Sickle cell disease (SCD) is an autosomal recessive haemoglobinopathy that we now encounter with increasing frequency in clinical practice in Ireland. The clinical hallmark is a triad of painful vaso-occlusion, micro-infarct end organ damage and a haemolytic anaemia. The disease is characterised by a point mutation in the beta globin gene leading to the substitution of valine for glutamic acid in the beta haemoglobin chain. This seemingly simple amino acid substitution causes a life-threatening and complex multi-organ disease with multiple pathophysiological pathways. Mortality has been high in SCD especially in the early childhood years.
Modern treatment approaches including new-born screening, pneumococcal prophylaxis, transcranial Doppler ultrasound and the introduction of early disease-modifying treatment has seen mortality decrease, the mean age at death increase, and fewer children dying from infection. Aggressive management strategies in childhood yield a sickle-related survival rate of 94 per cent at 18 years and 99 per cent at 16 years. This improvement in childhood mortality has not yet been seen in the adult population who have a median life expectancy in the US of 42 years for males and 48 years for females.
Most patients with SCD will experience vaso-occlusive events at some point in their life and these episodes account for over 90 per cent of all emergency hospital admissions. They can lead to acute organ failure or chronic organ damage affecting all systems. Diagnosis is now typically achieved in the neonatal period due to the introduction of a screening process where haemoglobin electrophoresis is performed on cord blood at delivery. This allows for the early detection of the condition, initiation of parental education and commencement of supportive therapy including antibiotic prophylaxis, pneumococcal vaccination and folic acid supplementation. The morbidity of SCD is highly variable, but can be devastating. Early introduction of disease-modifying treatment is essential to prevent or ameliorate the consequences of this disease.
Pain is a commonly seen presentation in children with SCD. The first episode of pain typically affects the small bones of the hands and is referred to as dactylitis. This affects approximately 50 per cent of children with SCD by two years of age. As these children get older the long bones become affected and by adolescence pain is typically associated with the ribs and vertebrae. This pain can be severe and debilitating.
Many other acute complications of SCD have life-threatening consequences. Acute chest syndrome is the most common cause of hospitalisation for patients with SCD, with a peak incidence in early childhood, and is responsible for approximately 25 per cent of sickle-related deaths. The neurological system can also be affected with the occurrence of stroke. Prior to the findings of the STOP study, 10 per cent of children with SCD had a stroke before the end of the second decade of life. Now children are screened with transcranial Doppler ultrasound, which has reduced the stroke risk rate to approximately 1 per cent. Acute splenic sequestration is a life-threatening complication that occurs in up to 30 per cent of patients with SCD up to six years of age. It is characterised by rapid enlarging of the spleen followed by circulatory collapse. All organs of the body are at risk of severely debilitating and life-threatening chronic complications. Some of the more commonly encountered complications include avascular necrosis (AVN), pulmonary hypertension and retinopathy. Avascular necrosis occurs with an incidence of 2.5 per 100 patient years and has even been described in children as young as five years old. It often requires treatment with joint replacement.
The primary defect in the pathogenesis of SCD is that the resulting haemoglobin is less soluble when exposed to deoxygenated conditions and forms polymers within the red blood cell (RBC). These polymers aggregate causing the RBC to enlarge and deform. This provides it with the characteristic sickle shape. Upon re-oxygenation the RBC cell typically resumes its normal biconcave form, however after numerous episodes of sickling, the cells become irreversibly sickled. These sickle shape cells also are more easily dehydrated when deoxygenated and as a result acquire abnormal intracellular signalling pathways, which activate RBC adhesion molecules on the RBC membrane. These adhesion molecules are involved in the adhesion of RBCs, endothelial cells, neutrophils, monocytes and platelets, inducing the activation of multiple pro-inflammatory pathways. The resulting abnormal RBC has a shorter life span and has increased adhesive interactions. The clinical implication is that the RBC haemolyses and there is a slowing of blood flow in the microcirculation leading to painful vaso-occlusion and micro infarct end organ damage.
The management of SCD is multidisciplinary and is comprised of strategies to treat acute sickle cell crisis and long-term disease modifying approaches to prevent complications. This long-term approach is divided into supportive measures, disease modifying treatment and curative options.
Hydroxyurea was approved by the US Food and Drug Administration (FDA) in 1998 and the European Medicines Agency in 2007 for the management of patients with SCD although its use in children is still considered to be off-label by the FDA. It has proven successful in the prevention of complications in SCD and reduces mortality. In spite of our two decades of experience of hydroxyurea we still do not have a full understanding of its mechanism of action. Primarily it affects cell division by inhibiting the enzyme ribonucleotide reductase and thus depletes the cell of deoxyribonucleotide triphosphates (dNTPs). This leads to arrest of cell division or cell death.
Hydroxyurea also works by increasing foetal haemoglobin (HbF) production at the expense of normal adult haemoglobin (HbA). It does this by interfering with beta globin gene expression at the beta globin locus. HbF is the predominant haemoglobin in foetal life and early infancy and binds to oxygen with higher affinity than normal adult haemoglobin. This allows adequate oxygen transfer to the foetus during gas exchange in the intervillous space between mother and baby where there is mixing of both oxygenated and deoxygenated maternal blood. By six months of age it becomes almost entirely replaced by adult haemoglobin. Hydroxyurea reverses this natural post-natal switch from HbF to HbA and this results in reduced polymerisation, sickling, adhesion and haemolysis. The microcirculation blood flow improves and vaso-occlusive events are reduced. Hydroxyurea’s ability to increase nitric oxide further improves blood flow in the microcirculation. Nitric oxide is a potent vasodilator that becomes depleted in haemolysis. Free haemoglobin released by haemolysed RBCs scavenges nitric oxide and depletes it. By reducing haemolysis and inhibiting the scavenging effect of free haemoglobin, the vasodilatory effect of nitric oxide is preserved.
Hydroxyurea is not helpful in the acute management of a crisis as it takes weeks to months to become effective. There is no specific marker in clinical use to determine if the treatment will be of any benefit to the patient and in clinical practice it is offered to any patient who may achieve benefit. Many reproducible studies demonstrate that hydroxyurea reduces mortality with long-term use and reduces long-term complications in both adults and children. The 2011 Baby HUG trial showed that infants treated with hydroxyurea had improved splenic function, reduced pain episodes, reduced chest syndromes, reduced dactylitis and reduced need for transfusion. The treatment is largely very well tolerated and the predominant side effect is cytopaenias. As a result, these patients require regular full blood counts.
Blood transfusion therapy in SCD is of benefit in both the acute management of vaso-occlusive events and in the chronic management to prevent micro-infarct end organ damage. Most patients with SCD will undergo numerous transfusions in their lifetime putting them at risk for transfusion-associated complications. A simple top-up red RBC transfusion dilutes the volume of sickle cells containing haemoglobin S and replaces them with normal RBCs containing haemoglobin A. The resulting normal RBCs have a longer lifespan than their sickled counterparts. There is feedback to the kidneys to reduce erythropoietin production and the production of new sickle cells is slowed. The transfused blood increases the oxygen saturation of the circulation, increasing oxygen delivery to the tissues. This principle of increasing oxygenation is used in the pre-operative setting where a top-up RBC transfusion to a haemoglobin value of 10g/dL is associated with a reduced incidence of post-operative vaso-occlusive events.
In the long-term management of SCD, reducing the haemoglobin S percentage to below 30 per cent leads to a reduction in vaso-occlusive pain and acute chest syndromes. Many patients with SCD are commenced on chronic transfusion programmes scheduled at patient specific intervals guided by the patient’s clinical findings, haemoglobin level and haemoglobin S percentage. Regular transfusions are required for secondary prevention of stroke, acute chest syndrome, painful events and priapism. The SIT trial randomly assigned children with SCD and silent cerebral infarcts to monthly transfusions versus observation for three years and found that there were significant improvements in the quality-of-life of patients receiving regular transfusions. There were also reduced rates of pain, acute chest syndrome and symptomatic avascular necrosis.
In July 2017 the US FDA-approved L-glutamine oral powder for patients five years and older to reduce the complications of SCD. This was the first drug licensed for the management of SCD since hydroxyurea in 1998. Many studies have demonstrated that RBCs that are sickled have increased susceptibility to oxidative stress. Oxidative stress is measured by changes in nicotinamide adenine dinucleotide (NAD) homeostasis and is defined as the NAD redox potential. NAD redox potential is 20-30 per cent lower in sickle RBCs, but NAD is found in higher levels in sickle cells than in controls. This suggests that in the event of oxidative stress there is increased uptake of NAD by the sickle RBC. Sickle RBCs absorb glutamine, a precursor of NAD at increased rates compared to non-sickle cells. A hypothesis was formed that with increased glutamine supplementation, increased transport and utilisation of glutamine in sickled RBCs will lead to increased NAD and NADH levels thus providing increased defence against oxidative stress. The benefits of administering both L-glutamine and hydroxyurea together appear to be greater than either agent alone.
It is known that activation of the inflammatory system plays an important role in the pathogenesis of SCD. Cytokines are released and they quickly activate white blood cells. These activated white and red blood cells then bind to the endothelial cells via several selectins and integrins expressed by endothelial cells. Adhesion of inflammatory and red blood cells to the endothelium is primarily initiated by P selectin. Both animal and human studies have identified that deficiency of P selectin in those with SCD leads to defective adhesion of white blood cells to endothelial walls. This ultimately protects from vaso-occlusion. There are numerous potential treatments targeting P selectin in various stages of investigation.
One of promise is crizanlizumab. It is a humanised monoclonal antibody that binds selectively to P selectin. A phase 2 multicentre randomised controlled trial known as SUSTAIN was reported in the New England Journal of Medicine (NEJM) in 2016. In this trial high-dose treatment was associated with reduced frequency of sickle cell pain events compared to placebo. The annual sickle cell-related pain event rate was reduced by 32.1 per cent in patients already treated with hydroxyurea and by 50 per cent in those who were not already receiving hydroxyurea. The treatment was well-tolerated and there is much promise for this therapy as it undergoes further investigation
Haematopoietic stem cell transplant
Haematopoietic stem cell transplant (HSCT) is recognised as a potentially curative treatment for SCD. The current gold standard is myeloablative HLA matched sibling donors due to the reduced risk of both graft versus host disease and graft rejection. There have also been approaches using less myeloablative conditioning regimens. There are trials ongoing exploring the use of unrelated donors and despite the successes of this technique in the treatment of malignant blood disorders, results in SCD patients have largely had unsatisfactory results. The major difficulty in employing HSCT as a curative treatment for patients with SCD remains patient selection. This is attributed to disease heterogeneity, challenges in identifying patients at high risk of developing advanced disease, patient eligibility due to advanced multi-organ disease and concerns relating to transplant-related mortality. In clinical practice the experience of HSCT and SCD has yielded a five-year survival rate of 90-97 per cent, a transplant-related mortality rate of 7-10 per cent and an SCD-free survival rate of 80-90 per cent. The role of early transplantation in children to reduce SCD mortality has not been fully explored, but remains an area of ongoing investigation. HLA-haploidentical transplant is an appealing treatment due to the expansion of the donor. A ‘half matched’ related donor, usually the mother or father is used. An optimal conditioning regimen has not yet been identified, but it remains an area of advancing research.
Less than 18 per cent of eligible patients have a HLA-matched sibling donor for transplant. As a result, gene therapy is an increasingly exciting area of research in SCD and it may provide a long-term, potentially curative, treatment. Successful, sustained gene therapy has been reported previously in mouse models by lentiviral transfer of an anti-sickling beta-globin variant. In 2017 the NEJM published the outcome of a 13-year-old boy who was enrolled in a clinical trial to receive gene therapy using a LentiGlobin BB305 vector. This lentiviral vector is currently being used in seven patients with SCD and 22 patients with beta thalassaemia. It has a stable safety profile and has no evidence of insertional oncogenesis at 30 months. In this boy the transduced cells engrafted and normal cell counts followed across all lineages by day 88 post-transplant. The investigators did not report any vector-related side effects and the child remains well.
The complications of SCD are devastating to patients and until now progress has been slow in the achievement of cure. Thankfully, due to the recent advances in our knowledge of SCD pathogenesis we have, however, reached an exciting time. We have more potential treatment targets than ever and it is likely that considering the numerous pathological mechanisms involved, optimal therapy will require a multi-targeted treatment approach. Dynamic international collaboration and availability of funding is essential to support the ongoing research required to treat this highly complex disease.
References on request
Recently, the World Federation of Haemophilia (WFH) and the European Haemophilia Consortium (EHC) organised separate conferences on advances in haemophilia treatment. At the WFH conference, clinicians, haemophilia societies, industry and regulators discussed topics such as use of extended half-life (EHL) factor concentrates, new novel therapies and gene therapy. The EHC conference included clinicians and patient organisation leaders and discussed a similar broad range of topics. The conferences were an opportunity for clinicians to discuss with each other and with patient organisation leaders the changing treatment landscape and how they are utilising new therapies.
For the past 40 years, haemophilia treatment has been relatively straightforward – you replace the missing clotting factor in the event of a bleed or ideally prevent bleeds by means of regular prophylaxis. The availability of EHL clotting factor concentrates (CFCs) has increased therapeutic options.
These new products are being used by many countries for some people with haemophilia. The conferences afforded an opportunity for reflection and discussion. Which people with haemophilia should be treated with EHL products? Is the objective less frequent infusions or higher trough levels leading to more protection from bleeding, or a combination of both objectives? Will the use of EHL CFCs result in greater adherence to treatment and improved quality-of-life?
The objective of prophylaxis for many years has been to maintain factor levels at more than 1 per cent at all times. There is a clear correlation between the amount of time each week that the factor level is below 1 per cent and bleeding risk. Ideally, the factor level would never go below 1 per cent. More recently, with the availability of EHL CFCs, the debate has moved on.
In 2016, the European Directorate for the Quality of Medicines and Healthcare (EDQM) – an official body of the Council of Europe – formally recommended that trough levels of 1 per cent were no longer adequate. Clinicians are debating what trough levels should be. There is no doubt that, in an ideal world, trough levels of 15 per cent or greater would almost completely eliminate bleeds. This level should be attainable in the future via gene therapy, or an equivalent level of protection may be available from some of the new subcutaneous therapies.
In the meantime, many clinicians and haemophilia society leaders are advocating for higher than current trough levels of up to 10 per cent, and at least increasing trough levels to between 3 and 5 per cent. This is more easily attainable with Factor IX (FIX) deficiency as the half-life extension is three- to five-fold compared to an average 50 per cent increase in half-life for FVIII. In Ireland, all people with severe FIX deficiency were switched to EHL FIX in 2017. Preliminary results are very encouraging with average troughs having increased from 5 to 8 per cent using weekly infusions or in some cases, infusion every 10 days or every two weeks.
Presently, following a national procurement process in late 2017, Ireland is changing all FVIII patients to treatments with an EHL FVIII product. This will result in individualised therapeutic regimes tailored for each person and, for many people, a decrease in the requirement for intravenous infusions from three times per week to twice per week. It should also result in the ability to have higher trough levels, probably at 3 per cent, and therefore enhanced protection from bleeding.
Mr Brian O’Mahony
At the conferences, there was a lot of information on changing treatment patterns in many countries. Ireland is the only country in the world to date that has switched all the people with haemophilia to an EHL factor. Canada has switched some patients, including all the children with severe FIX deficiency in some centres. The US is switching some patients and some large centres in Germany have switched 60 per cent of their FIX patient to an EHL factor. The UK are gradually switching some patients. The degree of switching to EHL FIX has been greater in many countries than the proportion currently switching to EHL FVIII due primarily to the much longer half-life extension with the FIX products.
A UK clinician stated that their patients who had switched to EHL – both FIX and FVIII – expressed great satisfaction with the decreased frequency of infusions, the diminution in aches and pains and the fact that they are not having to think about haemophilia on a daily basis. People with FIX deficiency in Ireland who have switched have expressed a broadly very positive experience. They bookmark the lower frequency of infusion, less aches and pains, the fact that their veins get a chance to recover and the increased convenience of travelling with lower amounts of factor.
There have also been reports from several countries showing a pattern of increased adherence to the prescribed treatment regime when switched to EHL. Three different centres reported adherence rates increasing from 68 per cent to 85 per cent, 73 per cent to 86 per cent and 60 per cent to 82 per cent respectively. We will need to monitor the impact of these new products on an ongoing basis using many parameters including adherence, bleeding levels, physical activity, joint function, ability to participate in work, education and recreation and impact on chronic pain.
Other therapeutic developments were also discussed and analysed. The bispecific antibody – emicizumab – which is being developed as the first ever subcutaneous weekly treatment for FVIII deficiency or for treatment of those with FVIII inhibitors, was licenced by the US Food and Drug Administration (FDA) in November for the treatment of inhibitors to FVIII. This new product has demonstrated exciting results in clinical trials and will be marketed as Hemlibra. In late February, the European Medicines Agency (EMA) licenced Hemlibra for the treatment of patients with inhibitors to FVIII.
This therapy is for prophylaxis only and delivers a constant level of protection against bleeding. In the event of a breakthrough bleeding episode occurring in a person with inhibitors, treatment will be required with one of the current bypassing agents. Hemlibra is currently licenced only for patients with FVIII inhibitors. Clinical trials are continuing on the use of Hemlibra for FVIII patients without inhibitors. Several Irish people with FVIII deficiency are participating in this clinical trial called Haven 3. If all goes well with the ongoing trials, it is expected that Hemlibra will be licenced for use in FVIII patients in Europe during the course of 2019. There is also a strong possibility that people with haemophilia in Ireland may participate in a clinical trial for another subcutaneous therapy – the investigational drug fitusiran – during the course of 2018.
Fitusiran, which suspended clinical trials following a serious adverse event in September, has received a positive indication from the FDA. In December, the FDA lifted the hold on clinical studies with fitusiran after the trial’s protocol was amended to better mitigate risks. The manufacturers will now enrol patients in the ATLAS phase 3 programme throughout 2018.
This product has potential for the treatment of FVIII or FIX deficiency, with or without inhibitors. It may also have potential for treatment of some severe von Willebrand cases or rare bleeding disorders.
Progress is continuing with gene therapy for FVIII deficiency. University College London (UCL) now has results demonstrating long-term expression of FIX following a single injection in 10 people with haemophilia. FIX levels vary from 2-7 per cent and it is now more than seven years since the first infusion.
Spark in the US has demonstrated FIX levels of an average of 33 per cent more than one year post-injection using a more potent FIX mutation for the gene therapy (the Padua mutation). This FIX mutation allows for the expression of FIX levels that are approximately 10-fold higher with no increased dose of the vector (injection). This mutation will also now be used by new FIX gene therapy trials from UCL (a trial which may well include Irish participants) and the new FIX trial from Uniqure in the Netherlands (who previously had expression of 5-6 per cent using a non-Padua mutation).
There have also been impressive gene therapy results from Biomarin showing a range of FVIII expression levels from 20 per cent to 200 per cent with an average of approximately 100 per cent.
Other ongoing FIX gene therapy clinical trials by Pfizer and Uniqure may also possibly recruit people in Ireland for their trials. Discussions and work are ongoing.
We fully expect that in this, our 50th anniversary year, some people with FIX deficiency in Ireland will be offered the opportunity to commence participation in clinical trials for gene therapy.
I am also participating in an international process that seeks to define and agree a set of core outcomes for gene therapy. There are many gene therapy trials underway and ideally, we would get agreement from each of the companies developing the therapies that they would measure the same set of core outcomes, thereby making it a more practical proposition to properly compare the outcomes of each trial.
New treatments discussed at the meetings were not solely limited to replacement therapies or novel therapies. Dr Alison Dougall, Dublin Dental University Hospital, set out some of the new game-changers in haemophilia dental care. These include the use of a low laser diode, which can help reduce bleeding with gum disease and the use of a newly licenced compound called Silver Diamine Fluoride, which may greatly assist in preventing or treating caries in children and avoid use of the dreaded drill.
The therapeutic landscape has never been more exciting or indeed more complex. There have been very few innovations in haemophilia treatment for the past 20 years (since recombinant FVIII in 1994), but we are now witnessing an explosion of new possibilities.
We are the first country globally to have all people with haemophilia A and B treated with the new generation of recombinant products. Coupled with the exciting new developments in subcutaneous therapies and the strong and real prospect of participation in gene therapy clinical trials, the exciting future we have long discussed may be arriving.
In fact, on the very day I am writing this, the first clinical trial for gene editing in FIX deficiency in Europe, being conducted by the company Sangamo, has just been approved.
The next five years in haemophilia treatment may well see more change than in the past 50 years, which is a nice thought with which to enter our 50th year as a society and as a community.
Using the cardiology solution’s electronic vetting, the team has been able to triage echos, reducing the number by 8.9 per cent in 2016 as a result of eliminating inappropriate requests and ensuring 80 per cent of requests from the hospital’s acute ward are carried out on the same day as ordered.
The adoption by SUH of McKesson Cardiology in 2013 provided an opportunity to streamline processes and improve workflow. Replacing a manual, paper-based process, echo orders are automatically received into McKesson Cardiology
from the HSE’s national NIMIS radiology system, and then fed directly through to the echocardiogram machines. All the echo images and measurements are then stored within the cardiology database, enabling the cardiac physiologists to undertake reports on the system.
Ms Anita Flynn, Senior Cardiac Physiologist, explains: “The process not only streamlined echo referrals but also provided doctors with access to the electronic reports at the touch of a button. For doctors previously used to time-consuming creation of paper orders and storing printed reports within patient charts, the entire process became far more efficient and effective.”
Achieving BSE accreditation
With the upgrade to their cardiology solution in 2015, SUH took a step further — leveraging the improved reporting and embedded BSE range measurements to support its bid for BSE accreditation to demonstrate the quality of services being delivered. Mr Anthony Ryan, Chief 2 Cardiac Physiologist, SUH, noted that BSE departmental accreditation “is a recognised benchmark of quality.
It indicates to patients, resource allocators and health professionals that an echo department meets quality standards.”
The department has leveraged the new software to achieve improvements at every step of the pathway, from initial echo orders through to reporting. A key aspect of the new workflow is the use of electronic vetting, which has enabled SUH to triage echo requests to both ensure urgent cases are prioritised and minimize unnecessary activity.
Using secure login, cardiac doctors and advanced nurse practitioners can order echos via NIMIS, which are now actively graded by the echo team. “If we don’t feel the doctor has included enough relevant information, we send the order back with a request for more clinical information,” Ms Flynn confirms.
“They have 10 working days to provide that information, at which point we will either approve the request or deny because it is not compliant with BSE guidelines.”
As a result of this vetting process, SUH reduced its echo workload by 8.9 per cent in 2016 by weeding-out inappropriate requests. At the same time, the triage process has ensured the hospital’s acute assessment patients are prioritised, with 80 per cent of echo requests received from the acute ward undertaken on the same day as ordered.
One of the most important additions to the cardiology solution was the inclusion of the BSE range checking, making redundant the cardiac physiologists’ previous use of wall charts or phone apps to verify measurement range. The system flags any measurements outside the BSE range, which helps to highlight abnormalities.
The system also helps with reporting, with predefined sentences built in. Ms Flynn adds: “Rather than typing out entire sentences regarding a particular echo pathology, using the drop-down boxes we can very quickly and efficiently create the report, with no spelling mistakes.”
In addition, in-built teaching files help trainee echo staff to gain confidence on the system quickly.
The SUH cardiac physiologist team also has access to the reporting database from all its PCs, freeing- up more machines for echo reporting, which ensures there are no backlogs. Ms Flynn confirms: “We didn’t want any reports outstanding for more than two or three days.
Utilising the integration between our cardiology solution and Cognos, we have been able to identify any problems in turnaround times, flagging individuals who were not reporting within 24 hours for inpatient, urgent and routine reports, in line with BSE targets.”
Understanding patient demographics
Approximately 10,000 people die each year from cardiovascular disease (CVD), including coronary heart disease, stroke and other circulatory diseases. CVD is the most common cause of death in Ireland, accounting for 36 per cent of all deaths, according to the HSE. Over one-fifth — 22 per cent — of premature deaths (under age 65) are from CVD. SUH, however, operates in the North-West, an area with a higherthan- average elderly population.
Within the cardiology solution, SUH is able to record a depth of patient information, including not only age, but also body surface area, height and weight, providing more accurate quantitative measurements about BMI, patient mobility and age demographics.
The team is able to demonstrate the number of geriatric and paediatric cardiac echos undertaken on both a monthly and yearly basis — revealing that over 42 per cent of patients were aged 65 years or over and 24 per cent aged over 80 in 2016. “Providing this information to management is key to ensuring we have the right resources of both staff and equipment, such as echo couches for elderly or obese patients,” says Mr Ryan.
Palpitations are a very common presenting complaint to front-line medical services (primary care and emergency departments (EDs)).
They are often a problematic symptom for several reasons:
Palpitations often cause great anxiety and distress for the patient, which can put a lot of pressure on the consulted medic.
Most palpitations are benign, but a small minority can represent a life-threatening condition. Efforts to identify the latter can sometimes overshadow investigations and referrals.
The patient is commonly asymptomatic when they present to their GP, so evaluation for pathology must be undertaken in the absence of signs.
Investigations are often normal and can give false reassurance.
In this article, I will offer five tips on how to approach these patients — how to get the most out of the history, the electrocardiography (ECG) and other investigations and, perhaps most importantly, how to risk stratify your patients.
Tip 1: What to ask in the history
Inevitably, the patient with palpitations will be asymptomatic when they consult their GP/front-line medic. Therefore, the history is crucial in formulating a differential diagnosis.
First, find out what the patient means by ‘palpitations’ (if they use that word) — make sure they don’t actually mean chest pain.
Get a clear but detailed description of the patient’s palpitations.
Ventricular ectopic beats are often described as ‘missed beats’, ‘skipped beats’ or ‘jumps’.
Supraventricular tachycardias usually have a sudden onset, with an elevated heart rate and an abrupt offset. Atrioventricular nodal re-entrant tachycardia (AVNRT), atrioventricular re-entrant tachycardia (AVRT), atrial tachycardia and atrial flutters usually have a regular pulse whereas atrial fibrillation (AF) is irregular.
Ventricular tachycardia usually starts abruptly (sometimes the patient may describe some ‘missed beats’ beforehand), gives an elevated heart rate and often is poorly tolerated by the patient.
It is essential to ascertain (by direct questioning if necessary) whether there are any other symptoms associated with the palpitations.
This is very important in order to risk-stratify the patient.
Symptoms such as chest pain, syncope and pre-syncope are red flags and should prompt the medic to look for structural heart disease and to make an urgent onward referral.
Tip 2: The value of clinical examination and basic investigations
The purpose of the clinical examination in a patient who presents with palpitations is to assess for structural heart disease. A patient with palpitations in the presence of structural heart disease is automatically high-risk and almost always requires an onward referral to a cardiologist (see Tip 5).
When examining the patient, look out for murmurs (aortic stenosis), overload or respiratory crepitations suggesting left ventricular dysfunction and, of course, arterial hypertension (a cause of ventricular ectopy).
The value of basic, cheap and available investigations in formulating a differential diagnosis is perhaps under-appreciated.
A lot can be taken from a basic blood panel, for example. Is the patient anaemic, causing a high output state and sinus tachycardia?
Does the patient have sinus tachycardia or even AF from thyrotoxicosis? What is the potassium? Is this actually renal failure?
Tip 3: Interpretation of the resting ECG
Even in the absence of ‘active palpitations’, the resting ECG can be very useful in the hunt for pathology.
Again, you are looking for features that suggest underlying structural heart disease.
On the resting ECG, look out for:
Left bundle branch block.
ST or T wave segment change suggestive of ischaemia.
Q waves of an old myocardial infarction (MI).
Left ventricular hypertrophy (LVH) by voltage with strain pattern.
Delta wave of Wolff-Parkinson-White (WPW) syndrome.
Heart block (first-, second- or third-degree).
Abnormal QT interval.
On this page, I have collated some ECGs of ‘lesser-spotted’ conditions associated with palpitations.
Figure 1 shows complete heart block.
On this ECG, we can see the following salient features of complete or third-degree heart block:
1. More P waves ($) than QRS (*).
2. Regular P waves (not associated with a QRS complex).
3. Regular QRS complexes (usually at a slower rate than the P waves).
4. Dissociation between the atria and ventricles.
In this example, the QRS complexes are wide (>120ms), indicating that the escape rhythm is coming from low in the conduction system. This is a high-risk situation.
Figure 2 shows ventricular pre-excitation, which when occurs in association with palpitations, gives the WPW syndrome.
The features of WPW evident on this ECG are:
1. Short PR interval (__).
This is caused by accelerated conduction between the atria and the ventricle as the action potential can bypass the AV node and get to the ventricle early via the accessory pathway.
2. Delta wave ($).
A delta wave is the slurred upstroke of the QRS seen across the precordium and in the limb leads here.
It is formed by the fusion of myocardial activation via the AV node (gives a normal, rapid upstroke to the QRS) and myocardial activation via the accessory, or bypass tract (giving a very broad and abnormal QRS).
Figure 3 shows the long QT syndrome.
Here, the QT interval is extremely long (measures 640ms).
Normal intervals are <430ms for men and for <450ms women.
The correct way to measure the QT interval is using the Tangent Method, where one measures from the start of the QRS to the end of the T wave, as determined by a tangent line from the end of the T wave to the isoelectric baseline.
Tip 4: Getting the most out of ambulatory monitoring
The aim of any period of ambulatory monitoring is to get a symptom-rhythm correlation, that is, to record the heart’s rhythm when the patient is having their symptoms of palpitations. This should give the rhythm diagnosis of the patient’s complaint, or indeed, demonstrate a normal sinus rhythm and rate, prompting a search for a non-cardiac cause.
In order to maximise the chance of obtaining a symptom-rhythm correlate, the duration of the monitoring period must match the symptom frequency.
Daily symptoms should be captured on a 24-hour Holter monitor, whereas if the patient reports infrequent monthly symptoms, an alternative form of monitoring should be sought.
In most cardiac departments, a variety of monitors are available. These usually include 24-hour, 48-hour, 72-hour, and seven-day monitors and patient-activated monitors, which can stay on for several weeks.
The newest generation of implantable loop recorders are extremely low-profile, with a battery life of up to three years (for example, the Reveal LINQ device by Medtronic, see Figure 4).
These devices are designed to be inserted in a procedure room within a few minutes and do not require any sutures.
They are most useful in patients with very infrequent symptoms. All have home monitoring capability and both automatic and patient-activated recording.
A very useful recent development in the field of ambulatory monitoring has been that of hand-held smartphone monitors. The AliveCor by Kardia attaches to the back of a smartphone. The two metal thumb pads (see Figure 5) record and display a single-lead ECG. Recordings and events can then be saved for review later by a physician.
Tip 5: How to risk-stratify
Perhaps the most important aspect in the approach to the patient with palpitations is risk stratification. Here, you identify the patient who is in danger or who needs urgent onward referral from the majority of patients who can be reassured.
Figure 6 shows a ‘traffic light’ approach to the risk stratification.
Red-flag symptoms signalling urgent referral include syncope or pre-syncope in association with palpitations and symptoms during exercise.
The patient with known or suspected high-risk structural heart disease (severe aortic stenosis, previous MI, congenital abnormality) who presents with palpitations should always be referred onwards in an urgent manner, as they are at risk of ventricular tachycardia.
The same goes for patients who have a family history of inherited cardiac disease (hypertrophic or dilated cardiomyopathy, Long QT syndrome, etc) or of sudden cardiac death.
A 12-lead ECG showing a broad, complex tachycardia mandates emergency transfer to hospital, as does complete (third-degree) heart block.
Second-degree heart block on ECG should also be urgently referred to the ED, as the risk of progression to complete heart block in high here.
Green — low risk.
Referral not usually required
Amber — medium risk.
Should be referred
Red — high risk.
Urgent/same-day referral to hospital
References available on request
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