLADELSESNUMMER (-NUMRE) EU/1/13/885/002 
MARKETING AUTHORISATION NUMBER(S) EU/1/13/885/002
Grad 3 eller 4 tilfælde indberettedes hos 0,4% af patienterne med mBC. 
Grade 3 or 4 events were reported in 0.4% of patients with MBC.
Tabel 1 Skema for dosisreduktion 
Table 1 Dose reduction schedule
Det mediane antal kræftmidler, som disse patienter havde fået, var 8,5 (5-19), og 7,0 (3-17) for metastatisk sygdom alene, inkluderende alle lægemidler anvendt til behandling af brystkræft. 
The median number of anti-cancer agents that patients had received in any setting was 8.5 (range, 5-19) and in the metastatic setting was 7.0 (range, 3-17), including all agents intended for the treatment of breast cancer.
Hvis LVEF fortsat er <50% og ikke er forbedret til <10% point fra baseline, skal trastuzumabemtansin seponeres 
If the LVEF remains < 50% and has not recovered to < 10% points from baseline, discontinue trastuzumab emtansine.
· Vejrtrækningsproblemer: Kadcyla kan forårsage alvorlige vejrtrækningsproblemer som åndenød (i hvile eller ved aktivitet) og hoste. 
· Breathing problems: Kadcyla can cause serious breathing problems such as shortness of breath (either at rest or while performing any type of activity) and cough.
Medianværdier for progressionfri overlevelse og samlet overlevelse var i trastuzumabemtansingruppen henholdsvis 10,8 måneder og ikke nået, sammenlignet med henholdsvis 5,7 måneder og 27,9 måneder i lapatinib plus capecitabin-gruppen. 
10.8 months and not reached, respectively, compared with 5.7 months and 27.9 months, respectively, for the lapatinib plus capecitabine group.
● de hyppigste NCI-CTCAE (National Cancer Institute - Common Terminology Criteria for Adverse Events) grad ≥3 bivirkninger (>2%) var trombocytopeni, forhøjede aminotransferaser, anæmi, neutropeni, træthed og hypokaliæmi. 
· the most common National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade ≥ 3 ADRs (> 2%) were thrombocytopenia, increased transaminases, anaemia, neutropenia, fatigue and hypokalaemia.
Dosisreduktion eller seponering i forbindelse med stigning i aminotransferaser og total-bilirubin er specificeret i pkt. 
Dose reductions or discontinuation for increased serum transaminases and total bilirubin are specified in section 4.2.
Alternativt lægemiddel uden eller med minimalt CYP3A4-hæmmende potentiale bør overvejes. 
Consider an alternate medicinal product with no or minimal potential to inhibit CYP3A4.
Symptomatisk hjertesvigt, Grad 3-4 LVSD eller Grad 3-4 hjertesvigt eller Grad 2 hjertesvigt ledsaget af LVEF <45% 
Symptomatic CHF, Grade 3-4 LVSD or Grade 3-4 heart failure, or