PART III - SECONDARY PREVENTION AND FOLLOW-UP
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Updated on March 31, 2015
PART III

Secondary prevention and follow-up

Francois Schiele

Summary

The only specific treatment after coronary angioplasty is the dual antiplatelet therapy, comprising an association of aspirin and a P2Y12 receptor inhibitor (clopidogrel or prasugrel). The duration of this association depends on the type of stent used (BMS or DES), the initial clinical presentation (stable angina vs ACS), and the estimated thrombotic and bleeding risks of the patient. A reduction in the duration of DAPT to one-three months according to the type of stent (BMS or latest generation DES) can be discussed in stable coronary artery disease. Conversely, after ACS, 12 months of DAPT remains the rule, but this duration can be extended longer term depending on the patient characteristics, and exact DAPT duration should be discussed on a case-by-case basis.

After PCI, as for all patients with established coronary atherosclerosis, patients should receive “optimal medical therapy” to slow progression of atherosclerosis and to avoid atherothrombotic complications. Thus, the control of risk factors with lifestyle measures, and the use of drugs of proven efficacy in terms of prevention of atherosclerosis and its complications should be reinforced.

Female gender, older age, diabetes, renal dysfunction or need for oral anticoagulation, the site of the treated lesion and the type of procedure all impact considerably on the modalities of follow-up and treatment after PCI.

Introduction: PCI and specificlesion and patient subsets

Advances in the pharmacological and technical environment for PCI, particularly the use of stents, have contributed to the spectacular development of PCI in recent years in terms of safety and efficacy. Nonetheless, the appropriate patient follow-up and medical therapy after the procedure remain major issues. PCI only yields a benefit in clinical terms if it is accompanied by the whole spectrum of lifestyle measures, medical follow-up and pharmacological therapy, both specific to PCI, and more generally, recommended for patients with atheromatous disease.

This chapter will describe the recommended approach to patient follow-up and secondary prevention therapy after PCI. There are general recommendations that can be applied to the majority of patients, but there are also a myriad of special situations that may require specific measures, depending, for example, on the characteristics or comorbidities presented by the patient, the coronary anatomy, the site of angioplasty, or the type of technique used during PCI.

Non specific secondary prevention after PCI

Coronary revascularisation can be seen as a consequence of the failure of primary or secondary prevention, and justifies optimization of anti-atherosclerotic therapy. In addition to appropriate pharmacological treatment to prevent further progression of atherosclerosis, a number of specific treatments are necessary after PCI.

MEASURES NOT-SPECIFIC TO PCI

Current recommendations for lifestyle modifications, risk factor control, medical therapy to prevent progression of atherosclerosis, stabilise the plaque, restore endothelial function or prevent thrombosis are all applicable after PCI. These measures are commonly known as “optimal medical treatment” (OMT) and are designed to reduce mortality and morbidity, while maintaining a favourable cost-efficacy profile [1, 2]. OMT associates lifestyle measures, strict risk factor control, and medical therapy with a combination of aspirin, angiotensin-converting enzyme inhibitors (ACEI), beta-blockers and statins ( Figure 1 ).

  • Aspirin should be prescribed at a dose of 75 to 100 mg/day, for life. Higher doses do not yield any demonstrable additional benefit, whereas they expose the patient to a higher risk of gastro-intestinal side effects or bleeding [3, 4, 5].
  • Long term dual antiplatelet therapy in addition to low dose aspirin, such as ticagrelor, at a dose of 90mg or 60mg, twice a day, should be considered in stable patients with previous MI, age over 50 and additional risk factor, and without bleeding risk [6].
  • ACEI (or angiotensin receptor antagonists, in case of ACEI intolerance) are recommended in all situations after PCI. In patients with normal left ventricular (LV) function, ramipril at a dose of 10mg/day is indicated in diabetic patients who also have one other risk factor [7]. In patients considered to be at “low risk”, without diabetes and with preserved LV function, perindopril at a dose of 8mg /day is recommended [4, 8]. The dosage of ACEI should be adapted to patient tolerance in terms of blood pressure and biology, with the aim, however, of attaining the aforementioned doses, which have been proven efficacious in these populations.
  • Beta-blockers are indicated to control angina during exercise, but are also recommended for at least the first year after an infarction [9]. The beneficial effect of beta-blockers in stable patients is less well established [10], except in patients with LV dysfunction, in whom metaprolol, bisoprolol and carvedilol are recommended [11]. In case of beta-blocker intolerance, verapamil can be prescribed [12]. In patients whose heart rate exceeds 70 bpm while under beta-blocker therapy, in sinus rhythm, ivabradine can be used as an anti-anginal agent, or to reduce incidence of cardiovascular events in case of systolic dysfunction [13].
  • Statins are recommended for all patients after PCI, irrespective of the initial level of LDL cholesterol [14, 15]. High doses of statins were shown to slow, if not prevent progression of coronary atherosclerosis [14, 15, 16, 17] and must be used in the setting of acute coronary syndrome (ACS)[18] . Depending on the LDL level achieved with statin therapy, further lipid lowering drugs must be discussed, such as ezetimibe, since the IMPROVE-IT trial showed an addidtional benefit of lowering LDL cholesterol level below 0.7 g/L with ezetimibe [19].
  • Treatments such as calcium channel blockers should be reserved for use as substitutes for beta-blocker therapy when these latter are not tolerated. Vitamins and antioxidants have not been shown to be beneficial after angioplasty, nor have omega-3 fatty acids. Finally, Cox-2 inhibitors should be avoided, as they predispose to accelerated development of atherosclerosis and arterial thrombosis. Similarly, non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of prostacyclin, although they have antiplatelet properties, and the dose of NSAIDs should be carefully adjusted to maintain a balance between the risk of stent thrombosis and the risk of bleeding complications.

Patients treated for ACS. A vast majority of patients undergoing PCI are submitted to this procedure in the context of ACS. This context of ACS impacts directly on the dose and duration of therapy. However, the association of aspirin and clopidogrel (or prasugrel or ticagrelor) is independent of the type of procedure or stent used, and must be prescribed for a minimum of one year after PCI. A randomised study showed that high dose atorvastatin therapy was more beneficial than lower dose statins, when initiated at the acute phase in patients submitted to PCI [20].

MEASURES SPECIFIC TO PCI

Certain aspects of secondary prevention are specific to patients undergoing PCI :

  • Lifestyle measures : A PCI procedure is an ideal opportunity to underline the importance of secondary prevention, or to deliver this message for the first time in patients in whom coronary disease had not previously been manifest. In particular, it is important to underline the necessity of lifestyle measures (balanced diet including a high proportion of fruit and vegetables, stop smoking, reduce weight, regular exercise), correction of modifiable risk factors, and compliance with medical therapy ( Figure 2 )
  • Medical therapy presents two specific features after PCI, namely association of antiplatelet agents, and therapeutic targets. Aspirin after PCI should be prescribed at doses corresponding to secondary prevention, namely 70 to 100mg/day. However, after PCI, aspirin must be associated with a platelet P2Y12 receptor antagonist, even in the absence of ACS. The duration of P2Y12 receptor inhibition depends on several factors, namely: the type of PCI procedure (particularly, the type of stent implanted, namely bare metal (BMS) or drug eluting stent (DES). With DES, the type of DES must also be taken in account as shorter DAPT durations after “new generation” DES have been demonstrated to be safe); the clinical situation (stable angina or ACS), and the bleeding risk. Generally, an association of aspirin and P2Y12 receptor antagonists should be prescribed for at least one year in case of bare metal stent implantation[21], and for 6 to 12 months in case of DES implantation [22], although longer prescriptions have been advocated [23]. In case of PCI in the setting of an ACS, any of three compounds (clopidogrel, prasugrel or ticagrelor) can be prescribed, whereas after PCI for stable angina, only clopidogrel is recommended. The use of other molecules can be envisaged if the response to clopidogrel is suboptimal. The particular importance of compliance with this treatment and its duration should be emphasised to the patient, because of the risk and potential severity of stent thrombosis [24, 25]. After one year, regardless of the initial clinical presentation, prolongation of DAPT with either clopidogrel[26] or ticagrelor [26] should be discussed according to the patients characteristics.

The therapeutic targets of medical therapy should also be re-evaluated after PCI, particularly if progression of atherosclerotic disease is observed, or in patients who are already being treated. In this case, recommendations for lifestyle changes and risk factor control need to be reinforced, and ACEI should be prescribed at maximum recomended doses. Treatment with statins has a proven beneficial effect on coronary atherosclerosis [16, 27]. A slowing of atherosclerosis progression has been proven for LDL cholesterol levels less than 0.7 g/L, namely 0.55 g/L [19].

Specific follow-up after PCI

FOLLOW-UP OF PATIENTS AFTER PCI

The only difference between follow-up post-PCI and follow-up of patients in secondary prevention is that after PCI, physicians should keep watch for potential complications specific to PCI, either early or late. Early complications include arterial puncture site complications, mostly among patients who had PCI via a femoral access, anaemia or nephrotoxicity. In these situations, current European guidelines recommended clinical and biological follow-up 7 days after PCI [28].

CLINICAL EVALUATION AND FUNCTIONAL TESTS, APART FROM DETECTION OF RESTENOSIS

The benefit of routine exercise stress tests in asymptomatic patients has never been clearly demonstrated. Early evaluation after PCI makes it possible to quantify residual ischemia. Later evaluation can help detect incident ischemia resulting from the progression of atherosclerosis. Current recommendations for coronary revascularisation stipulate that lung perfusion scans or stress echocardiography should be prefered over bicycle ergometry exercise stress testing, which is less sensitive and less specific, particularly if revascularisation was incomplete [28]. At two years after PCI, ischaemia screening tests are of limited interest in asymptomatic patients and there is no clear recommandation for the timing of such tests (recommendation Grade IIb, level of evidence C) ( Figure 3 ).

Two specific events may can occur after PCI and justify close follow-up, namely stent thrombosis and restenosis.

  • Stent thrombosis generally presents like ST segment elevation ACS. In patients who experience stent thrombosis while still under antiplatelet therapy, there is a likelihood that response to clopidogrel is suboptimal and these patients can potentially be considered as clopidogrel “non-responders” [29]. Nevertheless, the major determinant of stent thrombosis is premature DAPT cessation. In the PARIS study, three main reasons for DAPT cessation were identified, namely, medical decision (discontinuation), temporary interruption (due to intermittant conditions such as need for surgery) and cessation without medical advice (disruption). DAPT disruption was associated with higher event rates, mostly due to stent thrombosis [30]. Late stent thrombosis (i.e. occurring more than one year after PCI) has been described, with both bare-metal and active stents [23]. Prolonging DAPT beyond 12 months with clopidogrel [26] has been shown to reduce late stent thrombosis, particulary among patients treated with a paclitaxel eluting stent [31].
  • Restenosis is a different phenomenon than the initial atherosclerotic process, and arises from the injury caused to the arterial wall during PCI. It is characterised by neo-intimal proliferation of smooth muscle cells and extracellular matrix. After bare-metal stent implantation, this proliferation of restenosis tissue generally reduces the lumen diameter by approximately 1mm on average, but there are considerable variables between individuals, and between different lesion types. Thus, in 10 to 20% of cases, the restenosis can be extensive enough to reduce the vessel lumen significantly and cause myocardial ischemia.
  • Clinical detection of restenosis consists in detecting myocardial ischemia in the territory of the revascularised artery. It is helpful to have a functional evaluation of angina as well as a baseline ECG dating from before PCI to serve as a starting point for later evaluation. Restenosis can be clinically suspected if signs of ischaemia (re-)appear, and in asymptomatic patients, by a positive result on functional tests (functional evaluation, stress echo, myocardial perfusion). Since restenosis appears gradually after PCI and can become clinically manifest between 2 and 9 months post-PCI, it is recommended to perform clinical evaluation at around 6 months. Beyond 9 months, there is usually no further proliferation, and the situation generally remains stable.
  • Role of coronary angiography. If there is a clinical suspicion of restenosis, control angiography should be considered on a case-by-case basis, with a view to performing another revascularisation procedure where necessary, depending on the patient characteristics, functional tolerance, and the anatomy of the coronary arteries [28]. Systematic coronary angiography, in the absence of clinical manifestations of ischaemia, is not recommended, although it can be discussed in exceptional circumstances [32]. In addition to the invasive nature of the procedure, and the exposure to contrast medium and irradiation, it has been shwon that systematic control angiography leads to a twofold increase in revascularisation procedures [33, 34].

Specfic conditions for follow-up and secondary prevention after PCI: patient subsets.

Among the patient characteristics that can impact on follow-up and secondary prevention, several special populations need to be distinguished, namely female patients, elderly patients, diabetic patients, patients with renal insufficiency, and patients treated with oral anticoagulants.

WOMEN

Although women are under-represented in clinical trials, and the risk-benefit ratio of post-PCI therapies is less well established in female patients[35], there is nonetheless no justification for specific secondary prevention treatment in women after PCI [36]. Moreover aspirin, in secondary prevention, mediates its protective cardiovascular effect through a reduction in the rate of MI in men, but through a reduction in stroke in women [37]. Gender differences in the activity of cytochrome P450, responsible for the metabolism of many drugs, could explain the greater efficacy of certain molecules in women, although there are other differences which could account for this variability, such as the fact that women are, on average, older, more often diabetic and more frequently have renal dysfunction. The risk of bleeding complications could justify adjustment of therapy in women. The efficacy and safety of clopidogrel appear to be comparable in men and women [38], although it has been shown that the rate of hyporesponders to clopidogrel is higher among female patients [39]. Finally, the bleeding risk incurred by the association of aspirin and clopidogrel appears to be higher in women, although the difference does not reach statistical significance [38, 40, 41]. In practical terms, these specificities do not have an overall impact and no specific measures for female patients are advocated after PCI.

ELDERLY PATIENTS

In elderly patients, the question often arises of the bleeding risk incurred by the association of aspirin and thienopyridines, as well as the further question of the efficacy of statin therapy in this population. Although increasing age is a significant predictor of bleeding under dual antiplatelet therapy, the addition of clopidogrel to aspirin alone in the CURE study showed the same absolute beneficial effect in younger patients (<65 years) as in older patients [42]. In the TRITON study, prasugrel was associated with an excess of bleeding events in patients aged >75 years, and this increase cancelled out the benefit achieved in terms of thrombotic risk [43]. Finally, in the PLATO study, in patients planned to undergo invasive strategy, the benefit of ticagrelor was identical in patients above and below 65 years of age [44]. However, beyond 75 years of age, the reduction in thrombotic risk was lower, albeit without excess bleeding, thus rendering the net clincial benefit of ticagrelor non-significant. These comparative data from different P2Y12 receptor inhibitors were all obtained in patients with ACS only; thus, clodpigrel and ticagrelor can be used in patients older than 75 years.

The benefit of statin therapy in elderly patietns (70 to 82 years) for primary and secondary prevention was demonstrated with a reduction in mortality and in the rate of MI [45]. Similarly, the Cooperative Cardiovascular Project demonstrated the efficacy of beta-blockers after PCI in patients >65 years, with a 14% reduction in mortality at 1 year [46].

DIABETIC PATIENTS

In the days following a PCI procedure, particularly attention should be paid to the detection of nephrotoxicity in patients with diabetes [28]. The risk of contrast-induced nephrotoxicity is increased in diabetic patients and in those with renal insufficienty, and the increase in risk is proportional to the quantity of contrast medium used [47]. Myocardial ischemia can often be asymptomatic in diabetic patients, justifying the use of functional evaluations to detect restenosis, particularly since this phenomenon is more frequent in diabetic patients, regardless of the type of stent used. No specific additional treatment after PCI is required for diabetic patients, and secondary prevention and antithrombotic therapies also remain unchanged. The sole difference is a situation of PCI in the context of ACS, where treatment by prasugrel or ticagrelor should be preferred over clopidogrel in diabetic patients.

PATIENTS WITH RENAL INSUFFICIENCY

Patients with renal insufficiency are characterised by two distinct features:

  • The risk of contrast-induced nephrotoxicity. The mechanism of this nephrotoxicity is tubular necrosis, which generally regresses within a few weeks, and evolution towards end-stage renal disease is rare. There is no consensus on the threshold beyond which patients should not received contrast medium. In one report, 35% of radiologists used a threshold creatinine clearance value of 1.5 mg/dL, 27% used a threshold of 1.7 mg/dL, while a further 31% advocated a threshold of 2.0 mg/dL to determine patients in whom contrast medium should be contra-indicated [48]. The increase in creatinine is at its maximum 48 hours after the injection of iodinated contrast agents. The presence of pre-existing renal dysfunction favours nephrotoxocity, and thus, in addition to preventive measures before, during and immediately after PCI, it is also necessary to verify renal function in patients with renal insufficiency.
  • Tolerance to secondary prevention treatments. Secondary prevention measures should be the same in patients with renal insufficiency as in other patient subgroups. Only ACEI or ARA2 may pose a particular problem. The presence of renal dysfunction can represent an additional justification for the prescription of ACEI or ARA2, whose renal protective role has previously been demonstrated. Administration of ACEI should be closely monitored for biological tolerance, bearing in mind that a moderate increase (up to 20%) in creatinine after initiation of ACEI therapy can be observed and is related to the correction of glomerular hypertension.

PATIENTS TREATED WITH ORAL ANTICOAGULANTS

The presence of a mechanical prosthesis, thrombo-embolic disease or atrial fibrillation justifies prescription of long-term anticoagulant therapy, and when associated with antiplatelet agents, this can increase the risk of bleeding complications, either spontaneous bleeding or procedure-related. For this reason, bare metal stents should be preferred in these patient groups, in order to reduce to one month the duration of the triple association of antiplatelet, anticoagulant and antithrombotic agents, particularly outside the context of diabetes, long lesions or small-calibre vessels.

The duration of the triple association is one month for conventional stents, 3 to 6 months for drug-eluting stents (3 months for sirolimus- and 6 months for paclitaxel-eluting stents). During this time, strict monitoring of antivitamin K treatment is necessary, targeting an international normalized ratio (INR) value between 2 and 2.5. The dose of aspirin should be between 75 and 100mg, and the use of gastro-intestinal bleeding proxphylaxis is recommended (proton pump inhibitors (PPIs), H2 antagonists, or antacids). After this period, a combination of antivitamin K and clopidogrel is the only recommended treatment, and in stable patients at high risk of bleeding (as estimated by the HAS-BLED score), antivitamin K therapy alone is recommended, without any associated antiplatelet agent. Despite the lack of strong evidence in this patient subset, a position paper from the ESC has proposed to adapt the duration and type of antithrombotic treatment to the patient characteristics (namely, bleeding risk), and to the PCI setting (stable or ACS). In this document, the anti-thrombotic strategy can be chosen irrespective of the type of stent implanted (BMS or DES) and irrespective of the type of anticoagulant (Vitamin K antagonist or direct oral anticoagulant) [49] ( Figure 4 )

Lastly, beta blockers are preferentially indicated for the control of heart rate in patients with CAD and atrial fibrillation [28].

Specfic conditions for secondary prevention after PCI: lesions subsets

Situations specific to a site or technique of angioplasty can be defined such as main stem lesions, bifurcation lesions, chronic occlusion, restenosis or incomplete revascularisation, balloon angioplasty or rotational atherectomy. Specific strategies for secondary prevention and follow-up can be envisaged in these populations.

LEFT MAIN LESIONS (OR EQUIVALENT)

Suboptimal response to clopidogrel therapy, particularly in carriers of a loss-of-function allele for CYP2C19, is associated with a higher rate of cardiovascular events []. After PCI, irrespective of the site involved, there is an increased risk of stent thrombosis in clopidogrel hyporesponders [29], underlining the interest of monitoring for clopidogrel response (for example using functional or genetic testing), particularly in PCI of main vessels, like the main stem. Currently, although the use of high doses of clopidogrel in patients with suboptimal response has been shown to be beneficial [51], there is no scientific evidence to support a benefit of such monitoring, and current guidelines do not recommendation systematic monitoring.

Multiple stent implantation, small vessels, bifurcation are usually considered as situations at high risk of thrombosis. In these cases, and when the patient is not considered to be at high risk of bleeding, a longer duration of DAPT must be considered [6, 26].

PCI TECHNIQUE

The risk of restenosis, depending on the angioplasty technique used, can impact the follow-up strategy. Indeed, after balloon angioplasty alone, the expected restenosis rate is higher than after angioplasty with bare-metal or active stent implantation. Similarly, the use of atherectomy has reportedly been associated with an increased risk of restenosis [52]. Certain types of lesions more generally expose the patient to a higher risk of restenosis, such as bifurcation lesions, chronic occlusions, lesions on saphenous veing grafts, and in-stent restenosis. In these situations, tailored follow-up with easier access to control angiography, can be envisaged.

Conclusions

The interventional cardiologist’s job does not end at the door of the catheterisation laboratory, but rather covers the whole spectrum of treatment plus information to the patient and treating physicians regarding the modalities of prevention, specific treatment and follow-up.

Lifestyle measures and secondary prevention therapy are not specific to patients undergoing PCI, but the modalities of antiplatelet therapy and detection of early and late post-PCI complications do depend on the type of procedure performed, as well as on the patient’s characteristics. Only the interventional cardiologist is suitably qualified to dispense appropriate advice regarding the adaptation of treatment and follow-up according to the type of procedure, the type of stent, the lesion(s) treated, the complete or incomplete nature of the revascularisation, the bleeding risk, and the patient’s age, sex and renal function.

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